ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling.oSevere and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]oComplications of Allogeneic HSCT [see Warnings and Precautions (5.2)]. oSevere and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]. oComplications of Allogeneic HSCT [see Warnings and Precautions (5.2)]. oMost common adverse reactions (>=10%) with OPDIVO QVANTIG as monotherapy in patients with Renal Cell Carcinoma were: musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain. (6.1) oSafety of OPDIVO QVANTIG for the following indications is based on safety of intravenous nivolumab in these populations. The most common adverse reactions with intravenous nivolumab for these indications are presented below.oAs monotherapy for the treatment of advanced renal cell carcinoma; adjuvant treatment of completely resected Stage IIB, IIC, III, or IV melanoma; unresectable or metastatic melanoma; adjuvant treatment of NSCLC, metastatic NSCLC; squamous cell carcinoma of the head and neck; urothelial carcinoma; MSI-H or dMMR mCRC; hepatocellular carcinoma; esophageal cancer: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection. (6.1)oIn combination with cabozantinib for the first-line treatment of advanced renal cell carcinoma: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1)oIn combination with platinum-doublet chemotherapy for the neoadjuvant treatment of NSCLC: nausea, constipation, fatigue, decreased appetite, and rash. (6.1)oIn combination with cisplatin and gemcitabine for the treatment of urothelial cancer: nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. (6.1)oIn combination with fluoropyrimidine- and platinum- containing chemotherapy for the treatment of esophageal cancer and gastric cancer: nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oMost common adverse reactions (>=10%) with OPDIVO QVANTIG as monotherapy in patients with Renal Cell Carcinoma were: musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain. (6.1) oSafety of OPDIVO QVANTIG for the following indications is based on safety of intravenous nivolumab in these populations. The most common adverse reactions with intravenous nivolumab for these indications are presented below.. oAs monotherapy for the treatment of advanced renal cell carcinoma; adjuvant treatment of completely resected Stage IIB, IIC, III, or IV melanoma; unresectable or metastatic melanoma; adjuvant treatment of NSCLC, metastatic NSCLC; squamous cell carcinoma of the head and neck; urothelial carcinoma; MSI-H or dMMR mCRC; hepatocellular carcinoma; esophageal cancer: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection. (6.1). oIn combination with cabozantinib for the first-line treatment of advanced renal cell carcinoma: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1). oIn combination with platinum-doublet chemotherapy for the neoadjuvant treatment of NSCLC: nausea, constipation, fatigue, decreased appetite, and rash. (6.1). oIn combination with cisplatin and gemcitabine for the treatment of urothelial cancer: nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. (6.1). oIn combination with fluoropyrimidine- and platinum- containing chemotherapy for the treatment of esophageal cancer and gastric cancer: nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain. (6.1). 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO QVANTIG as single agent in 247 patients enrolled in CHECKMATE-67T, with additional data from intravenous nivolumab single-agent (1994 patients), and from intravenous nivolumab in combination with cabozantinib (320 patients) for select adverse reactions.. Advanced Renal Cell Carcinoma. CHECKMATE-67T was multicenter, randomized, open-label study in adult patients with advanced or metastatic RCC. Patients received OPDIVO QVANTIG dose of 1,200 mg of nivolumab and 20,000 units of hyaluronidase subcutaneously every weeks (n=247) or mg/kg of nivolumab intravenously every weeks (n=245). Among patients who received OPDIVO QVANTIG, 52% were exposed for months or longer and 20% were exposed for greater than year. Serious adverse reactions occurred in 28% of patients who received OPDIVO QVANTIG. Serious adverse reactions in >1% of patients included pleural effusion (1.6%), pneumonitis (1.6%), hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). Fatal adverse reactions occurred in patients (1.2%) who received OPDIVO QVANTIG and included myocarditis, myositis, and colitis complications.Permanent discontinuation of OPDIVO QVANTIG due to an adverse reaction occurred in 10% of patients. The most common adverse reaction which resulted in permanent discontinuation was pneumonitis (2%). Dosage interruptions of OPDIVO QVANTIG due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in >2% of patients included COVID-19 (4.5%), increased blood creatinine (2.8%), anemia, diarrhea, and fatigue (2.4% each).The most common adverse reactions (>=10%) were musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain.Tables and summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-67T.Table 5: Adverse Reactions in >=5% of Adult Patients with RCC Receiving OPDIVO QVANTIG in CHECKMATE-67T Toxicity was graded per NCI CTCAE v5. Includes multiple related termsAdverse ReactionOPDIVO QVANTIG(n=247)Intravenous Nivolumab(n=245)All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)General Fatiguea 202.4253.3 Injection site reactiona 8000 Edema50.4110.8Musculoskeletal and Connective Tissue Musculoskeletal paina 311.6393.3Skin and Subcutaneous Tissue Pruritus160.4210 Rasha 151.2131.2Gastrointestinal Diarrheaa 110.4140.4 Abdominal paina 100100.4 Nausea8090 Constipation8060 Vomiting60.44.90Respiratory, Thoracic, and Mediastinal Cough110110Endocrine Hypothyroidisma 120170Metabolism and Nutrition Hyperglycemia92.4132.0 Decreased appetite90110.8Clinically important adverse reactions in <5% of patients who received OPDIVO QVANTIG include:Cardiac: myocarditisRespiratory, thoracic, and mediastinal: pneumonitis, dyspneaEndocrine: adrenal insufficiency, hyperthyroidism, thyroiditisGastrointestinal: colitis, pancreatitisHepatobiliary: hepatitisNervous system: peripheral neuropathySkin and subcutaneous tissue: psoriasis, erythemaMusculoskeletal and connective tissue: arthritisBlood and lymphatic system: eosinophiliaEye disorders: uveitisImmune system: hypersensitivityTable 6: Laboratory Values Worsening from Baselinea (>=20%) in Patients with RCC Receiving OPDIVO QVANTIG in CHECKMATE-67Ta Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO QVANTIG group (range: 232 to 235 patients) and intravenous nivolumab group (range: 240 to 244 patients).Laboratory AbnormalityOPDIVO QVANTIGIntravenous NivolumabAll Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Hematology Hemoglobin decreased467489 Lymphocytes decreased366459Chemistry Creatinine increased381.3430.4 Sodium decreased342.6402.5 Potassium increased343.0452.9 Alkaline phosphatase increased322.1332.0 Calcium increased292.1314.1 Albumin decreased 251.7350.4 ALT increased211.3264.1. Adverse Reactions in Patients Treated with Intravenous Nivolumab The safety of OPDIVO QVANTIG for its approved indications [see Indications and Usage (1)] has been established in adequate and well-controlled clinical studies of intravenous nivolumab. Below is description of adverse reactions in these adequate and well-controlled clinical studies.. First-line Renal Cell Carcinoma CHECKMATE-214The safety of intravenous nivolumab with ipilimumab was evaluated in CHECKMATE-214, randomized open-label trial in 1082 patients with previously untreated advanced RCC; patients received intravenous nivolumab mg/kg over 60 minutes with ipilimumab mg/kg intravenously every weeks for doses followed by intravenous nivolumab as single agent at dose of mg/kg by intravenous infusion every weeks (n=547) or sunitinib 50 mg orally daily for the first weeks of 6-week cycle (n=535) [see Clinical Studies (14.1) ]. The median duration of treatment was 7.9 months (range: day to 21.4+ months) in intravenous nivolumab and ipilimumab-treated patients and 7.8 months (range: day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the intravenous nivolumab and ipilimumab arm were exposed to treatment for >6 months and 38% of patients were exposed to treatment for >1 year.Serious adverse reactions occurred in 59% of patients receiving intravenous nivolumab and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of intravenous nivolumab and ipilimumab patients. Fifty-four percent (54%) of patients receiving intravenous nivolumab and ipilimumab had dose interruption for an adverse reaction.The most frequent serious adverse reactions reported in >=2% of patients treated with intravenous nivolumab and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in >=20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in >=30% of intravenous nivolumab and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia.Tables and summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of intravenous nivolumab and ipilimumab-treated patients in CHECKMATE-214.Table 7: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab and Ipilimumab CHECKMATE-214Toxicity was graded per NCI CTCAE v4. Includes asthenia. Includes peripheral edema, peripheral swelling. Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption. Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.Adverse ReactionIntravenous Nivolumab and Ipilimumab (n=547)Sunitinib(n=535)Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Adverse Reaction99659976General Fatiguea 5886913 Pyrexia250.7170.6 Edemab 160.5170.6Skin and Subcutaneous Tissue Rashc 393.7251.1 Pruritus/generalized pruritus330.5110Gastrointestinal Diarrhea384.6586 Nausea302431.5 Vomiting200.9282.1 Abdominal pain 191.6241.9 Constipation170.4180Musculoskeletal and Connective Tissue Musculoskeletal paind 374402.6 Arthralgia231.3160Respiratory, Thoracic and Mediastinal Cough/productive cough280.2250.4 Dyspnea/exertional dyspnea202.4212.1Metabolism and Nutrition Decreased appetite211.8290.9Nervous System Headache190.9230.9Endocrine Hypothyroidism180.4270.2Table 8: Laboratory Values Worsening from Baselinea Occurring in >15% of Patients on Intravenous Nivolumab and Ipilimumab CHECKMATE-214a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and ipilimumab group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients).Laboratory AbnormalityIntravenous Nivolumab and IpilimumabSunitinibGrades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Chemistry Increased lipase48205120 Increased creatinine422.1461.7 Increased ALT417442.7 Increased AST404.8602.1 Increased amylase3912337 Hyponatremia3910367 Increased alkaline phosphatase292321 Hyperkalemia292.4282.9 Hypocalcemia210.4350.6 Hypomagnesemia160.4261.6Hematology Anemia433649 Lymphopenia3656314In addition, among patients with TSH <= ULN at baseline, lower proportion of patients experienced treatment-emergent elevation of TSH ULN in the intravenous nivolumab and ipilimumab group compared to the sunitinib group (31% and 61%, respectively).CHECKMATE-9ERThe safety of intravenous nivolumab with cabozantinib was evaluated in CHECKMATE-9ER, randomized, open-label study in patients with previously untreated advanced RCC. Patients received intravenous nivolumab 240 mg over 30 minutes every weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for weeks on treatment followed by weeks off (n=320) [see Clinical Studies (14.1) ]. Cabozantinib could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in intravenous nivolumab and cabozantinib-treated patients. In this trial, 82% of patients in the intravenous nivolumab and cabozantinib arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year.Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab and cabozantinib. The most frequent (>=2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in (0.9%) patients.Adverse reactions leading to discontinuation of either intravenous nivolumab or cabozantinib occurred in 20% of patients: 7% intravenous nivolumab only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either intravenous nivolumab or cabozantinib occurred in 83% of patients: 3% intravenous nivolumab only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially.The most common adverse reactions reported in >=20% of patients treated with intravenous nivolumab and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.Tables and 10 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER.Table 9: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab and Cabozantinib CHECKMATE-9ERToxicity was graded per NCI CTCAE v4. Includes abdominal discomfort, abdominal pain lower, abdominal pain upper. Includes gastroesophageal reflux disease. Includes asthenia. Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure. Includes mucosal inflammation, aphthous ulcer, mouth ulceration. Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic.g Includes blood pressure increased, blood pressure systolic increased. Includes primary hypothyroidism. Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.j Includes productive cough. Includes nasopharyngitis, pharyngitis, rhinitis.Adverse ReactionIntravenous Nivolumab and Cabozantinib(n=320)Sunitinib(n=320)Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Gastrointestinal Diarrhea647474.4 Nausea270.6310.3 Abdominal paina 221.9150.3 Vomiting171.9210.3 Dyspepsiab 150220.3General Fatiguec 518508Hepatobiliary Hepatotoxicityd 4411265Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome408418 Stomatitise 373.4464.4 Rashf 363.1140 Pruritus190.34.40Vascular Hypertensiong 36133914Endocrine Hypothyroidismh 340.3300.3Musculoskeletal and Connective Tissue Musculoskeletal paini 333.8293.1 Arthralgia180.390.3Metabolism and Nutrition Decreased appetite281.9201.3Nervous System Dysgeusia240220 Headache160120.6Respiratory, Thoracic and Mediastinal Coughj 200.3170 Dysphonia170.33.40Infections and Infestations Upper respiratory tract infectionk 200.380.3Table 10: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on Intravenous Nivolumab and Cabozantinib CHECKMATE-9ERa Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and cabozantinib group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients).Laboratory AbnormalityIntravenous Nivolumab and CabozantinibSunitinibGrades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Chemistry Increased ALT799.8393.5 Increased AST777.9572.6 Hypophosphatemia69284810 Hypocalcemia541.9240.6 Hypomagnesemia471.3250.3 Hyperglycemia443.5441.7 Hyponatremia43113612 Increased lipase41143813 Increased amylase4110286 Increased alkaline phosphatase412.8371.6 Increased creatinine391.3420.6 Hyperkalemia354.7271 Hypoglycemia260.8140.4Hematology Lymphopenia426.64510 Thrombocytopenia410.3709.7 Anemia372.5614.8 Leukopenia370.3665.1 Neutropenia353.26712. Previously Treated Renal Cell Carcinoma CHECKMATE-025The safety of intravenous nivolumab was evaluated in CHECKMATE-025, randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received intravenous nivolumab mg/kg over 60 minutes by intravenous infusion every weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.1) ]. The median duration of treatment was 5.5 months (range: day to 29.6+ months) in intravenous nivolumab-treated patients and 3.7 months (range: days to 25.7+ months) in everolimus-treated patients.Rate of death on treatment or within 30 days of the last dose was 4.7% on the intravenous nivolumab arm. Serious adverse reactions occurred in 47% of patients receiving intravenous nivolumab. Study therapy was discontinued for adverse reactions in 16% of intravenous nivolumab patients. Forty-four percent (44%) of patients receiving intravenous nivolumab had dose interruption for an adverse reaction.The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (>=20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common laboratory abnormalities which have worsened compared to baseline in >=30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and hyperkalemia. In addition, among patients with TSH ULN at baseline, greater proportion of patients experienced treatment-emergent elevation of TSH ULN in the intravenous nivolumab group compared to the everolimus group (26% and 14%, respectively).Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025.Table 11: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab CHECKMATE-025Toxicity was graded per NCI CTCAE v4.a Includes asthenia, decreased activity, fatigue, and malaise.b Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI).c Includes colitis, enterocolitis, and gastroenteritis.d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema.Adverse ReactionIntravenous Nivolumab(n=406)Everolimus(n=397)Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Adverse Reaction98569662General Fatiguea 566577 Pyrexia170.7200.8Respiratory, Thoracic and Mediastinal Cough/productive cough340380.5 Dyspnea/exertional dyspnea273312 Upper respiratory infectionb 180110Gastrointestinal Nausea280.5291 Diarrheac 252.2321.8 Constipation230.5180.5 Vomiting 160.5160.5Skin and Subcutaneous Tissue Rashd 281.5361 Pruritus/generalized pruritus190140Metabolism and Nutrition Decreased appetite231.2301.5Musculoskeletal and Connective Tissue Arthralgia201140.5 Back pain213.4162.8Other clinically important adverse reactions in CHECKMATE-025 were:General Disorders and Administration Site Conditions: peripheral edema/edemaGastrointestinal Disorders: abdominal pain/discomfortMusculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal painNervous System Disorders: headache/migraine, peripheral neuropathyInvestigations: weight decreasedSkin Disorders: palmar-plantar erythrodysesthesiaTable 12: Laboratory Values Worsening from Baselinea Occurring in >15% of Patients on Intravenous Nivolumab CHECKMATE-025a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients).Laboratory AbnormalityIntravenous NivolumabEverolimusGrades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Hematology Lymphopenia4265311 Anemia3986916Chemistry Increased creatinine422451.6 Increased AST332.8391.6 Increased alkaline phosphatase322.3320.8 Hyponatremia327266 Hyperkalemia304202.1 Hypocalcemia230.9261.3 Increased ALT223.2310.8 Hypercalcemia193.260.3Lipids Increased triglycerides321.56711 Increased cholesterol210.3551.4. Unresectable or Metastatic Melanoma. Previously Treated Metastatic MelanomaCHECKMATE-037The safety of intravenous nivolumab was evaluated in CHECKMATE-037, randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.2)]. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade adverse reactions (except for endocrinopathies) or Grade ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, positive test for hepatitis or C, and history of HIV. Patients received intravenous nivolumab mg/kg by intravenous infusion over 60 minutes every weeks (n=268) or investigators choice of chemotherapy (n=102): dacarbazine 1000 mg/m2 intravenously every weeks or carboplatin AUC mg/mL/min and paclitaxel 175 mg/m2 intravenously every weeks. The median duration of exposure was 5.3 months (range: day to 13.8+ months) in intravenous nivolumab-treated patients and was months (range: day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received intravenous nivolumab for >6 months and 3% of patients received intravenous nivolumab for >1 year.The population characteristics in the intravenous nivolumab group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status (59%) or (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the intravenous nivolumab group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%).Serious adverse reactions occurred in 41% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving intravenous nivolumab had dose interruption for an adverse reaction. Grade and adverse reactions occurred in 42% of patients receiving intravenous nivolumab. The most frequent Grade and adverse reactions reported in 2% to <5% of patients receiving intravenous nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in >=20% of patients) was rash.Tables 13 and 14 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037. Table 13: Adverse Reactions Occurring in >=10% of Intravenous Nivolumab-Treated Patients and at Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of >=5% All Grades or >=2% Grades 3-4) CHECKMATE-037Toxicity was graded per NCI CTCAE v4.a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis.b Includes rhinitis, pharyngitis, and nasopharyngitis.Adverse ReactionIntravenous Nivolumab(n=268)Chemotherapy(n=102)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Skin and Subcutaneous Tissue Rasha 210.470 Pruritus1903.90Respiratory, Thoracic and Mediastinal Cough17060Infections Upper respiratory tract infectionb 11020General Peripheral edema10050Clinically important adverse reactions in <10% of patients who received intravenous nivolumab were:Cardiac Disorders: ventricular arrhythmiaEye Disorders: iridocyclitisGeneral Disorders and Administration Site Conditions: infusion-related reactionsInvestigations: increased amylase, increased lipaseNervous System Disorders: dizziness, peripheral and sensory neuropathySkin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasisTable 14: Laboratory Abnormalities Worsening from Baselinea Occurring in >=10% of Intravenous Nivolumab-Treated Patients and at Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of >=5% All Grades or >=2% Grades 3-4) CHECKMATE-037a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients).Laboratory AbnormalityIntravenous NivolumabChemotherapyAll Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Increased AST282.4121Hyponatremia255181.1Increased alkaline phosphatase222.4131.1Increased ALT161.650Hyperkalemia15260. Previously Untreated Metastatic Melanoma CHECKMATE-066The safety of intravenous nivolumab was also evaluated in CHECKMATE-066, randomized, double-blind, active-controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.2)]. The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received intravenous nivolumab mg/kg by intravenous infusion over 60 minutes every weeks (n=206) or dacarbazine 1000 mg/m2 intravenously every weeks (n=205). The median duration of exposure was 6.5 months (range: day to 16.6 months) in intravenous nivolumab-treated patients. In this trial, 47% of patients received intravenous nivolumab for >6 months and 12% of patients received intravenous nivolumab for >1 year.The trial population characteristics in the intravenous nivolumab group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the intravenous nivolumab group with ECOG performance status (71% vs. 59%).Serious adverse reactions occurred in 36% of patients receiving intravenous nivolumab. Adverse reactions led to permanent discontinuation of intravenous nivolumab in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of intravenous nivolumab discontinuations. Grade and adverse reactions occurred in 41% of patients receiving intravenous nivolumab.The most frequent Grade and adverse reactions reported in >=2% of patients receiving intravenous nivolumab were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in >=20% of patients and at higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.Table 15: Adverse Reactions Occurring in >=10% of Intravenous Nivolumab-Treated Patients and at Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of >=5% All Grades or >=2% Grades 3-4) CHECKMATE-066Toxicity was graded per NCI CTCAE v4.a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema.b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain.c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and skin reaction.d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis.Adverse ReactionIntravenous Nivolumab(n=206)Dacarbazine(n=205)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)General Fatigue491.9393.4 Edemaa 121.54.90Musculoskeletal and Connective Tissue Musculoskeletal painb 322.9252.4Skin and Subcutaneous Tissue Rashc 281.5120 Pruritus230.5120 Vitiligo1100.50 Erythema1002.90Infections Upper respiratory tract infectiond 17060Clinically important adverse reactions in <10% of patients who received intravenous nivolumab were:Nervous System Disorders: peripheral neuropathyTable 16: Laboratory Abnormalities Worsening from Baselinea Occurring in >=10% of Intravenous Nivolumab-Treated Patients and at Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of >=5% All Grades or >=2% Grades 3-4) CHECKMATE-066a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients).Laboratory AbnormalityIntravenous NivolumabDacarbazineAll Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Increased ALT253190.5Increased AST243.6190.5Increased alkaline phosphatase212.6141.6Increased bilirubin133.160CHECKMATE-067The safety of intravenous nivolumab, administered with ipilimumab or as single agent, was evaluated in CHECKMATE-067, randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.2)]. The trial excluded patients with autoimmune disease, medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, positive test result for hepatitis or C, or history of HIV.Patients were randomized to receive:oIntravenous nivolumab mg/kg over 60 minutes with ipilimumab mg/kg by intravenous infusion every weeks for doses followed by intravenous nivolumab as single agent at dose of mg/kg by intravenous infusion over 60 minutes every weeks (nivolumab and ipilimumab arm; n=313), oroIntravenous nivolumab mg/kg by intravenous infusion over 60 minutes every weeks (nivolumab arm; n=313), oroIpilimumab mg/kg by intravenous infusion every weeks for up to doses (ipilimumab arm; n=311).The median duration of exposure to intravenous nivolumab was 2.8 months (range: day to 36.4 months) for the intravenous nivolumab and ipilimumab arm and 6.6 months (range: day to 36.0 months) for the intravenous nivolumab arm. In the intravenous nivolumab and ipilimumab arm, 39% were exposed to intravenous nivolumab for >=6 months and 30% exposed for >1 year. In the intravenous nivolumab arm, 53% were exposed for >=6 months and 40% for >1 year.The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status (73%) or (27%), 93% with American Joint Committee on Cancer (AJCC) Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with history of brain metastasis, and 22% had received adjuvant therapy.Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade or adverse reactions (72% and 51%) all occurred more frequently in the intravenous nivolumab and ipilimumab arm relative to the intravenous nivolumab arm.The most frequent (>=10%) serious adverse reactions in the intravenous nivolumab and ipilimumab arm and the intravenous nivolumab arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1%). The most frequent adverse reactions leading to discontinuation of both drugs in the intravenous nivolumab and ipilimumab arm and of intravenous nivolumab in the intravenous nivolumab arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%).The most common (>=20%) adverse reactions in the intravenous nivolumab and ipilimumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. The most common (>=20%) adverse reactions in the intravenous nivolumab arm were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract infection, decreased appetite, headache, constipation, arthralgia, and vomiting.Tables 17 and 18 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.Table 17: Adverse Reactions Occurring in >=10% of Patients on the Intravenous Nivolumab and Ipilimumab Arm or the Intravenous Nivolumab Arm and at Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of >=5% All Grades or >=2% Grades 3-4) CHECKMATE-067Toxicity was graded per NCI CTCAE v4.a Includes asthenia and fatigue.b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash.c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.e Includes hypertension and blood pressure increased.Adverse ReactionIntravenous Nivolumab andIpilimumab(n=313)Intravenous Nivolumab(n=313)Ipilimumab(n=311)All Grades (%)Grades3-4 (%)All Grades (%)Grades3-4 (%)All Grades (%)Grades3-4 (%)General Fatiguea 627591.6514.2 Pyrexia401.6160180.6Gastrointestinal Diarrhea5411365477 Nausea443.8300.6311.9 Vomiting313.8201171.6Skin and Subcutaneous Tissue Rashb 536401.9423.5 Vitiligo90100.350Musculoskeletal and Connective Tissue Musculoskeletal painc 322.6423.8361.9 Arthralgia210.3211160.3Metabolism and Nutrition Decreased appetite291.9220241.3Respiratory, Thoracic and Mediastinal Cough/productive cough270.3280.6220 Dyspnea/exertional dyspnea242.9181.3170.6Infections Upper respiratory tract infectiond 230220.3170Endocrine Hypothyroidism190.611050 Hyperthyroidism111.36010Investigations Decreased weight1207070.3Vascular Hypertensione 72.211592.3Clinically important adverse reactions in <10% of patients who received intravenous nivolumab with ipilimumab or intravenous nivolumab as single agent were:Gastrointestinal Disorders: stomatitis, intestinal perforationSkin and Subcutaneous Tissue Disorders: vitiligoMusculoskeletal and Connective Tissue Disorders: myopathy, Sjogrens syndrome, spondyloarthropathy, myositis (including polymyositis)Nervous System Disorders: neuritis, peroneal nerve palsyTable 18: Laboratory Abnormalities Worsening from Baselinea Occurring in >=20% of Patients Treated with Intravenous Nivolumab with Ipilimumab or Single-Agent Intravenous Nivolumab and at Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of >=5% All Grades or >=2% Grades 3-4) CHECKMATE-067a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and ipilimumab (range: 75 to 297); intravenous nivolumab (range: 81 to 306); ipilimumab (range: 61 to 301).Laboratory AbnormalityIntravenous Nivolumab andIpilimumabIntravenous NivolumabIpilimumabAll Grades (%)Grade3-4 (%)All Grades (%)Grade3-4 (%)All Grades (%)Grade3-4 (%)Chemistry Increased ALT 5516253292.7 Hyperglycemia 535.3467260 Increased AST 5213293.7291.7 Hyponatremia4510223.3267 Increased lipase43223212247 Increased alkaline phosphatase416272232 Hypocalcemia311.1150.7200.7 Increased amylase2710192.7151.6 Increased creatinine 262.7190.7171.3Hematology Anemia522.7412.6416 Lymphopenia395414.9294. oIntravenous nivolumab mg/kg over 60 minutes with ipilimumab mg/kg by intravenous infusion every weeks for doses followed by intravenous nivolumab as single agent at dose of mg/kg by intravenous infusion over 60 minutes every weeks (nivolumab and ipilimumab arm; n=313), or. oIntravenous nivolumab mg/kg by intravenous infusion over 60 minutes every weeks (nivolumab arm; n=313), or. oIpilimumab mg/kg by intravenous infusion every weeks for up to doses (ipilimumab arm; n=311).. Adjuvant Treatment of Melanoma. CHECKMATE-76KThe safety of intravenous nivolumab as single agent was evaluated in CHECKMATE-76K, randomized (2:1), double-blind trial in 788 patients with completely resected Stage IIB/C melanoma who received intravenous nivolumab 480 mg by intravenous infusion over 30 minutes every weeks (n=524) or placebo by intravenous infusion over 30 minutes every weeks (n=264) for up to year [see Clinical Studies (14.3)]. The median duration of exposure was 11 months in patients treated with intravenous nivolumab and 11 months in patients treated with placebo.Serious adverse reactions occurred in 18% of patients treated with intravenous nivolumab. fatal adverse reaction occurred in (0.2%) patient (heart failure and acute kidney injury). Permanent discontinuation of intravenous nivolumab due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of intravenous nivolumab in >1% of patients included diarrhea (1.1%), arthralgia (1.7%), and rash (1.7%).Dosage interruptions of intravenous nivolumab due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dosage interruption in >1% of patients included COVID-19 infection, infusion related reaction, diarrhea, arthralgia, and increased ALT.The most common adverse reactions (reported in >=20% of patients) were fatigue, musculoskeletal pain, rash, diarrhea, and pruritus.Tables 19 and 20 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-76K.Table 19: Adverse Reactions Occurring in >=10% of Patients Treated with Intravenous Nivolumab CHECKMATE-76KToxicity was graded per NCI CTCAE v5.a Includes asthenia.b Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, spinal pain, pain in extremity.c Includes dermatitis, dermatitis acneiform, dyshidrotic eczema, eczema, eczema asteatotic, eyelid rash, genital rash, pemphigoid, penile rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, toxic skin eruption.d Includes autoimmune colitis, colitis, diarrhea, enteritis, enterocolitise Includes autoimmune hypothyroidism, blood thyroid stimulating hormone increased.f Includes cluster headache, migraine.Adverse ReactionIntravenous Nivolumab(n=524)Placebo(n=264)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)General Fatiguea 360.4340.4Musculoskeletal and connective tissue Musculoskeletal painb 300.4260.4Skin and Subcutaneous Tissue Rashc 281.1150.4 Pruritus200.2110Gastrointestinal Diarrhead 231.3160 Nausea140110Endocrine Hypothyroidisme 1402.30Nervous system Headachef 120.2140.8Table 20: Laboratory Abnormalities Worsening from Baselinea Occurring in >=10% of Intravenous Nivolumab-Treated Patients CHECKMATE-76Ka Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 262 to 513 patients) and placebo group (range: 138 to 261 patients).Laboratory AbnormalityIntravenous Nivolumab(n=524)Placebo(n=264)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Hematology Anemia190140 Lymphopenia171.1171.7 Neutropenia100100.4Chemistry AST increased252.2160.4 Lipase increased222.9212.3 ALT increased202.1150.4 Amylase increased170.490 Creatinine increased150.4130 Sodium decreased130.6110.4 Potassium increased131151.1CHECKMATE-238The safety of intravenous nivolumab as single agent was evaluated in CHECKMATE-238, randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received intravenous nivolumab mg/kg by intravenous infusion over 60 minutes every weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every weeks for doses then every 12 weeks beginning at Week 24 for up to year (n=453) [see Clinical Studies (14.3)]. The median duration of exposure was 11.5 months in intravenous nivolumab-treated patients and was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received intravenous nivolumab for >6 months.Serious adverse reactions occurred in 18% of intravenous nivolumab-treated patients. Study therapy was discontinued for adverse reactions in 9% of intravenous nivolumab-treated patients and 42% of ipilimumab-treated patients. Twenty-eight percent of intravenous nivolumab-treated patients had at least one omitted dose for an adverse reaction. Grade or adverse reactions occurred in 25% of intravenous nivolumab-treated patients.The most frequent Grade and adverse reactions reported in >=2% of intravenous nivolumab-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).Tables 21 and 22 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238.Table 21: Adverse Reactions Occurring in >=10% of Intravenous Nivolumab-Treated Patients CHECKMATE-238Toxicity was graded per NCI CTCAE v4.a Includes asthenia.b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness.c Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized, erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption.d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity.e Includes postural dizziness and vertigo.f Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis.g Includes secondary hypothyroidism and autoimmune hypothyroidism.Adverse ReactionIntravenous Nivolumab(n=452)Ipilimumab 10 mg/kg(n=453)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)General Fatiguea 570.9552.4Gastrointestinal Diarrhea372.45511 Nausea230.2280 Abdominal painb 210.2230.9 Constipation10090Skin and Subcutaneous Tissue Rashc 351.1475.3 Pruritus280371.1Musculoskeletal and Connective Tissue Musculoskeletal paind 320.4270.4 Arthralgia190.4130.4Nervous System Headache230.4312.0 Dizzinesse 11080Infections Upper respiratory tract infectionf 220150.2Respiratory, Thoracic and Mediastinal Cough/productive cough190190 Dyspnea/exertional dyspnea100.4100.2Endocrine Hypothyroidismg 120.27.50.4Table 22: Laboratory Abnormalities Worsening from Baselinea Occurring in >=10% of Intravenous Nivolumab-Treated Patients CHECKMATE-238a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 400 to 447 patients) and ipilimumab 10 mg/kg group (range: 392 to 443 patients).Laboratory AbnormalityIntravenous NivolumabIpilimumab 10 mg/kgAll Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Hematology Lymphopenia270.4120.9 Anemia260340.5 Leukopenia1402.70.2 Neutropenia13060.5Chemistry Increased Lipase257239 Increased ALT251.84012 Increased AST241.3339 Increased Amylase173.3133.1 Hyponatremia161.1223.2 Hyperkalemia120.290.5 Increased Creatinine120130 Hypocalcemia100.7160.5. Non-Small Cell Lung Cancer. Neoadjuvant Treatment of Resectable (Tumors >=4 cm or Node Positive) Non-Small Cell Lung CancerCHECKMATE-816The safety of intravenous nivolumab in combination with platinum-doublet chemotherapy was evaluated in CHECKMATE-816, randomized, open-label, multicenter trial in patients with resectable NSCLC [see Clinical Studies (14.4)]. Patients received either intravenous nivolumab 360 mg administered in combination with platinum-doublet chemotherapy administered every weeks for cycles; or platinum-doublet chemotherapy administered every weeks for cycles.The median age of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 84); 72% male; 47% White, 50% Asian, and 2% Black/African American.Serious adverse reactions occurred in 30% of patients who were treated with intravenous nivolumab in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy.Study therapy with intravenous nivolumab in combination with platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one treatment withheld for an adverse reaction. The most common adverse reactions (>=1%) resulting in permanent discontinuation of intravenous nivolumab in combination with platinum-doublet chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and fatigue (1.1%).The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased appetite, and rash. The most common Grade or laboratory abnormalities (>=2%) were neutropenia, hyperglycemia, leukopenia, lymphopenia, increased amylase, anemia, thrombocytopenia, and hyponatremia.Tables 23 and 24 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-816.Table 23: Adverse Reactions in >10% of Patients with Early-Stage NSCLC Receiving Neoadjuvant Intravenous Nivolumab and Platinum-Doublet Chemotherapy in CHECKMATE-816Toxicity was graded per NCI CTCAE v4.a Includes fatigue and asthenia.b Includes rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, drug eruption, maculopapular rash, and pruritic rash.c Includes peripheral neuropathy, dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensory neuropathy.Adverse ReactionIntravenous Nivolumab and Platinum-Doublet Chemotherapy(n=176)Platinum-Doublet Chemotherapy(n=176)All Grades(%)Grades or (%)All Grades(%)Grades or (%)Gastrointestinal Nausea380.6451.1 Constipation340321.1 Vomiting111.1130.6General Fatiguea 262.3231.1 Malaise150.6140.6Metabolism and Nutrition Decreased appetite201.1232.3Skin and Subcutaneous Tissue Rashb 202.370 Alopecia110150Nervous System Peripheral neuropathyc 13060Table 24: Select Laboratory Values Worsening from Baselinea Occurring in >20% of Patients with Early-Stage NSCLC Receiving Neoadjuvant Intravenous Nivolumab and Platinum-Doublet Chemotherapy in CHECKMATE-816a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and platinum-doublet chemotherapy group (range: 73 to 171 patients) and platinum-doublet chemotherapy group (range: 68 to 171 patients).Laboratory AbnormalityIntravenous Nivolumab and Platinum-Doublet Chemotherapya Platinum-Doublet Chemotherapya All Grades(%)Grades or (%)All Grades(%)Grades or (%)Hematology Anemia633.5706 Neutropenia58225827 Leukopenia5355111 Lymphopenia384.7311.8 Thrombocytopenia242.9223Chemistry Hyperglycemia376352.9 Hypomagnesemia251.2291.2 Hyponatremia252.4281.8 Increased amylase233.6131.8 Increased ALT230201.2. Neoadjuvant and Adjuvant Treatment of Resectable (Tumors >=4 cm or Node Positive) Non-Small Cell Lung Cancer CHECKMATE-77TThe safety of intravenous nivolumab in combination with neoadjuvant platinum-doublet chemotherapy followed by surgery and continued adjuvant treatment with intravenous nivolumab as single agent after surgery was evaluated in CHECKMATE-77T, randomized, double-blind, multicenter trial in patients with previously untreated resectable Stage IIA (>4 cm) to IIIB (T3N2 or T4N2) NSCLC (per the AJCC Cancer Staging Manual 8th Edition) [see Clinical Studies (14.5)]. Patients with active autoimmune disease or medical condition that required immunosuppression were ineligible. The median duration of exposure to intravenous nivolumab was 10.3 months (range: day to 22.3 months). The study population characteristics were: median age 66 years (range: 35 86); 71% male; 72% White, 25% Asian, 1.7% Black/African American, and 1.5% other race; and 6% Hispanic or Latino.Adverse reactions occurring in patients with resectable NSCLC receiving intravenous nivolumab in combination with platinum-doublet chemotherapy, given as neoadjuvant treatment and followed as single agent adjuvant treatment after surgery, were generally similar to those occurring in patients in other clinical trials across tumor types receiving intravenous nivolumab in combination with chemotherapy.Neoadjuvant Phase of CHECKMATE-77TA total of 228 patients received at least dose of intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment and 230 patients received at least dose of placebo in combination with platinum-doublet chemotherapy as neoadjuvant treatment.Serious adverse reactions occurred in 21% of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent (>=2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis (0.4% each).Permanent discontinuation of any study drug due to an adverse reaction occurred in 13% of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent (>=1%) adverse reaction that led to permanent discontinuation of any study drug was peripheral sensory neuropathy (2.2%).Of the 228 intravenous nivolumab-treated patients and 230 placebo-treated patients who received neoadjuvant treatment, 5.3% (n=12) and 3.5% (n=8), respectively, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in intravenous nivolumab-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2 patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19, and myositis (1 patient each). Of the 178 intravenous nivolumab-treated patients who received surgery, 4.5% (n=8) experienced delay of surgery (surgery more than weeks from last neoadjuvant treatment) due to adverse reactions. Of the 178 placebo-treated patients who received surgery, 3.9% (n=7) experienced delay of surgery due to adverse reactions.Of the 178 intravenous nivolumab-treated patients who received surgery, 7% (n=13) did not receive adjuvant treatment due to adverse reactions. Of the 178 placebo-treated patients who received surgery, 2.8% (n=5) did not receive adjuvant treatment due to adverse reactions.Adjuvant Phase of CHECKMATE-77TA total of 142 patients in the intravenous nivolumab arm and 152 patients in the placebo arm received at least dose of adjuvant treatment.Of the patients who received single agent intravenous nivolumab as adjuvant treatment, 22% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. Permanent discontinuation of adjuvant intravenous nivolumab due to an adverse reaction occurred in 14% of patients; the most frequent (>=1%) adverse reactions that led to permanent discontinuation of adjuvant intravenous nivolumab were pneumonitis (4.2%) and diarrhea (1.4%).Second-line Treatment of Metastatic NSCLCCHECKMATE-017 and CHECKMATE-057The safety of intravenous nivolumab was evaluated in CHECKMATE-017, randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies (14.6) ]. These trials excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received intravenous nivolumab mg/kg over 60 minutes by intravenous infusion every weeks or docetaxel 75 mg/m2 intravenously every weeks. The median duration of therapy in intravenous nivolumab-treated patients in CHECKMATE-017 was 3.3 months (range: day to 21.7+ months) and in CHECKMATE-057 was 2.6 months (range: to 24.0+ months). In CHECKMATE-017, 36% of patients received intravenous nivolumab for at least months and 18% of patients received intravenous nivolumab for at least year and in CHECKMATE-057, 30% of patients received intravenous nivolumab for >6 months and 20% of patients received intravenous nivolumab for >1 year.Across both trials, the median age of intravenous nivolumab-treated patients was 61 years (range: 37 to 85); 38% were >=65 years of age, 61% were male, and 91% were White. Ten percent of patients had brain metastases and ECOG performance status was (26%) or (74%).In CHECKMATE-057, in the intravenous nivolumab arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued in 11% of patients and was delayed in 28% of patients for an adverse reaction.The most frequent serious adverse reactions reported in >=2% of patients receiving intravenous nivolumab were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions (>=20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.Tables 25 and 26 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057.Table 25: Adverse Reactions Occurring in >=10% of Intravenous Nivolumab-Treated Patients and at Higher Incidence than Docetaxel (Between Arm Difference of >=5% All Grades or >=2% Grades 3-4) CHECKMATE-017 and CHECKMATE-057Toxicity was graded per NCI CTCAE v4.Adverse ReactionIntravenous Nivolumab(n=418)Docetaxel(n=397)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Respiratory, Thoracic and Mediastinal Cough310.7240Metabolism and Nutrition Decreased appetite281.4231.5Skin and Subcutaneous Tissue Pruritus100.220Other clinically important adverse reactions observed in intravenous nivolumab-treated patients and which occurred at similar incidence in docetaxel-treated patients and not listed elsewhere in section include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades).Table 26: Laboratory Abnormalities Worsening from Baselinea Occurring in >=10% of Intravenous Nivolumab-Treated Patients for all NCI CTCAE Grades and at Higher Incidence than Docetaxel (Between Arm Difference of >=5% All Grades or >=2% Grades 3-4) CHECKMATE-017 and CHECKMATE-057a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients), except for TSH: intravenous nivolumab group n=314 and docetaxel group n=297.b Not graded per NCI CTCAE v4.Laboratory AbnormalityIntravenous NivolumabDocetaxelAll Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Chemistry Hyponatremia357344.9 Increased AST271.9130.8 Increased alkaline phosphatase260.7180.8 Increased ALT221.7170.5 Increased creatinine180120.5 Increased TSHb 14N/A6N/A. Squamous Cell Carcinoma of the Head and Neck. CHECKMATE-141The safety of intravenous nivolumab was evaluated in CHECKMATE-141, randomized, active-controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with progression during or within months of receiving prior platinum-based therapy [see Clinical Studies (14.7) ]. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma). Patients received intravenous nivolumab mg/kg by intravenous infusion over 60 minutes every weeks (n=236) or investigators choice of either cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly). The median duration of exposure to nivolumab was 1.9 months (range: day to 16.1+ months) in intravenous nivolumab-treated patients. In this trial, 18% of patients received intravenous nivolumab for >6 months and 2.5% of patients received intravenous nivolumab for >1 year.The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the intravenous nivolumab group were >=65 years of age and 37% in the comparator group were >=65 years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG performance status was (20%) or (78%), 45% of patients received only one prior line of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and 90% had prior radiation therapy.Serious adverse reactions occurred in 49% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC.The most frequent serious adverse reactions reported in >=2% of patients receiving intravenous nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in >=10% of intravenous nivolumab-treated patients and at higher incidence than investigators choice were cough and dyspnea. The most common laboratory abnormalities occurring in >=10% of intravenous nivolumab-treated patients and at higher incidence than investigators choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH.. Urothelial Carcinoma. Adjuvant Treatment of Urothelial Carcinoma (UC)CHECKMATE-274The safety of intravenous nivolumab was evaluated in CHECKMATE-274, randomized, double-blind, multicenter trial of adjuvant intravenous nivolumab versus placebo in adult patients who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal pelvis or ureter) and were at high risk of recurrence [see Clinical Studies (14.8)]. Patients received intravenous nivolumab 240 mg by intravenous infusion over 30 minutes every weeks (n=351) or placebo (n=348) until recurrence or unacceptable toxicity for maximum of year. The median duration of intravenous nivolumab treatment was 8.8 months (range: to 12.5).Serious adverse reactions occurred in 30% of intravenous nivolumab patients. The most frequent serious adverse reaction reported in >=2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). Intravenous nivolumab was discontinued for adverse reactions in 18% of patients. Intravenous nivolumab was delayed for adverse reaction in 33% of patients.The most common adverse reactions (reported in >=20% of patients) were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection.Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-274.Table 27: Adverse Reactions Occurring in >=10% of Patients CHECKMATE-274Toxicity was graded per NCI CTCAE v4.a Includes acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis contact, eczema, eczema asteatotic, eczema nummular, erythema, erythema multiforme, lichen sclerosus, lichenoid keratosis, pemphigoid, photosensitivity reaction, pigmentation disorder, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rosacea, skin exfoliation, skin lesion, skin reaction, toxic skin eruption, and urticaria.b Includes colitis, colitis microscopic, diarrhea, duodenitis, enteritis, immune-mediated enterocolitis.c Includes abdominal pain, abdominal discomfort, abdominal tenderness, lower and upper abdominal pain.d Includes musculoskeletal pain, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.e Includes cystitis, escherichia urinary tract infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, urethritis, urinary tract infection, urinary tract infection bacterial, urinary tract infection staphylococcal, and urosepsis.f Includes upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis.g Includes acute kidney injury, autoimmune nephritis, blood creatinine increased, glomerular filtration rate decreased, immune-mediated nephritis, nephritis, renal failure, and renal impairment.h Includes cough, productive cough, and upper-airway cough syndrome.i Includes dyspnea and exertional dyspnea.j Includes dizziness, postural dizziness and vertigo.k Includes aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, cholangitis, drug-induced liver injury, hepatic failure, hepatic function abnormal, hepatitis, hepatocellular injury, hyperbilirubinemia, gamma-glutamyl transferase increased, liver injury, and transaminases increased.Adverse ReactionIntravenous Nivolumab(n=351)Placebo(n=348)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Skin and Subcutaneous Tissue Rasha 361.7190.3 Pruritus300160General Fatigue/Asthenia361.1320.3 Pyrexia100.3100.3Gastrointestinal Diarrheab 302.8271.7 Nausea160.6130 Abdominal painc 150.9150.6 Constipation130.3150.3Musculoskeletal and Connective Tissue Musculoskeletal paind 280.6240.9 Arthralgia110.3130Infections Urinary tract infectione 226239 Upper respiratory tract infectionf 160.3160.6Endocrine Hyperthyroidism1101.10 Hypothyroidism1102.30Renal and Urinary Disorders Renal dysfunctiong 171.7160.9Respiratory, Thoracic and Mediastinal Coughh 140110 Dyspneai 110.360.3Metabolism and Nutrition Decreased appetite130.970.3Nervous System Disorders Dizzinessj 110.390Hepatobiliary Hepatitisk 11480.6Table 28: Laboratory Abnormalities Worsening from Baselinea Occurring in >=10% of Patients CHECKMATE-274a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 322 to 348 patients) and placebo group (range: 312 to 341 patients).Laboratory AbnormalityIntravenous Nivolumab(n=351)Placebo(n=348)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Chemistry Increased creatinine361.7362.6 Increased amylase348233.2 Increased lipase33123110 Hyperkalemia325306 Increased alkaline phosphatase242.3150.6 Increased AST243.5160.9 Increased ALT232.9150.6 Hyponatremia224.1171.8 Hypocalcemia171.2110.9 Hypomagnesemia16090 Hypercalcemia120.380.3Hematology Lymphopenia332.9271.5 Anemia301.4280.9 Neutropenia110.6100.3First-line Treatment of Unresectable or Metastatic UCCHECKMATE-901The safety of intravenous nivolumab was evaluated in CHECKMATE-901, randomized, open-label trial in cisplatin-eligible patients with unresectable or metastatic UC [see Clinical Studies (14.8)]. Patients received either intravenous nivolumab 360 mg with cisplatin and gemcitabine every weeks for up to cycles followed by single-agent intravenous nivolumab 480 mg every weeks up to years (n=304), or cisplatin and gemcitabine chemotherapy every weeks for up to cycles (n=288). Patients discontinuing cisplatin alone were permitted to switch to carboplatin.Among patients who received intravenous nivolumab with chemotherapy, the median duration of intravenous nivolumab exposure was 7.4 months (range: 0.03 to 47.9 months). Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab in combination with chemotherapy. The most frequent serious adverse reactions reported in >=2% of patients who received intravenous nivolumab with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). The most common adverse reactions (reported in >=20% of patients) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy.Fatal adverse reactions occurred in 3.6% of patients who received intravenous nivolumab in combination with chemotherapy; these included sepsis (1%).Intravenous nivolumab and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction.Tables 29 and 30 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-901.Table 29: Adverse Reactions Occurring in >=10% of Treated Patients CHECKMATE-901Toxicity was graded per NCI CTCAE v4.a Includes colitis, immune-mediated enterocolitis.b Includes upper abdominal pain, lower abdominal pain, abdominal discomfort, epigastric discomfort, gastrointestinal pain, and hepatic pain.c Includes asthenia.d Includes peripheral edema, swelling, peripheral swelling, localized edema, swelling, face edema, testicular edema, gravitational edema, and edema genital.e Includes hyperthermia, body temperature increased and hyperpyrexia.f Includes back pain, arthralgia, bone pain, arthritis, musculoskeletal chest pain, non-cardiac chest pain, myalgia, neck pain, pain in extremity, and spinal pain.g Includes maculopapular rash, erythematous rash, macular rash, papular rash, pustular rash, acneiform dermatitis, dermatitis, allergic dermatitis, atopic dermatitis, exfoliative rash, eczema asteatotic, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, eczema, dermatitis exfoliative generalized, and skin exfoliation.h Includes paresthesia, peripheral sensory neuropathy, hypoesthesia, dysesthesia, neuralgia, hyperesthesia, peripheral motor neuropathy, polyneuropathy.i Includes occipital neuralgia.j Includes urosepsis, cystitis, pyelonephritis, pyelonephritis acute, urinary tract infection enterococcal, escherichia urinary tract infection.k Includes blood stimulating hormone increased.l Includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, anuria, azotemia.Adverse ReactionIntravenous Nivolumab and Platinum-Doublet Chemotherapy(n=304)Platinum-Doublet Chemotherapy (n=288)All Grades(%)Grades 3-4 (%)All Grades(%)Grades 3-4 (%)Gastrointestinal disorders Nausea520.3531 Constipation300280.7 Vomiting231.3192.1 Diarrheaa 192140 Abdominal painb 140.390.3General Fatiguec 483.9434.2 Edemad 18090.3 Pyrexiae 141140Musculoskeletal and Connective Tissue Musculoskeletal painf 333210.3Metabolism and Nutrition Decreased appetite301.6191Skin and Subcutaneous Tissue Rashg 252.370.3 Pruritus170.73.50Nervous System Disorders Peripheral neuropathyh 200.7140 Headachei 11050Infections Urinary tract infectionj 198188Endocrine disorders Hypothyroidismk 1700.30Renal and Urinary Disorders Renal dysfunctionl 146111.7 Hematuria11171.4Investigations Weight decreased110.360Table 30: Selected Laboratory Abnormalities Worsening from Baselinea Occurring in >=20% of Patients CHECKMATE-901a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 289-301 patients) and chemotherapy group (range: 265-281 patients).Laboratory AbnormalityIntravenous Nivolumab and Platinum-Doublet Chemotherapy(n=304)Platinum-Doublet Chemotherapy(n=288)Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Hematology Anemia88218021 Neutropenia82357628 Lymphopenia71175613 Thrombocytopenia6013518Chemistry Increased creatinine532.4421.1 Hypomagnesemia483.8391.5 Hyponatremia4313398 Hyperglycemia413.9373.2 Hypocalcemia362.1241.1 Hyperkalemia333.0321.1 Increased amylase324.2233.6 Increased AST312.4170.7 Increased ALT292.4190.7Previously Treated Advanced or Metastatic UCCHECKMATE-275The safety of intravenous nivolumab was evaluated in CHECKMATE-275, single arm trial in which 270 patients with locally advanced or metastatic UC had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies (14.8)]. Patients received intravenous nivolumab mg/kg by intravenous infusion over 60 minutes every weeks until disease progression or unacceptable toxicity. The median duration of treatment was 3.3 months (range: to 13.4+). Forty-six percent (46%) of patients had dose interruption for an adverse reaction.Fourteen patients (5.2%) died from causes other than disease progression. This includes patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with intravenous nivolumab. Serious adverse reactions occurred in 54% of patients. Intravenous nivolumab was discontinued for adverse reactions in 17% of patients.The most frequent serious adverse reactions reported in >=2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in >=20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite.Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275.Table 31: Adverse Reactions Occurring in >=10% of Patients CHECKMATE-275Toxicity was graded per NCI CTCAE v4.a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.b Includes abdominal discomfort, lower and upper abdominal pain.c Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular, maculopapular, or pruritic.d Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism, hypothyroidism, thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased, tri-iodothyronine increased.Adverse ReactionIntravenous Nivolumab(n=270)All Grades (%)Grades 3-4 (%)Adverse Reaction9951General Asthenia/fatigue/malaise467 Pyrexia/tumor associated fever170.4 Edema/peripheral edema/peripheral swelling130.4Musculoskeletal and Connective Tissue Musculoskeletal paina 302.6 Arthralgia100.7Metabolism and Nutrition Decreased appetite222.2Gastrointestinal Nausea220.7 Diarrhea172.6 Constipation160.4 Abdominal painb 131.5 Vomiting121.9Respiratory, Thoracic and Mediastinal Cough/productive cough180 Dyspnea/exertional dyspnea143.3Infections Urinary tract infection/escherichia/fungal urinary tract infection177Skin and Subcutaneous Tissue Rashc 161.5 Pruritus120Endocrine Thyroid disordersd 150Table 32: Laboratory Abnormalities Worsening from Baseline Occurring in >=10% of Patients CHECKMATE-275a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: range: 84 to 256 patients.Laboratory AbnormalityIntravenous Nivolumaba All Grades (%)Grades 3-4 (%)Chemistry Hyperglycemia422.4 Hyponatremia4111 Increased creatinine392 Increased alkaline phosphatase335.5 Hypocalcemia260.8 Increased AST243.5 Increased lipase207 Hyperkalemia191.2 Increased ALT181.2 Increased amylase184.4 Hypomagnesemia160Hematology Lymphopenia429 Anemia407 Thrombocytopenia152.4 Leukopenia110. MSI-H or dMMR Metastatic Colorectal Cancer. CHECKMATE-142The safety of intravenous nivolumab administered as single agent or in combination with ipilimumab was evaluated in CHECKMATE-142, multicenter, non-randomized, multiple parallel-cohort, open-label trial [see Clinical Studies (14.9) ]. In CHECKMATE-142, 74 patients with mCRC received intravenous nivolumab mg/kg by intravenous infusion over 60 minutes every weeks until disease progression or until intolerable toxicity and 119 patients with mCRC received intravenous nivolumab mg/kg and ipilimumab mg/kg every weeks for doses, then intravenous nivolumab mg/kg every weeks until disease progression or until unacceptable toxicity.In the intravenous nivolumab with ipilimumab cohort, serious adverse reactions occurred in 47% of patients. Treatment was discontinued in 13% of patients and delayed in 45% of patients for an adverse reaction. The most frequent serious adverse reactions reported in >=2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common adverse reactions (reported in >=20% of patients) were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting.Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-142. Based on the design of CHECKMATE-142, the data below cannot be used to identify statistically significant differences between the two cohorts summarized below for any adverse reaction.Table 33: Adverse Reactions Occurring in >=10% of Patients CHECKMATE-142Toxicity was graded per NCI CTCAE v4.a Includes asthenia.b Includes peripheral edema and peripheral swelling.c Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.d Includes back pain, pain in extremity, myalgia, neck pain, and bone pain.e Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized.f Includes nasopharyngitis and rhinitis.Adverse ReactionIntravenous Nivolumab(n=74)Intravenous Nivolumab and Ipilimumab(n=119)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)General Fatiguea 545496 Pyrexia240360 Edemab 12070Gastrointestinal Diarrhea432.7453.4 Abdominal painc 342.7305 Nausea341.4260.8 Vomiting284.1201.7 Constipation200150Musculoskeletal and Connective Tissue Musculoskeletal paind 281.4363.4 Arthralgia190140.8Respiratory, Thoracic and Mediastinal Cough260190.8 Dyspnea81131.7Skin and Subcutaneous Tissue Rashe 231.4254.2 Pruritus190281.7 Dry Skin70110Infections Upper respiratory tract infectionf 20090Endocrine Hyperglycemia192.761 Hypothyroidism50140.8 Hyperthyroidism40120Nervous System Headache160171.7 Dizziness140110Metabolism and Nutrition Decreased appetite141.4201.7Psychiatric Insomnia90130.8Investigations Weight decreased80100Clinically important adverse reactions reported in <10% of patients receiving intravenous nivolumab with ipilimumab were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%).Table 34: Laboratory Abnormalities Worsening from Baselinea Occurring in >=10% of Patients CHECKMATE-142a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Number of evaluable patients ranges from 62 to 71 for the intravenous nivolumab cohort and from 87 to 114 for the intravenous nivolumab and ipilimumab cohort.Laboratory AbnormalityIntravenous Nivolumab(n=74)Intravenous Nivolumab and Ipilimumab(n=119)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Hematology Anemia507429 Lymphopenia367256 Neutropenia204.3180 Thrombocytopenia161.4260.9Chemistry Increased alkaline phosphatase372.8285 Increased lipase33193912 Increased ALT322.83312 Increased AST311.44012 Hyponatremia274.3265 Hypocalcemia190160 Hypomagnesemia170180 Increased amylase164.8363.4 Increased bilirubin144.2215 Hypokalemia140151.8 Increased creatinine120253.6 Hyperkalemia110230.9. Hepatocellular Carcinoma. CHECKMATE-040The safety of intravenous nivolumab mg/kg in combination with ipilimumab mg/kg was evaluated in subgroup comprising 49 patients with HCC and Child-Pugh Class cirrhosis enrolled in Cohort of CHECKMATE-040, multicenter, multiple-cohort, open-label trial [see Clinical Studies (14.10) who progressed on or were intolerant to sorafenib. Intravenous nivolumab and ipilimumab were administered every weeks for doses, followed by single-agent intravenous nivolumab 240 mg every weeks until disease progression or unacceptable toxicity. During the intravenous nivolumab and ipilimumab combination period, 33 of 49 (67%) patients received all planned doses of intravenous nivolumab and ipilimumab. During the entire treatment period, the median duration of exposure to intravenous nivolumab was 5.1 months (range: to 35+ months) and to ipilimumab was 2.1 months (range: to 4.5 months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction.The most frequent serious adverse reactions (reported in >=4% of patients) were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis.Tables 35 and 36 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-040.Table 35: Adverse Reactions Occurring in >=10% of Patients Receiving Intravenous Nivolumab in Combination with Ipilimumab in Cohort of CHECKMATE-040Adverse ReactionIntravenous Nivolumab and Ipilimumab(n=49)All Grades (%)Grades 3-4 (%)Skin and Subcutaneous Tissue Rash538 Pruritus534Musculoskeletal and Connective Tissue Musculoskeletal pain412 Arthralgia100Gastrointestinal Diarrhea394 Abdominal pain226 Nausea200 Ascites146 Constipation140 Dry mouth120 Dyspepsia122 Vomiting122 Stomatitis100Respiratory, Thoracic and Mediastinal Cough370 Dyspnea140 Pneumonitis102Metabolism and Nutrition Decreased appetite352General Fatigue272 Pyrexia270 Malaise182 Edema162 Influenza-like illness140 Chills100Nervous System Headache220 Dizziness200Endocrine Hypothyroidism200 Adrenal insufficiency184Investigations Weight decreased200Psychiatric Insomnia180Blood and Lymphatic System Anemia104Infections Influenza102Vascular Hypotension100Clinically important adverse reactions reported in <10% of patients who received intravenous nivolumab with ipilimumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%).Table 36: Laboratory Abnormalities Worsening from Baseline Occurring in >=10% of Patients Receiving Intravenous Nivolumab in Combination with Ipilimumab in Cohort of CHECKMATE-040Laboratory AbnormalityIntravenous Nivolumab and Ipilimumab(n=47)All Grades (%)Grades 3-4 (%)Hematology Lymphopenia5313 Anemia434.3 Neutropenia439 Leukopenia402.1 Thrombocytopenia344.3Chemistry Increased AST6640 Increased ALT6621 Increased bilirubin5511 Increased lipase5126 Hyponatremia4932 Hypocalcemia470 Increased alkaline phosphatase404.3 Increased amylase3815 Hypokalemia262.1 Hyperkalemia234.3 Increased creatinine210 Hypomagnesemia110In patients who received intravenous nivolumab with ipilimumab, virologic breakthrough occurred in of 28 (14%) patients and of (50%) patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough was defined as at least 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined as 1 log increase in HCV RNA from baseline.. Esophageal Cancer. Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction CancerCHECKMATE-577The safety of intravenous nivolumab was evaluated in CHECKMATE-577, randomized, placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following chemoradiotherapy (CRT) [see Clinical Studies (14.11) ]. The trial excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Patients received either intravenous nivolumab 240 mg or placebo by intravenous infusion over 30 minutes every weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every weeks beginning at week 17. Patients were treated until disease recurrence, unacceptable toxicity, or for up to 1-year total duration. The median duration of exposure was 10.1 months (range: <0.1 to 14 months) in intravenous nivolumab-treated patients and months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received intravenous nivolumab, 61% were exposed for >6 months and 54% were exposed for >9 months.Serious adverse reactions occurred in 33% of patients receiving intravenous nivolumab. serious adverse reaction reported in >=2% of patients who received intravenous nivolumab was pneumonitis. fatal adverse reaction of myocardial infarction occurred in one patient who received intravenous nivolumab.Intravenous nivolumab was discontinued in 12% of patients and was delayed in 28% of patients for an adverse reaction.Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-577.Table 37: Adverse Reactions Occurring in >=10% of Patients Receiving Intravenous Nivolumab CHECKMATE-577a Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.b Includes gastroesophageal reflux.c Includes asthenia.d Includes productive cough.e Includes dyspnea exertional.f Includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, exfoliative rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic.g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, spinal pain.Adverse ReactionIntravenous Nivolumab(n=532)Placebo(n=260)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Adverse Reaction96349332Gastrointestinal Diarrhea290.9290.8 Nausea230.8210 Abdominal Paina 170.8201.5 Vomiting150.6161.2 Dysphagia130.8173.5 Dyspepsiab 120.2160.4 Constipation110120General Fatiguec 341.3291.5Respiratory, Thoracic and Mediastinal Coughd 200.2210.4 Dyspneae 120.8120.4Skin and Subcutaneous Tissue Rashf 210.9100.4 Pruritus130.460Investigations Weight decreased130.490Musculoskeletal and Connective Tissue Musculoskeletal paing 210.6200.8 Arthralgia100.280Metabolism and Nutrition Decreased appetite150.9100.8Endocrine Hypothyroidism1101.50Table 38: Laboratory Abnormalities Worsening from Baselinea Occurring in >=10% of Patients CHECKMATE-577a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 163 to 526 patients) and Placebo group (range: 86 to 256 patients).b Includes alanine aminotransferase increased, aspartate aminotransferase increased.Laboratory AbnormalityIntravenous Nivolumab(n=532)Placebo(n=260)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Chemistry Increased AST272.1220.8 Increased alkaline phosphatase250.8180.8 Increased albumin210.2180 Increased ALT201.9161.2 Increased amylase203.9131.3 Hyponatremia191.7121.2 Hyperkalemia170.8151.6 Hypokalemia121111.2 Transaminases increasedb 111.561.2Hematology Lymphopenia44173512 Anemia270.8210.4 Neutropenia241.5230.4First-line Treatment of Unresectable Advanced or Metastatic ESCC CHECKMATE-648The safety of intravenous nivolumab in combination with chemotherapy or in combination with ipilimumab was evaluated in CHECKMATE-648, randomized, active-controlled, multicenter, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC [see Clinical Studies (14.11) ]. Patients received one of the following treatments:ointravenous nivolumab 240 mg on days and 15, 5-FU (fluorouracil) 800 mg/m2/day intravenously on days through (for days), and cisplatin 80 mg/m2 intravenously on day (of 4-week cycle).ointravenous nivolumab mg/kg every weeks in combination with ipilimumab mg/kg every weeks.o5-FU (fluorouracil) 800 mg/m2/day intravenously on days through (for days), and cisplatin 80 mg/m2 intravenously on day (of 4-week cycle).Among patients who received intravenous nivolumab with chemotherapy, the median duration of exposure was 5.7 months (range: 0.1 to 30.6 months). Among patients who received intravenous nivolumab and ipilimumab, the median duration of exposure was 2.8 months (range: to 24 months).Serious adverse reactions occurred in 62% of patients receiving intravenous nivolumab in combination with chemotherapy and in 69% of patients receiving intravenous nivolumab in combination with ipilimumab. The most frequent serious adverse reactions reported in >=2% of patients who received intravenous nivolumab with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). The most frequent serious adverse reactions reported in >=2% of patients who received intravenous nivolumab with ipilimumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%).Fatal adverse reactions occurred in (1.6%) patients who received intravenous nivolumab in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury and in (1.6%) patients who received intravenous nivolumab in combination with ipilimumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome.Intravenous nivolumab and/or chemotherapy were discontinued in 39% of patients and were delayed in 71% of patients for an adverse reaction. Intravenous nivolumab and/or ipilimumab were discontinued in 23% of patients and were delayed in 46% of patients for an adverse reaction.The most common adverse reactions reported in >=20% of patients treated with intravenous nivolumab in combination with chemotherapy were nausea, decreased appetite, fatigue, constipation, stomatitis, diarrhea, and vomiting. The most common adverse reactions reported in >=20% of patients treated with intravenous nivolumab in combination with ipilimumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation.Tables 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648.Table 39: Adverse Reactions in >=10% of Patients CHECKMATE-648Toxicity was graded per NCI CTCAE v4.a Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.c Includes asthenia and malaise.d Includes tumor associated fever.e Includes swelling, generalized edema, edema peripheral, and peripheral swelling.f Includes hyperesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy.g Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, and rash pruritic.h Includes productive cough.i Includes organizing pneumonia, pneumonia bacterial, and pneumonia pseudomonal.j Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, and spinal pain.Adverse ReactionIntravenous Nivolumab with Cisplatin and 5-FU(n=310)Intravenous Nivolumab and Ipilimumab(n=322)Cisplatin and 5-FU(n=304)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Gastrointestinal Nausea654.2220.6562.6 Constipation441.0200.3431 Stomatitisa 449110.6353 Diarrhea292.9221.9202 Vomiting232.3151.6193 Dysphagia147125124.9 Abdominal painb 131.9100.9110.7Metabolism and Nutrition Decreased appetite517174506General Fatiguec 473.5282.5414.9 Pyrexiad 190.3230.9120.3 Edemae 16070130Nervous System Peripheral neuropathyf 181.32.80131Psychiatric Insomnia16080100.3Skin and Subcutaneous Tissue Rashg 160.6313.170 Pruritus110170.93.60 Alopecia100110Respiratory, Thoracic and Mediastinal Coughh 160.3130.3130.3Infections and Infestations Pneumoniai 135148102.6Endocrine Hypothyroidism701400.30Investigations Weight decreased120.6121.9111Musculoskeletal and Connective Tissue Musculoskeletal painj 110.3140.680.3Table 40: Laboratory Values Worsening from Baselinea Occurring in >=10% of Patients CHECKMATE-648a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab with cisplatin and 5-FU group (range: 60 to 305 patients), intravenous nivolumab and ipilimumab group (range: 59 to 307 patients) or cisplatin and 5-FU group (range: 56 to 283 patients).Laboratory AbnormalityIntravenous Nivolumab with Cisplatin and 5-FU(n=310)Intravenous Nivolumab and Ipilimumab(n=322)Cisplatin and 5-FU(n=304)Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Hematology Anemia81215276614 Lymphopenia67235013448 Neutropenia6118131.34813 Leukopenia5311395 Thrombocytopenia433.3121292.8Chemistry Hyponatremia52154511408 Hypocalcemia433320230.7 Increased creatinine412.3150.7310.7 Hypomagnesemia351.7150251.8 Hyperglycemia340434.3360.8 Hyperkalemia332.3231.6240.7 Hypokalemia299195176 Increased alkaline phosphatase261.3313.3150 Increased AST233.3396111.4 Increased ALT232.333680.7 Hypoglycemia180.4151.270 Hypercalcemia112.615280Previously-Treated Unresectable Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)ATTRACTION-3The safety of intravenous nivolumab was evaluated in ATTRACTION-3, randomized, active-controlled, open-label, multicenter trial in 209 patients with unresectable advanced, recurrent or metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum-based chemotherapy [see Clinical Studies (14.11) ]. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients received intravenous nivolumab 240 mg by intravenous infusion over 30 minutes every weeks (n=209) or investigators choice: docetaxel 75 mg/m2 intravenously every weeks (n=65) or paclitaxel 100 mg/m2 intravenously once week for weeks followed by week off (n=143). Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 2.6 months (range: to 29.2 months) in intravenous nivolumab-treated patients and 2.6 months (range: to 21.4 months) in docetaxel- or paclitaxel-treated patients. Among patients who received intravenous nivolumab, 26% were exposed for >6 months and 10% were exposed for >1 year.Serious adverse reactions occurred in 38% of patients receiving intravenous nivolumab. Serious adverse reactions reported in >=2% of patients who received intravenous nivolumab were pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse reactions occurred in patients who received intravenous nivolumab: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).Intravenous nivolumab was discontinued in 13% of patients and was delayed in 27% of patients for an adverse reaction.Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, in ATTRACTION-3.Table 41: Adverse Reactions Occurring in >=10% of Patients Receiving Intravenous Nivolumab ATTRACTION-3Toxicity was graded per NCI CTCAE v4.a Includes urticaria, drug eruption, eczema, eczema asteatotic, eczema nummular, palmar-plantar erythrodysesthesia syndrome, erythema, erythema multiforme, blister, skin exfoliation, Stevens-Johnson syndrome, dermatitis, dermatitis described as acneiform, bullous, or contact, and rash described as maculo-papular, generalized, or pustular.b Includes hypophagia, and food aversion.c Includes colitis.d Includes spondylolisthesis, periarthritis, musculoskeletal chest pain, neck pain, arthralgia, back pain, myalgia, pain in extremity, arthritis, bone pain, and periarthritis calcarea.e Includes influenza, influenza like illness, pharyngitis, nasopharyngitis, tracheitis, and bronchitis and upper respiratory infection with bronchitis.f Includes pneumonia aspiration, pneumonia bacterial, and lung infection. Two patients (1.0%) died of pneumonia in the intravenous nivolumab treatment arm. Two patients (1.0%) died of pneumonia in the chemotherapy treatment arm; these deaths occurred with paclitaxel only.g Includes productive cough.h Includes tumor-associated fever.i Includes asthenia.j Includes hemoglobin decreased, and iron deficiency anemia.k Includes blood thyroid stimulating hormone increased.Adverse ReactionIntravenous Nivolumab(n=209)Docetaxel or Paclitaxel(n=208)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Skin and Subcutaneous Tissue Rasha 221.9281 Pruritus12070Metabolism and Nutrition Decreased appetiteb 211.9355Gastrointestinal Diarrheac 181.9171.4 Constipation170190 Nausea110200.5Musculoskeletal and Connective Tissue Musculoskeletal paind 170261.4Infections Upper respiratory tract infectione 171140 Pneumoniaf 135199Respiratory, Thoracic and Mediastinal Coughg 160140.5General Pyrexiah 160.5190.5 Fatiguei 121.4274.8Blood and Lymphatic System Anemiaj 1383013Endocrine Hypothyroidismk 1101.40Table 42: Laboratory Abnormalities Worsening from Baselinea Occurring in >=10% of Patients ATTRACTION-3a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (209 patients) and Docetaxel or Paclitaxel group (range: 207 to 208 patients).Laboratory AbnormalityIntravenous Nivolumab(n=209)Docetaxel or Paclitaxel(n=208)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Chemistry Increased creatinine780.5680.5 Hyperglycemia525625 Hyponatremia42115012 Increased AST406301 Increased alkaline phosphatase334.8241.0 Increased ALT315221.9 Hypercalcemia226142.9 Hyperkalemia220.5311 Hypoglycemia141.4140.5 Hypokalemia112.9133.4Hematology Lymphopenia46197243 Anemia4297117 Leukopenia110.57945. ointravenous nivolumab 240 mg on days and 15, 5-FU (fluorouracil) 800 mg/m2/day intravenously on days through (for days), and cisplatin 80 mg/m2 intravenously on day (of 4-week cycle).. ointravenous nivolumab mg/kg every weeks in combination with ipilimumab mg/kg every weeks.. o5-FU (fluorouracil) 800 mg/m2/day intravenously on days through (for days), and cisplatin 80 mg/m2 intravenously on day (of 4-week cycle).. Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma. CHECKMATE-649The safety of intravenous nivolumab in combination with chemotherapy was evaluated in CHECKMATE-649, randomized, multicenter, open-label trial in patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma [see Clinical Studies (14.12) ]. The trial excluded patients who were known human epidermal growth factor receptor (HER2) positive or had untreated central nervous system (CNS) metastases. Patients were randomized to receive intravenous nivolumab in combination with chemotherapy or chemotherapy. Patients received one of the following treatments:ointravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every weeks or mFOLFOX6 every weeks.ointravenous nivolumab 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every weeks or CapeOX every weeks.Patients were treated with intravenous nivolumab in combination with chemotherapy or chemotherapy until disease progression, unacceptable toxicity, or up to years. The median duration of exposure was 6.8 months (range: to 33.5 months) in intravenous nivolumab and chemotherapy-treated patients. Among patients who received intravenous nivolumab and chemotherapy, 54% were exposed for >6 months and 28% were exposed for >1 year.Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with intravenous nivolumab in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. Serious adverse reactions occurred in 52% of patients treated with intravenous nivolumab in combination with chemotherapy. Intravenous nivolumab and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction.The most frequent serious adverse reactions reported in >=2% of patients treated with intravenous nivolumab in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The most common adverse reactions reported in >=20% of patients treated with intravenous nivolumab in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.Tables 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-649.Table 43: Adverse Reactions in >=10% of Patients Receiving Intravenous Nivolumab and Chemotherapy CHECKMATE-649Toxicity was graded per NCI CTCAE v4.a Includes dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy.b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.c Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.d Includes asthenia.e Includes tumor associated fever.f Includes swelling, generalized edema, edema peripheral, and peripheral swelling.g Includes blood albumin decreased.h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.i Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, nodular rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash vesicular.j Includes productive cough.k Includes nasopharyngitis, pharyngitis, and rhinitis.Adverse ReactionIntravenous Nivolumab and mFOLFOX6 or CapeOX(n=782)mFOLFOX6 or CapeOX(n=767)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Adverse Reaction99699859Nervous System Peripheral neuropathya 537464.8 Headache110.860.3Gastrointestinal Nausea483.2443.7 Diarrhea395343.7 Vomiting314.2294.2 Abdominal painb 272.8242.6 Constipation250.6210.4 Stomatitisc 171.8130.8General Fatigued 447405 Pyrexiae 191110.4 Edemaf 120.580.1Metabolism and Nutrition Decreased appetite293.6262.5 Hypoalbuminemiag 140.390.3Investigations Weight decreased171.3150.7 Increased lipase14783.7 Increased amylase123.150.4Musculoskeletal and Connective Tissue Musculoskeletal painh 201.3142Skin and Subcutaneous Tissue Rashi 181.74.40.1 Palmar-plantar erythrodysesthesia syndrome131.5120.8Respiratory, Thoracic and Mediastinal Coughj 130.190Infections and Infestations Upper respiratory tract infectionk 100.170.1Table 44: Laboratory Values Worsening from Baselinea Occurring in >=10% of Patients CHECKMATE-649a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and mFOLFOX6 or CapeOX group (407 to 767 patients) or mFOLFOX6 or CapeOX group (range: 405 to 735 patients).Laboratory AbnormalityIntravenous Nivolumab and mFOLFOX6 or CapeOX(n=782)mFOLFOX6 or CapeOX(n=767)Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Hematology Neutropenia73296223 Leukopenia6912599 Thrombocytopenia687634.4 Anemia59146010 Lymphopenia5912499Chemistry Increased AST524.6471.9 Hypocalcemia421.6371 Hyperglycemia413.9382.7 Increased ALT373.4301.9 Hyponatremia346245 Hypokalemia277244.8 Hyperbilirubinemia242.8212 Increased creatinine15190.5 Hyperkalemia141.4110.7 Hypoglycemia120.790.2 Hypernatremia110.57.10. ointravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every weeks or mFOLFOX6 every weeks.. ointravenous nivolumab 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every weeks or CapeOX every weeks.. 6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of intravenous nivolumab. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Eye: Vogt-Koyanagi-Harada (VKH) syndrome Complications of Intravenous Nivolumab Treatment After Allogeneic HSCT: Treatment refractory, severe acute and chronic GVHD Blood and lymphatic system disorders: Hemophagocytic lymphohistiocytosis (HLH) (including fatal cases), autoimmune hemolytic anemia (including fatal cases).

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES . 14.1Advanced Renal Cell Carcinoma Previously Treated Renal Cell Carcinoma OPDIVO QVANTIGThe efficacy of OPDIVO QVANTIG was evaluated in CHECKMATE-67T (NCT04810078), multicenter, randomized, open-label study in patients with advanced or metastatic clear cell renal cell carcinoma. Patients 18 years of age or older with histologically confirmed advanced or metastatic renal cell carcinoma with clear cell component, including those with sarcomatoid features, and who received no more than prior systemic treatment regimens were randomized to receive OPDIVO QVANTIG (containing 1,200 mg of nivolumab and 20,000 units of hyaluronidase) every weeks subcutaneously, or nivolumab mg/kg every weeks intravenously. Patients with untreated, symptomatic central nervous system (CNS) metastases; leptomeningeal metastases; concurrent malignancies requiring treatment or history of prior malignancy within the previous years; active, known, or suspected autoimmune disease; or who received prior treatment with checkpoint inhibitor were excluded from the study. Patients with asymptomatic, stable CNS metastases that did not require immediate treatment were eligible if there was no evidence of progression within 28 days prior to the first dose of study drug administration. Stratification factors for randomization were weight (<80 kg vs >=80 kg) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification (favorable vs intermediate, vs poor risk). The primary objective was to assess the nivolumab exposure of subcutaneous administration of OPDIVO QVANTIG as compared to the intravenous administration of nivolumab. The secondary objective of the study was to evaluate overall response rate (ORR) by blinded independent central review (BICR).A total of 495 patients were randomized to receive either OPDIVO QVANTIG (n=248) or intravenous nivolumab (n=247). The median age was 65 years (range: 20 to 93), with 51% >=65 years of age and 14% >=75 years of age; 68% male; 85% White, 12.5% not reported, 1% American Indian or Alaska Native, 0.8% Asian, and 0.4% Black; 36% Hispanic or Latino, 33% not Hispanic or Latino, and 31% not reported. Fifty-seven percent of patients weighed <80 kg and 43% weighed >=80 kg. Baseline Karnofsky performance status was 70 (7%), 80 (20%), 90 (34%), or 100 (39%). Patient distribution by IMDC risk categories was 21% favorable, 62% intermediate, and 17% poor.When comparing subcutaneous administration of OPDIVO QVANTIG to the intravenous administration of nivolumab, CHECKMATE-67T met the predefined acceptance margin for pharmacokinetic endpoints, with the lower boundary of 90% confidence interval of geometric mean ratios of not less than 0.8 for both serum nivolumab Cavg over 28 days and Cmin at steady state. [see Clinical Pharmacology 12.3]. Efficacy results are shown in Table 45.Table 45: Efficacy Results CHECKMATE-67Ta Confidence interval based on the Clopper and Pearson method.OPDIVO QVANTIGN=248Intravenous NivolumabN=247ORR per BICR, (%) 60 (24)45 (18) 95% CIa (19, 30)(14, 24)RCC Trials Intravenous NivolumabThe effectiveness of OPDIVO QVANTIG has been established for the following:oas monotherapy, for advanced renal cell carcinoma (RCC) following treatment with intravenous nivolumab and ipilimumab combination therapy (CHECKMATE-214 study).oin combination with cabozantinib, for the first-line treatment of adult patients with advanced RCC (CHECKMATE-9ER study).oas monotherapy, for the treatment of adult patients with advanced RCC who have received prior anti-angiogenic therapy (CHECKMATE-025 study).Use of OPDIVO QVANTIG for these RCC indications is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab in the CHECKMATE-67T trial [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. Below is description of the efficacy results of these adequate and well-controlled studies of intravenous nivolumab in these RCC populations.. oas monotherapy, for advanced renal cell carcinoma (RCC) following treatment with intravenous nivolumab and ipilimumab combination therapy (CHECKMATE-214 study).. oin combination with cabozantinib, for the first-line treatment of adult patients with advanced RCC (CHECKMATE-9ER study).. oas monotherapy, for the treatment of adult patients with advanced RCC who have received prior anti-angiogenic therapy (CHECKMATE-025 study).. First-line Renal Cell Carcinoma. CHECKMATE-214CHECKMATE-214 (NCT02231749) was randomized (1:1), open-label trial in patients with previously untreated advanced RCC. Patients were included regardless of their PD-L1 status. CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and region.Efficacy was evaluated in intermediate/poor risk patients with at least or more of prognostic risk factors as per the IMDC criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status <80%, hemoglobin less than the lower limit of normal, corrected calcium of >10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal).Patients were randomized to nivolumab mg/kg and ipilimumab mg/kg intravenously every weeks for doses followed by nivolumab mg/kg intravenously every two weeks (n=425), or sunitinib 50 mg orally daily for the first weeks of 6-week cycle (n=422). Treatment continued until disease progression or unacceptable toxicity.The trial population characteristics were: median age was 61 years (range: 21 to 85) with 38% >=65 years of age and 8% >=75 years of age. The majority of patients were male (73%) and White (87%) and 26% and 74% of patients had baseline KPS of 70% to 80% and 90% to 100%, respectively.The major efficacy outcome measures were OS, PFS (independent radiographic review committee [IRRC]-assessed) and confirmed ORR (IRRC-assessed) in intermediate/poor risk patients. In this population, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to intravenous nivolumab and ipilimumab as compared with sunitinib (Table 46 and Figure 1). OS benefit was observed regardless of PD-L1 expression level. The trial did not demonstrate statistically significant improvement in PFS. Efficacy results are shown in Table 46 and Figure 1.Table 46: Efficacy Results CHECKMATE-214a Not Reachedb Based on stratified proportional hazards model.c Based on stratified log-rank test.d p-value is compared to alpha 0.002 in order to achieve statistical significance.e Based on the stratified DerSimonian-Laird test.f p-value is compared to alpha 0.001 in order to achieve statistical significance.g Not Significant at alpha level of 0.009.Intermediate/Poor-RiskIntravenous Nivolumab and Ipilimumab(n=425)Sunitinib(n=422)Overall Survival Deaths (%)140 (32.9)188 (44.5) Median survival (months)NRa 25.9 Hazard ratio (99.8% CI)b 0.63 (0.44, 0.89) p-valuec,d <0.0001Confirmed Overall Response Rate (95% CI)41.6% (36.9, 46.5)26.5% (22.4, 31.0) p-valuee,f <0.0001 Complete response (CR)40 (9.4)5 (1.2) Partial response (PR)137 (32.2)107 (25.4) Median duration of response (months) (95% CI)NRa (21.8, NRa)18.2 (14.8, NRa)Progression-free Survival Disease progression or death (%)228 (53.6)228 (54.0) Median (months)11.68.4 Hazard ratio (99.1% CI)a 0.82 (0.64, 1.05) p-valuec NSg Figure 1: Overall Survival (Intermediate/Poor Risk Population) CHECKMATE-214CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to intravenous nivolumab and ipilimumab (n=125) or to sunitinib (n=124). These patients were not evaluated as part of the efficacy analysis population. OS in favorable risk patients receiving intravenous nivolumab and ipilimumab compared to sunitinib has hazard ratio of 1.45 (95% CI: 0.75, 2.81). The efficacy of intravenous nivolumab and ipilimumab in previously untreated renal cell carcinoma with favorable-risk disease has not been established.CHECKMATE-9ERCHECKMATE-9ER (NCT03141177) was randomized, open-label study of intravenous nivolumab combined with cabozantinib versus sunitinib in patients with previously untreated advanced RCC. CHECKMATE-9ER excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression. Patients were stratified by IMDC prognostic score (favorable vs. intermediate vs. poor), PD-L1 tumor expression (>=1% vs. <1% or indeterminate), and region (US/Canada/Western Europe/Northern Europe vs. Rest of World).Patients were randomized to nivolumab 240 mg intravenously every weeks and cabozantinib 40 mg orally daily (n=323), or sunitinib 50 mg orally daily for the first weeks of 6-week cycle (4 weeks on treatment followed by weeks off) (n=328). Treatment continued until disease progression per RECIST v1.1 or unacceptable toxicity. Treatment beyond RECIST-defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at Week 12, then every weeks until Week 60, and then every 12 weeks thereafter.The trial population characteristics were: median age 61 years (range: 28 to 90) with 38% >=65 years of age and 10% >=75 years of age. The majority of patients were male (74%) and White (82%) and 23% and 77% of patients had baseline KPS of 70% to 80% and 90% to 100%, respectively. Patient distribution by IMDC risk categories was 22% favorable, 58% intermediate, and 20% poor.The major efficacy outcome measure was PFS (BICR assessed). Additional efficacy outcome measures were OS and ORR (BICR assessed). The trial demonstrated statistically significant improvement in PFS, OS, and ORR for patients randomized to intravenous nivolumab and cabozantinib compared with sunitinib. Consistent results for PFS were observed across pre-specified subgroups of IMDC risk categories and PD-L1 tumor expression status. An updated OS analysis was conducted when 271 deaths were observed based on the pre-specified number of deaths for the pre-planned final analysis of OS. Efficacy results are shown in Table 47 and Figures and 3.Table 47: Efficacy Results CHECKMATE-9ERa Based on Kaplan-Meier estimates.b Stratified Cox proportional hazards model.c Based on stratified log-rank testd 2-sided p-values from stratified log-rank test.e Not Reachedf p-value is compared with the allocated alpha of 0.0111 for this interim analysisg CI based on the Clopper-Pearson method.h 2-sided p-value from Cochran-Mantel-Haenszel test.Intravenous Nivolumab and Cabozantinib(n=323)Sunitinib(n=328)Progression-free Survival Disease progression or death (%)144 (45)191 (58) Median PFS (months)a (95% CI)16.6 (12.5, 24.9)8.3 (7.0, 9.7) Hazard ratio (95% CI)b 0.51 (0.41, 0.64) p-valuec,d <0.0001Overall Survival Deaths (%)67 (21)99 (30) Median OS (months)a (95% CI)NRe NR (22.6, NRe) Hazard ratio (98.89% CI)b 0.60 (0.40, 0.89) p-valuec,d,f 0.0010Updated Overall Survival Deaths (%)121 (37)150 (46) Median OS (months)a (95% CI)37.7 (35.5, NR)34.3 (29.0, NR) Hazard ratio (95% CI)b 0.70 (0.55, 0.90)Confirmed Objective Response Rate (95% CI)g 55.7% (50.1, 61.2)27.1% (22.4, 32.3) p-valueh <0.0001 Complete Response26 (8%)15 (4.6%) Partial Response 154 (48%)74 (23%) Median duration of response in months (95% CI)a 20.2 (17.3, NRe)11.5 (8.3, 18.4)Figure 2: Progression-free Survival CHECKMATE-9ERFigure 3: Updated Overall Survival CHECKMATE-9ERIn an exploratory analysis, the updated analysis of OS in patients with IMDC favorable, intermediate, intermediate/poor, and poor risk demonstrated HR (95% CI) of 1.03 (0.55, 1.92), 0.74 (0.54, 1.01), 0.65 (0.50, 0.85), and 0.49 (0.31, 0.79), respectively.. oq-os-checkmate-214. oq-pfs-checkmate-9er. oq-updated-os-checkmate-9er. Previously Treated Renal Cell Carcinoma. CHECKMATE-025CHECKMATE-025 (NCT01668784) was randomized (1:1), open-label trial in patients with advanced RCC who had experienced disease progression during or after one or two prior anti-angiogenic therapy regimens. Patients had to have Karnofsky Performance Score (KPS) >=70% and patients were included regardless of their PD-L1 status. The trial excluded patients with any history of or concurrent brain metastases, prior treatment with an mTOR inhibitor, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by region, Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group and the number of prior anti-angiogenic therapies. Patients were randomized to nivolumab mg/kg by intravenous infusion every weeks (n=410) or everolimus 10 mg orally daily (n=411). The first tumor assessments were conducted weeks after randomization and continued every weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. The major efficacy outcome measure was overall survival (OS).The trial population characteristics were: median age was 62 years (range: 18 to 88) with 40% >=65 years of age and 9% >=75 years of age. The majority of patients were male (75%) and White (88%) and 34% and 66% of patients had baseline KPS of 70% to 80% and 90% to 100%, respectively. The majority of patients (77%) were treated with one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 34% favorable, 47% intermediate, and 19% poor.The trial demonstrated statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with everolimus at the prespecified interim analysis when 398 events were observed (70% of the planned number of events for final analysis). OS benefit was observed regardless of PD-L1 expression level. Efficacy results are shown in Table 48 and Figure 4.Table 48: Efficacy Results CHECKMATE-025a Not Reachedb Based on stratified proportional hazards model.c Based on stratified log-rank test.d p-value is compared with 0.0148 of the allocated alpha for this interim analysis.Intravenous Nivolumab(n=410)Everolimus(n=411)Overall Survival Deaths (%)183 (45)215 (52) Median survival (months) (95% CI)25.0 (21.7, NRa)19.6 (17.6, 23.1) Hazard ratio (95% CI)b 0.73 (0.60, 0.89) p-valuec,d 0.0018Confirmed Overall Response Rate (95% CI)21.5% (17.6, 25.8)3.9% (2.2, 6.2) Median duration of response (months) (95% CI)23.0 (12.0, NRa)13.7 (8.3, 21.9) Median time to onset of confirmed response (months) (min, max)3.0 (1.4, 13.0)3.7 (1.5, 11.2)Figure 4: Overall Survival CHECKMATE-025. oq-os-checkmate-025. 14.2Unresectable or Metastatic Melanoma Previously Treated Metastatic MelanomaThe effectiveness of OPDIVO QVANTIG has been established for the treatment of previously treated unresectable or metastatic melanoma. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of this adequate and well-controlled study of intravenous nivolumab in this melanoma population. OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.CHECKMATE-037CHECKMATE-037 (NCT01721746) was multicenter, open-label trial that randomized (2:1) patients with unresectable or metastatic melanoma to receive nivolumab mg/kg intravenously every weeks or investigators choice of chemotherapy, either single-agent dacarbazine 1000 mg/m2 every weeks or the combination of carboplatin AUC intravenously every weeks and paclitaxel 175 mg/m2 intravenously every weeks. Patients were required to have progression of disease on or following ipilimumab treatment and, if BRAF V600 mutation positive, BRAF inhibitor. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or history of Grade ipilimumab-related adverse reactions (except for endocrinopathies) or Grade ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event. Tumor assessments were conducted weeks after randomization then every weeks for the first year, and every 12 weeks thereafter.Efficacy was evaluated in single-arm, non-comparative, planned interim analysis of the first 120 patients who received intravenous nivolumab in CHECKMATE-037 and in whom the minimum duration of follow-up was months. The major efficacy outcome measures in this population were confirmed overall response rate (ORR) as measured by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response.Among the 120 patients treated with intravenous nivolumab, the median age was 58 years (range: 25 to 88), 65% of patients were male, 98% were White, and the ECOG performance score was (58%) or (42%). Disease characteristics were M1c disease (76%), BRAF V600 mutation positive (22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic therapies for metastatic disease (68%).The ORR was 32% (95% confidence interval [CI]: 23, 41), consisting of complete responses and 34 partial responses in intravenous nivolumab-treated patients. Of 38 patients with responses, 87% had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of months or longer.There were responses in patients with and without BRAF V600 mutation-positive melanoma. total of 405 patients were randomized and the median duration of OS was 15.7 months (95% CI: 12.9, 19.9) in nivolumab-treated patients compared to 14.4 months (95% CI: 11.7, 18.2) (HR 0.95; 95.54% CI: 0.73, 1.24) in patients assigned to investigators choice of treatment. Figure summarizes the OS results.Figure 5: Overall Survival CHECKMATE-037The primary OS analysis was not adjusted to account for subsequent therapies, with 54 (40.6%) patients in the chemotherapy arm subsequently receiving an anti-PD1 treatment. OS may be confounded by dropout, imbalance of subsequent therapies, and differences in baseline factors.. Previously Untreated Metastatic Melanoma. The effectiveness of OPDIVO QVANTIG has been established for the treatment of previously untreated unresectable or metastatic melanoma. Use of OPDIVO QVANTIG for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of these adequate and well-controlled studies of intravenous nivolumab in this melanoma population.OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.CHECKMATE-066CHECKMATE-066 (NCT01721772) was multicenter, double-blind, randomized (1:1) trial in 418 patients with BRAF V600 wild-type unresectable or metastatic melanoma. Patients were randomized to receive either nivolumab mg/kg by intravenous infusion every weeks or dacarbazine 1000 mg/m2 intravenously every weeks until disease progression or unacceptable toxicity. Randomization was stratified by PD-L1 status (>=5% of tumor cell membrane staining by immunohistochemistry vs. <5% or indeterminate result) and stage (M0/M1a/M1b versus M1c). Key eligibility criteria included histologically confirmed, unresectable or metastatic, cutaneous, mucosal, or acral melanoma; no prior therapy for metastatic disease; completion of prior adjuvant or neoadjuvant therapy at least weeks prior to randomization; ECOG performance status or 1; absence of autoimmune disease; and absence of active brain or leptomeningeal metastases. The trial excluded patients with ocular melanoma. Tumor assessments were conducted weeks after randomization then every weeks for the first year and then every 12 weeks thereafter. The major efficacy outcome measure was overall survival (OS). Additional outcome measures included investigator-assessed progression-free survival (PFS) and ORR per RECIST v1.1.The trial population characteristics were: median age was 65 years (range: 18 to 87), 59% were male, and 99.5% were White. Disease characteristics were M1c stage disease (61%), cutaneous melanoma (74%), mucosal melanoma (11%), elevated LDH level (37%), PD-L1 >=5% tumor cell membrane expression (35%), and history of brain metastasis (4%). More patients in the intravenous nivolumab arm had an ECOG performance status of (71% vs. 58%).CHECKMATE-066 demonstrated statistically significant improvement in OS for the intravenous nivolumab arm compared with the dacarbazine arm in an interim analysis based on 47% of the total planned events for OS. At the time of analysis, 88% (63/72) of intravenous nivolumab-treated patients had ongoing responses, which included 43 patients with ongoing response of months or longer. Efficacy results are shown in Table 49 and Figure 6.Table 49: Efficacy Results CHECKMATE-066a Not Reached.b Based on stratified proportional hazards model.c Based on stratified log-rank test.d p-value is compared with the allocated alpha of 0.0021 for this interim analysis.Intravenous Nivolumab(n=210)Dacarbazine(n=208)Overall Survival Deaths (%)50 (24)96 (46) Median (months) (95% CI)NRa 10.8 (9.3, 12.1) Hazard ratio (95% CI)b 0.42 (0.30, 0.60) p-valuec,d <0.0001Progression-free Survival Disease progression or death (%)108 (51)163 (78) Median (months) (95% CI)5.1 (3.5, 10.8)2.2 (2.1, 2.4) Hazard ratio (95% CI)b 0.43 (0.34, 0.56) p-valuec,d <0.0001Overall Response Rate34%9% (95% CI)(28, 41)(5, 13) Complete response rate4%1% Partial response rate30%8%Figure 6: Overall Survival CHECKMATE-066CHECKMATE-067CHECKMATE-067 (NCT01844505) was multicenter, randomized (1:1:1), double-blind trial in 945 patients with previously untreated, unresectable or metastatic melanoma to one of the following arms: intravenous nivolumab and ipilimumab, intravenous nivolumab, or ipilimumab. Patients were required to have completed adjuvant or neoadjuvant treatment at least weeks prior to randomization and have no prior treatment with anti-CTLA-4 antibody and no evidence of active brain metastasis, ocular melanoma, autoimmune disease, or medical conditions requiring systemic immunosuppression.Patients were randomized to receive:oNivolumab mg/kg with ipilimumab mg/kg intravenously every weeks for doses, followed by nivolumab as single agent at dose of mg/kg by intravenous infusion every weeks (nivolumab and ipilimumab arm),oNivolumab mg/kg by intravenous infusion every weeks (nivolumab arm), oroIpilimumab mg/kg intravenously every weeks for doses, followed by placebo every weeks (ipilimumab arm).Randomization was stratified by PD-L1 expression (>=5% vs. <5% tumor cell membrane expression) as determined by clinical trial assay, BRAF V600 mutation status, and stage per the AJCC staging system (M0, M1a, M1b vs. M1c). Tumor assessments were conducted 12 weeks after randomization then every weeks for the first year, and every 12 weeks thereafter. The major efficacy outcome measures were investigator-assessed PFS per RECIST v1.1 and OS. Additional efficacy outcome measures were confirmed ORR and duration of response.The trial population characteristics were: median age 61 years (range: 18 to 90); 65% male; 97% White; ECOG performance score (73%) or (27%). Disease characteristics were: AJCC Stage IV disease (93%); M1c disease (58%); elevated LDH (36%); history of brain metastases (4%); BRAF V600 mutation-positive melanoma (32%); PD-L1 >=5% tumor cell membrane expression as determined by the clinical trials assay (46%); and prior adjuvant therapy (22%).CHECKMATE-067 demonstrated statistically significant improvements in OS and PFS for patients randomized to either intravenous nivolumab-containing arm as compared with the ipilimumab arm. The trial was not designed to assess whether adding ipilimumab to intravenous nivolumab improves PFS or OS compared to intravenous nivolumab as single agent. Efficacy results are shown in Table 50 and Figure 7.Table 50: Efficacy Results CHECKMATE-067a OS results are based on final OS analysis with 28 months of minimum follow-up; PFS (co-primary endpoint) and ORR (secondary endpoint) results were based on primary analysis with months of minimum follow-up.b Based on stratified proportional hazards model.c Based on stratified log-rank test.d If the maximum of the two OS p-values is less than 0.04 (a significance level assigned by the Hochberg procedure), then both p-values are considered significant.e p-value is compared with .005 of the allocated alpha for final PFS treatment comparisons.f Based on the stratified Cochran-Mantel-Haenszel test.+ Censored observationIntravenous Nivolumab andIpilimumab (n=314)Intravenous Nivolumab(n=316)Ipilimumab (n=315)Overall Survivala Deaths (%)128 (41)142 (45)197 (63) Hazard ratiob (vs. ipilimumab)(95% CI)0.55(0.44, 0.69)0.63(0.50, 0.78) p-valuec, <0.0001<0.0001Progression-free Survivala Disease progression or death 151 (48%)174 (55%)234 (74%) Median (months)(95% CI)11.5(8.9, 16.7)6.9 (4.3, 9.5)2.9 (2.8, 3.4) Hazard ratiob (vs. ipilimumab)(95% CI)0.42(0.34, 0.51)0.57(0.47, 0.69) p-valuec, <0.0001<0.0001Confirmed Overall Response Ratea 50%40%14% (95% CI)(44, 55)(34, 46)(10, 18) p-valuef <0.0001<0.0001 Complete response8.9%8.5%1.9% Partial response 41%31%12%Duration of Response Proportion >=6 months in duration76%74%63% Range (months)1.2+ to 15.8+1.3+ to 14.6+1.0+ to 13.8+Figure 7: Overall Survival CHECKMATE-067Based on minimum follow-up of 48 months, the median OS was not reached (95% CI: 38.2, NR) in the intravenous nivolumab and ipilimumab arm. The median OS was 36.9 months (95% CI: 28.3, NR) in the intravenous nivolumab arm and 19.9 months (95% CI: 16.9, 24.6) in the ipilimumab arm.Based on minimum follow-up of 28 months, the median PFS was 11.7 months (95% CI: 8.9, 21.9) in the intravenous nivolumab and ipilimumab arm, 6.9 months (95% CI: 4.3, 9.5) in the intravenous nivolumab arm, and 2.9 months (95% CI: 2.8, 3.2) in the ipilimumab arm. Based on minimum follow-up of 28 months, the proportion of responses lasting >=24 months was 55% in the intravenous nivolumab and ipilimumab arm, 56% in the intravenous nivolumab arm, and 39% in the ipilimumab arm.. oNivolumab mg/kg with ipilimumab mg/kg intravenously every weeks for doses, followed by nivolumab as single agent at dose of mg/kg by intravenous infusion every weeks (nivolumab and ipilimumab arm),. oNivolumab mg/kg by intravenous infusion every weeks (nivolumab arm), or. oIpilimumab mg/kg intravenously every weeks for doses, followed by placebo every weeks (ipilimumab arm).. oq-os-checkmate-066. oq-os-checkmate-067. oq-os-checkmate-037. 14.3Adjuvant Treatment of Melanoma The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. Use of OPDIVO QVANTIG for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of these adequate and well-controlled studies of intravenous nivolumab in these melanoma populations.OPDIVO QVANTIG is not indicated for the treatment of pediatric patients. CHECKMATE-76KCHECKMATE-76K (NCT04099251) was randomized, double-blind trial in 790 patients with completely resected Stage IIB/C melanoma. Patients were randomized (2:1) to receive nivolumab 480 mg or placebo by intravenous infusion every weeks for up to year or until disease recurrence or unacceptable toxicity. Enrollment required complete resection of the primary melanoma with negative margins and negative sentinel lymph node within 12 weeks prior to randomization, and ECOG performance status of or 1. The trial excluded patients with ocular/uveal or mucosal melanoma, autoimmune disease, any condition requiring systemic treatment with either corticosteroids (>=10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery. Randomization was stratified by AJCC 8th staging system edition (T3b vs. T4a vs. T4b). The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause, whichever occurred first and as assessed by the investigator. Tumor assessments were conducted every 26 weeks during years 1-3 and every 52 weeks thereafter until year 5.The trial population characteristics were: median age 62 years (range: 19 to 92), 61% were male, 98% were White, 0.4% Black or African American, 0.1% Asian, and 1.1% race unknown, 2.2% Hispanic or Latino, 58% Not Hispanic or Latino, 40% ethnicity unknown, and 94% had an ECOG performance status of 0. Sixty one percent had stage IIB and 39% had stage IIC melanoma.CHECKMATE-76K demonstrated statistically significant improvement in RFS for patients randomized to the intravenous nivolumab arm compared with the placebo arm. Efficacy results are shown in Table 51 and Figure 8.Table 51: Efficacy Results CHECKMATE-76Ka Not reached.b Based on Kaplan-Meier estimates.c Hazard Ratio is intravenous nivolumab over placebo based on stratified Cox proportional hazard model.d Based on 2-sided stratified log-rank test. Boundary for statistical significance: p-value <0.033.Intravenous Nivolumabn=526Placebon=264Recurrence-free Survival Number of events, (%) 66 (13%)69 (26%)Median (months)b (95% CI)NRa (28.5, NR)NRa (21.6, NR)Hazard ratioc (95% CI) p-valued 0.42(0.30, 0.59)p<0.0001Figure 8: Recurrence-free Survival CHECKMATE-76KCHECKMATE-238CHECKMATE-238 (NCT02388906) was randomized, double-blind trial in 906 patients with completely resected Stage IIIB/C or Stage IV melanoma. Patients were randomized (1:1) to receive nivolumab mg/kg by intravenous infusion every weeks or ipilimumab 10 mg/kg intravenously every weeks for doses then every 12 weeks beginning at Week 24 for up to year. Enrollment required complete resection of melanoma with margins negative for disease within 12 weeks prior to randomization. The trial excluded patients with history of ocular/uveal melanoma, autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (>=10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed >=6 months prior to randomization. Randomization was stratified by PD-L1 status (positive [based on 5% level] vs. negative/indeterminate) and AJCC stage (Stage IIIB/C vs. Stage IV M1a-M1b vs. Stage IV M1c). The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause, whichever occurs first and as assessed by the investigator. Patients underwent imaging for tumor recurrence every 12 weeks for the first years then every months thereafter.The trial population characteristics were: median age was 55 years (range: 18 to 86), 58% were male, 95% were White, and 90% had an ECOG performance status of 0. Disease characteristics were AJCC Stage IIIB (34%), Stage IIIC (47%), Stage IV (19%), M1a-b (14%), BRAF V600 mutation positive (42%), BRAF wild-type (45%), elevated LDH (8%), PD-L1 >=5% tumor cell membrane expression determined by clinical trial assay (34%), macroscopic lymph nodes (48%), and tumor ulceration (32%).CHECKMATE-238 demonstrated statistically significant improvement in RFS for patients randomized to the intravenous nivolumab arm compared with the ipilimumab 10 mg/kg arm. Efficacy results are shown in Table 52 and Figure 9.Table 52: Efficacy Results CHECKMATE-238a Not reached.b Based on stratified proportional hazards model.c Based on stratified log-rank test.d p-value is compared with 0.0244 of the allocated alpha for this analysis.e At the time of the final OS analysis, fewer overall survival events were observed than originally anticipated (approximately 302).Intravenous NivolumabN=453Ipilimumab 10 mg/kgN=453Recurrence-free Survival Number of events, (%) 154 (34%)206 (45%) Median (months) (95% CI)NRa NRa (16.56, NRa) Hazard ratiob (95% CI) p-valuec,d 0.65(0.53, 0.80) p<0.0001Overall SurvivalNumber of events, (%)e 100 (22%)111 (25%)Median (months) (95% CI)NRa NRa Hazard ratiob (95% CI) p-value0.87(0.67, 1.14)0.3148Figure 9: Recurrence-free Survival CHECKMATE-238. oq-rfs-checkmate-76k. oq-rfs-checkmate-238. 14.4Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer The effectiveness of OPDIVO QVANTIG has been established for the neoadjuvant treatment of resectable (tumors >=4 cm or node positive) NSCLC in combination with platinum doublet chemotherapy. Use of OPDIVO QVANTIG for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab (CHECKMATE-816, NCT02998528), and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this lung cancer population.CHECKMATE-816CHECKMATE-816 (NCT02998528) was randomized, open label trial in patients with resectable NSCLC. The trial included patients with resectable, histologically confirmed Stage IB (>=4 cm), II, or IIIA NSCLC (per the 7th edition American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging criteria), ECOG performance status or 1, and measurable disease (per RECIST version 1.1). Patients with unresectable or metastatic NSCLC, known EGFR mutations or ALK translocations, Grade or greater peripheral neuropathy, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study.Patients were randomized to receive either: onivolumab 360 mg administered intravenously over 30 minutes and platinum-doublet chemotherapy administered intravenously every weeks for up to cycles, oroplatinum-doublet chemotherapy administered every weeks for up to cycles.Platinum-doublet chemotherapy consisted of paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC or AUC (any histology); pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 (non-squamous histology); or gemcitabine 1000 mg/m2 or 1250 mg/m2 and cisplatin 75 mg/m2 (squamous histology). In the platinum-doublet chemotherapy arm, two additional treatment regimen options included vinorelbine 25 mg/m2 or 30 mg/m2 and cisplatin 75 mg/m2; or docetaxel 60 mg/m2 or 75 mg/m2 and cisplatin 75 mg/m2 (any histology).Stratification factors for randomization were tumor PD-L1 expression level (>=1% versus <1% or non-quantifiable), disease stage (IB/II versus IIIA), and sex (male versus female). Tumor assessments were performed at baseline, within 14 days of surgery, every 12 weeks after surgery for years, then every months for years, and every year for years until disease recurrence or progression. The major efficacy outcome measures were event-free survival (EFS) based on blinded independent central review (BICR) assessment and pathologic complete response (pCR) as evaluated by blinded independent pathology review (BIPR). Additional efficacy outcome measures included OS.A total of 358 patients were randomized to receive either intravenous nivolumab in combination with platinum-doublet chemotherapy (n=179) or platinum-doublet chemotherapy (n=179). The median age was 65 years (range: 34 to 84) with 51% of patients >=65 years and 7% of patients >=75 years, 50% were Asian, 47% were White, 2% were Black, and 71% were male. Baseline ECOG performance status was (67%) or (33%); 50% had tumors with PD-L1 expression >=1%; 35% had stage IB/II and 64% had stage IIIA disease; 51% had tumors with squamous histology and 49% had tumors with non-squamous histology; and 89% were former/current smokers.Eighty-three percent of patients in the intravenous nivolumab in combination with platinum-doublet chemotherapy arm had definitive surgery compared to 75% of patients in the platinum-doublet chemotherapy arm.The study demonstrated statistically significant improvements in EFS and pCR. Efficacy results are presented in Table 53 and Figure 10.Table 53: Efficacy Results CHECKMATE-816Minimum follow-up for EFS was 21 months.a Kaplan-Meier estimate.b Based on stratified Cox proportional hazard model.c Based on stratified log-rank test. Boundary for statistical significance: p-value <0.0262.d Based on Clopper and Pearson method.e Strata-adjusted difference based on Cochran-Mantel-Haenszel method of weighting.f From stratified CMH test.Intravenous Nivolumab and Platinum-Doublet Chemotherapy(n=179)Platinum-Doublet Chemotherapy(n=179)Event-free Survival (EFS) per BICR Events (%)64 (35.8)87 (48.6) Median (months) (95% CI)31.6(30.2, NR)20.8(14.0, 26.7) Hazard Ratiob (95% CI)0.63(0.45, 0.87) Stratified log-rank p-valuec 0.0052Pathologic Complete Response (pCR) per BIPR Number of patients with pCR 434 pCR Rate (%), (95% CI)d 24.0 (18.0, 31.0)2.2 (0.6, 5.6) Estimated treatment difference (95% CI)e 21.6 (15.1, 28.2) p-valuef <0.0001Figure 10: Event-Free Survival CHECKMATE-816At the time of the EFS analysis, 26% of the patients had died. prespecified interim analysis for OS resulted in HR of 0.57 (95% CI: 0.38, 0.87), which did not cross the boundary for statistical significance.. onivolumab 360 mg administered intravenously over 30 minutes and platinum-doublet chemotherapy administered intravenously every weeks for up to cycles, or. oplatinum-doublet chemotherapy administered every weeks for up to cycles.. oq-efs-checkmate-816. 14.5Neoadjuvant and Adjuvant Treatment of Resectable Non-Small Cell Lung Cancer The effectiveness of OPDIVO QVANTIG has been established for neoadjuvant treatment of resectable (tumors >=4 cm or node positive) NSCLC and no EGFR mutations or ALK rearrangements in combination with platinum doublet chemotherapy followed by adjuvant treatment with intravenous nivolumab. Use of OPDIVO QVANTIG for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab (CHECKMATE-77T, NCT04025879), and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this lung cancer population.CHECKMATE-77TThe efficacy of intravenous nivolumab, in combination with platinum-doublet chemotherapy, followed by surgery, and continued adjuvant treatment with intravenous nivolumab as single agent, was investigated in CHECKMATE-77T (NCT04025879), randomized, double-blind trial in 461 patients with resectable NSCLC. The trial included patients with resectable, suspected or histologically confirmed Stage IIA (>4 cm) to IIIB (T3-T4 N2) NSCLC (per the 8th edition American Joint Committee on Cancer (AJCC) Staging Manual), and ECOG performance status or 1. Patients with unresectable or metastatic NSCLC, EGFR mutations or known ALK translocations, brain metastasis, Grade or greater peripheral neuropathy, interstitial lung disease or active, non-infectious pneumonitis (symptomatic and/or requiring treatment), active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Randomization was stratified by tumor PD-L1 expression level (>=1% versus <1% versus indeterminate/not evaluable), disease stage (Stage II versus Stage III), and tumor histology (squamous versus nonsquamous).Patients were randomized (1:1) to receive either:oNeoadjuvant nivolumab 360 mg administered intravenously over 30 minutes in combination with one of the following platinum-doublet chemotherapy regimens every weeks for four cycles:Paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC or AUC (any histology)Pemetrexed 500 mg/m2, and cisplatin 75 mg/m2 or carboplatin AUC or AUC (nonsquamous histology)Cisplatin 75 mg/m2 and docetaxel 75 mg/m2 (squamous histology). Within 90 days after the surgery, nivolumab 480 mg was administered intravenously over 30 minutes every weeks.oroNeoadjuvant placebo administered intravenously over 30 minutes in combination with platinum-doublet chemotherapy (see above) every weeks for four cycles. Within 90 days after the surgery, placebo was administered intravenously over 30 minutes every weeks.All study medications were administered via intravenous infusion. Treatment continued until disease progression, recurrence, or unacceptable toxicity for up to 13 cycles (1 year). Tumor assessments were performed every 12 weeks for years, then every 24 weeks for up to years or until disease recurrence or progression was confirmed by BICR. The trial was not designed to isolate the effect of intravenous nivolumab in each phase (neoadjuvant or adjuvant) of treatment.The major efficacy outcome measure was event-free survival (EFS) based on BICR assessment. Additional efficacy outcome measures included overall survival (OS), pathologic complete response (pCR), and major pathologic response (MPR).The median age was 66 years (range: 35 to 86); 71% were male; 72% were White, 25% were Asian, 1.7% were Black, and 1.5% were mixed race/ race unknown/ not reported; and 6% were Hispanic or Latino. Baseline ECOG performance status was (62%) or (38%); 56% had tumors with PD-L1 expression >=1% and 40% had tumors with PD-L1 expression <1%; 35% had stage II and 64% had stage III disease; 23% had N1 disease and 39% had N2 disease; 51% had tumors with squamous histology and 49% had tumors with nonsquamous histology; and 90% were former/current smokers.Seventy-eight percent of patients in the neoadjuvant intravenous nivolumab in combination with platinum-doublet chemotherapy followed by adjuvant intravenous nivolumab arm had definitive surgery compared to 77% of patients in the neoadjuvant placebo and platinum-doublet chemotherapy followed by placebo arm.The study demonstrated statistically significant improvement in EFS for patients treated with neoadjuvant intravenous nivolumab in combination with platinum-doublet chemotherapy followed by single agent intravenous nivolumab compared with patients randomized to placebo in combination with platinum-doublet chemotherapy followed by placebo. Efficacy results are presented in Table 54 and Figure 11.Table 54: Efficacy Results CHECKMATE-77Ta Kaplan-Meier estimate.b Based on stratified Cox proportional hazard model.c Based on stratified log-rank test. Boundary for statistical significance: p-value <0.0264.Neoadjuvant Intravenous Nivolumab and Platinum-Doublet Chemotherapy/Adjuvant Intravenous Nivolumab(n=229)Neoadjuvant Placebo and Platinum-Doublet Chemotherapy/Adjuvant Placebo(n=232)Event-free Survival (EFS) per BICR Events (%)76 (33%)113 (49%) Median (months)a (95% CI)NR(28.9, NR)18.4(13.6, 28.1) Hazard Ratiob (95% CI)0.58(0.43, 0.78) Stratified log-rank p-valuec 0.00025Figure 11: Event-Free Survival CHECKMATE-77TIn pre-specified descriptive analysis, the pCR rate was 25% (95% CI: 20, 31) in the intravenous nivolumab arm and 4.7% (95% CI: 2.4, 8) in the placebo arm. At the time of the EFS analysis, OS data were immature.. oNeoadjuvant nivolumab 360 mg administered intravenously over 30 minutes in combination with one of the following platinum-doublet chemotherapy regimens every weeks for four cycles:Paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC or AUC (any histology)Pemetrexed 500 mg/m2, and cisplatin 75 mg/m2 or carboplatin AUC or AUC (nonsquamous histology)Cisplatin 75 mg/m2 and docetaxel 75 mg/m2 (squamous histology).. Paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC or AUC (any histology). Pemetrexed 500 mg/m2, and cisplatin 75 mg/m2 or carboplatin AUC or AUC (nonsquamous histology). Cisplatin 75 mg/m2 and docetaxel 75 mg/m2 (squamous histology).. Within 90 days after the surgery, nivolumab 480 mg was administered intravenously over 30 minutes every weeks.. oNeoadjuvant placebo administered intravenously over 30 minutes in combination with platinum-doublet chemotherapy (see above) every weeks for four cycles. Within 90 days after the surgery, placebo was administered intravenously over 30 minutes every weeks.. oq-efs-checkmate-77t. 14.6Metastatic Non-Small Cell Lung Cancer Second-line Treatment of Metastatic NSCLC. The effectiveness of OPDIVO QVANTIG has been established for the treatment of NSCLC previously treated with platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO QVANTIG. Use of OPDIVO QVANTIG for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of this adequate and well-controlled study of intravenous nivolumab in this lung cancer population.CHECKMATE-017CHECKMATE-017 (NCT01642004) was randomized (1:1), open-label trial in 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Patients received nivolumab mg/kg by intravenous infusion every weeks (n=135) or docetaxel 75 mg/m2 intravenously every weeks (n=137). Randomization was stratified by prior paclitaxel vs. other prior treatment and region (US/Canada vs. Europe vs. Rest of World). This trial included patients regardless of their PD-L1 status. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically returned to baseline at least weeks prior to enrollment, and either off corticosteroids, or on stable or decreasing dose of <10 mg daily prednisone equivalents. The first tumor assessments were conducted weeks after randomization and continued every weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS.The trial population characteristics were: median age was 63 years (range: 39 to 85) with 44% >=65 years of age and 11% >=75 years of age. The majority of patients were White (93%) and male (76%); the majority of patients were enrolled in Europe (57%) with the remainder in US/Canada (32%) and the rest of the world (11%). Baseline ECOG performance status was (24%) or (76%) and 92% were former/current smokers. Baseline disease characteristics of the population as reported by investigators were Stage IIIb (19%), Stage IV (80%), and brain metastases (6%). All patients received prior therapy with platinum-doublet regimen and 99% of patients had tumors of squamous-cell histology.The trial demonstrated statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with docetaxel at the prespecified interim analysis when 199 events were observed (86% of the planned number of events for final analysis). Efficacy results are shown in Table 55 and Figure 12.Table 55: Efficacy Results CHECKMATE-017a Based on stratified proportional hazards model.b Based on stratified log-rank test.c p-value is compared with 0.0315 of the allocated alpha for this interim analysis.d Based on the stratified Cochran-Mantel-Haenszel test.e Not ReachedIntravenous Nivolumab(n=135)Docetaxel(n=137)Overall Survival Deaths (%)86 (64%)113 (82%) Median (months) (95% CI)9.2(7.3, 13.3)6.0(5.1, 7.3) Hazard ratio (95% CI)a 0.59 (0.44, 0.79) p-valueb,c 0.0002Overall Response Rate27 (20%)12 (9%) (95% CI)(14, 28)(5, 15) p-valued 0.0083 Complete response1 (0.7%)0 Median duration of response (months) (95% CI)NRe (9.8, NRe)8.4 (3.6, 10.8)Progression-free Survival Disease progression or death (%)105 (78%)122 (89%) Median (months)3.52.8 Hazard ratio (95% CI)a 0.62 (0.47, 0.81) p-valueb 0.0004Figure 12: Overall Survival CHECKMATE-017Archival tumor specimens were retrospectively evaluated for PD-L1 expression. Across the trial population, 17% of 272 patients had non-quantifiable results. Among the 225 patients with quantifiable results, 47% had PD-L1 negative squamous NSCLC, defined as <1% of tumor cells expressing PD-L1 and 53% had PD-L1 positive squamous NSCLC defined as >=1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratios for survival were 0.58 (95% CI: 0.37, 0.92) in the PD-L1 negative subgroup and 0.69 (95% CI: 0.45, 1.05) in the PD-L1 positive subgroup.CHECKMATE-057CHECKMATE-057 (NCT01673867) was randomized (1:1), open-label trial in 582 patients with metastatic non-squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Appropriate prior targeted therapy in patients with known sensitizing EGFR mutation or ALK translocation was allowed. Patients received nivolumab mg/kg by intravenous infusion every weeks (n=292) or docetaxel 75 mg/m2 intravenously every weeks (n=290). Randomization was stratified by prior maintenance therapy (yes vs. no) and number of prior therapies (1 vs. 2). The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. The first tumor assessments were conducted weeks after randomization and continued every weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS. In addition, prespecified analyses were conducted in subgroups defined by PD-L1 expression.The trial population characteristics: median age was 62 years (range: 21 to 85) with 42% of patients >=65 years and 7% of patients >=75 years. The majority of patients were White (92%) and male (55%); the majority of patients were enrolled in Europe (46%) followed by the US/Canada (37%) and the rest of the world (17%). Baseline ECOG performance status was (31%) or (69%), 79% were former/current smokers, 3.6% had NSCLC with ALK rearrangement, 14% had NSCLC with EGFR mutation, and 12% had previously treated brain metastases. Prior therapy included platinum-doublet regimen (100%) and 40% received maintenance therapy as part of the first-line regimen. Histologic subtypes included adenocarcinoma (93%), large cell (2.4%), and bronchoalveolar (0.9%).CHECKMATE-057 demonstrated statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with docetaxel at the prespecified interim analysis when 413 events were observed (93% of the planned number of events for final analysis). Efficacy results are shown in Table 56 and Figure 13.Table 56: Efficacy Results CHECKMATE-057a Based on stratified proportional hazards model.b Based on stratified log-rank test.c p-value is compared with .0408 of the allocated alpha for this interim analysis.d Based on the stratified Cochran-Mantel-Haenszel test.e Not Reached.Intravenous Nivolumab(n=292)Docetaxel(n=290)Overall Survival Deaths (%)190 (65%)223 (77%) Median (months) (95% CI)12.2(9.7, 15.0)9.4(8.0, 10.7) Hazard ratio (95% CI)a 0.73 (0.60, 0.89) p-valueb,c 0.0015Overall Response Rate56 (19%)36 (12%) (95% CI)(15, 24)(9, 17) p-valued 0.02 Complete response4 (1.4%)1 (0.3%) Median duration of response (months) (95% CI)17(8.4, NRe)6(4.4, 7.0)Progression-free Survival Disease progression or death (%)234 (80%)245 (84%) Median (months)2.34.2 Hazard ratio (95% CI)a 0.92 (0.77, 1.11) p-valueb 0.39Figure 13: Overall Survival CHECKMATE-057Archival tumor specimens were evaluated for PD-L1 expression following completion of the trial. Across the trial population, 22% of 582 patients had non-quantifiable results. Of the remaining 455 patients, the proportion of patients in retrospectively determined subgroups based on PD-L1 testing using the PD-L1 IHC 28-8 pharmDx assay were: 46% PD-L1 negative, defined as <1% of tumor cells expressing PD-L1 and 54% had PD-L1 expression, defined as >=1% of tumor cells expressing PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% had >=1% but <5% tumor cells with positive staining, 7% had >=5% but <10% tumor cells with positive staining, and 67% had >=10% tumor cells with positive staining. Figures 14 and 15 summarize the results of prespecified analyses of OS and PFS in subgroups determined by percentage of tumor cells expressing PD-L1.Figure 14: Forest Plot: OS Based on PD-L1 Expression CHECKMATE-057Figure 15: Forest Plot: PFS Based on PD-L1 Expression CHECKMATE-057. oq-os-checkmate-017. oq-os-checkmate-057. oq-forest-plot-os-checkmate-057. oq-forest-plot-pfs-checkmate-057. 14.7Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck The effectiveness of OPDIVO QVANTIG has been established for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after platinum-based therapy. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this head and neck carcinoma population.CHECKMATE-141CHECKMATE-141 (NCT02105636) was randomized (2:1), active-controlled, open-label trial enrolling patients with metastatic or recurrent SCCHN who had experienced disease progression during or within months of receiving platinum-based therapy administered in either the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. The trial excluded patients with autoimmune disease, medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma), or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. Patients were randomized to receive nivolumab mg/kg by intravenous infusion every weeks or investigators choice of cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly).Randomization was stratified by prior cetuximab treatment (yes/no). The first tumor assessments were conducted weeks after randomization and continued every weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and ORR.A total of 361 patients were randomized; 240 patients to the intravenous nivolumab arm and 121 patients to the investigators choice arm (docetaxel: 45%; methotrexate: 43%; and cetuximab: 12%). The trial population characteristics were: median age was 60 years (range: 28 to 83) with 31% >=65 years of age, 83% were White, 12% Asian, and 4% were Black, and 83% male. Baseline ECOG performance status was (20%) or (78%), 76% were former/current smokers, 90% had Stage IV disease, 45% of patients received only one prior line of systemic therapy, the remaining 55% received two or more prior lines of systemic therapy, and 25% had HPVp16-positive tumors, 24% had HPV p16-negative tumors, and 51% had unknown status.The trial demonstrated statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with investigators choice at pre-specified interim analysis (78% of the planned number of events for final analysis). There were no statistically significant differences between the two arms for PFS (HR=0.89; 95% CI: 0.70, 1.13) or ORR (13.3% [95% CI: 9.3, 18.3] vs. 5.8% [95% CI: 2.4, 11.6] for nivolumab and investigators choice, respectively). Efficacy results are shown in Table 57 and Figure 16.Table 57: Overall Survival CHECKMATE-141a Based on stratified proportional hazards model.b Based on stratified log-rank test.c p-value is compared with 0.0227 of the allocated alpha for this interim analysis.Intravenous Nivolumab(n=240)Cetuximab, Methotrexate or Docetaxel(n=121)Overall Survival Deaths (%)133 (55%)85 (70%) Median (months) (95% CI)7.5(5.5, 9.1)5.1(4.0, 6.0) Hazard ratio (95% CI)a 0.70 (0.53, 0.92) p-valueb,c 0.0101Figure 16: Overall Survival CHECKMATE-141Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1 IHC 28-8 pharmDx assay. Across the trial population, 28% (101/361) of patients had non-quantifiable results. Among the 260 patients with quantifiable results, 43% (111/260) had PD-L1 negative SCCHN, defined as <1% of tumor cells expressing PD-L1, and 57% (149/260) had PD-L1 positive SCCHN, defined as >=1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratio for survival was 0.89 (95% CI: 0.54, 1.45) with median survivals of 5.7 and 5.8 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 negative subgroup. The HR for survival was 0.55 (95% CI: 0.36, 0.83) with median survivals of 8.7 and 4.6 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 positive SCCHN subgroup.. oq-os-checkmate-141. 14.8Urothelial Carcinoma Adjuvant Treatment of Urothelial Carcinoma (UC) at High Risk of Recurrence. The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of UC at high risk of recurrence. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this UC population.CHECKMATE-274CHECKMATE-274 (NCT02632409) was randomized, double-blind, placebo-controlled study of adjuvant intravenous nivolumab in patients who were within 120 days of radical resection (R0) of UC of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence. High risk of recurrence was defined as either 1) ypT2-ypT4a or ypN+ for patients who received neoadjuvant cisplatin or 2) pT3-pT4a or pN+ for patients who did not receive neoadjuvant cisplatin and who also either were ineligible for or refused adjuvant cisplatin. Patients were randomized 1:1 to receive nivolumab 240 mg or placebo by intravenous infusion every weeks until recurrence or until unacceptable toxicity for maximum treatment duration of year. Patients were stratified by pathologic nodal status (N+ vs. N0/x with <10 nodes removed vs. N0 with >=10 nodes removed), tumor cells expressing PD-L1 (>=1% vs. <1%/indeterminate as determined by the central lab using the PD-L1 IHC 28-8 pharmDx assay), and use of neoadjuvant cisplatin (yes vs. no).The trial population characteristics were: median age of 67 years (range: 30 to 92); 76% male; 76% White, 22% Asian, 0.7% Black, and 0.1% American Indian or Alaska Native. Of the 335 (47%) of patients with node-positive UC, 44 (6%) had non-muscle-invasive (<pT2) primary tumors. ECOG performance status was (63%), (35%), or (2%). Prior neoadjuvant cisplatin had been given to 43% of patients; of the 57% who did not receive prior neoadjuvant cisplatin, reasons listed were ineligibility (22%), patient preference (33%), and other/not reported (2%). Tumor PD-L1 expression was >=1% in 40% of patients, and 21% of patients had upper tract UC.The major efficacy outcome measures were investigator-assessed DFS in all randomized patients and in patients with tumors expressing PD-L1 >=1%. DFS was defined as time to first recurrence (local urothelial tract, local non-urothelial tract, or distant metastasis), or death. Additional efficacy outcome measures included OS.At the pre-specified interim analysis, CHECKMATE-274 demonstrated statistically significant improvement in DFS for patients randomized to intravenous nivolumab vs. placebo in the all randomized patient population, as well as in the subpopulation of patients with PD-L1 >=1%, as shown in Table 58 and Figure 17.In exploratory subgroup analyses in patients with upper tract UC (n=149), no improvement in DFS was observed in the nivolumab arm compared to the placebo arm. The unstratified DFS hazard ratio estimate was 1.15 (95% CI: 0.74, 1.80).In an exploratory subgroup analysis in patients with PD-L1 expression of <1% (n=414), the unstratified DFS hazard ratio estimate was 0.83 (95% CI: 0.64, 1.08).OS data is immature with 33% of deaths in the overall randomized population. In the UTUC subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm).Table 58: Efficacy Results CHECKMATE-274N.R. Not Reached, N.E. Not Estimablea Includes disease at baseline events (protocol deviations): n=1 in intravenous nivolumab arm and n=3 in placebo arm.b Based on Kaplan-Meier estimates.c Stratified Cox proportional hazard model. Hazard ratio is intravenous nivolumab over placebo.d Log-rank test stratified by prior neoadjuvant cisplatin, pathological nodal status, PD-L1 status (>=1% vs <1%/indeterminate). Boundary for statistical significance in all randomized patients: p-value <0.01784.e Log-rank test stratified by prior neoadjuvant cisplatin, pathological nodal status. Boundary for statistical significance in all randomized patients with PD-L1 >=1%: p-value <0.01282.All RandomizedPD-L1 >=1%Intravenous Nivolumab(n=353)Placebo(n=356)Intravenous Nivolumab(n=140)Placebo(n=142)Disease-free Survival Eventsa, (%) Local recurrence Distant recurrence Death170 (48)47 (13)108 (31)14 (4)204 (57)64 (18)127 (36)10 (3)55 (39)10 (7)40 (29)5 (4)81 (57)24 (17)52 (37)5 (4) Median DFS (months)b (95% CI)20.8(16.5, 27.6)10.8(8.3, 13.9)N.R.(21.2, N.E.)8.4(5.6, 21.2) Hazard ratioc (95% CI)0.70(0.57, 0.86)0.55(0.39, 0.77) p-value0.0008d 0.0005e Figure 17: Disease-free Survival in All Randomized Patients CHECKMATE-274. oq-dfs-checkmate-274. First-line Treatment of Unresectable or Metastatic UC. The effectiveness of OPDIVO QVANTIG has been established for the first-line treatment of unresectable or metastatic UC in combination with cisplatin and gemcitabine. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this UC population.CHECKMATE-901CHECKMATE-901 (NCT 03036098) was randomized, open-label study in patients with previously untreated unresectable or metastatic UC. Prior neoadjuvant or adjuvant chemotherapy were permitted as long as the disease recurrence took place >=12 months from completion of therapy. Patients who were ineligible for cisplatin and those with active CNS metastases were excluded. Stratification factors for randomization were PD-L1 status (>=1% vs. <1% or indeterminate) and liver metastasis. Patients were randomized 1:1 to receive either:oIntravenous nivolumab 360 mg and cisplatin 70 mg/m2 on Day and gemcitabine 1000 mg/m2 on Days and of 21-day cycle of 21-day cycle for up to cycles followed by single-agent intravenous nivolumab 480 mg every weeks until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, intravenous nivolumab was continued for up to years from first dose.oCisplatin 70 mg/m2 on Day and gemcitabine 1000 mg/m2 on Days and of 21-day cycle for up to cycles, until disease progression or unacceptable toxicity.The major efficacy outcome measures were OS and PFS as assessed by BICR using RECIST v1.1. Additional efficacy outcome measures included ORR as assessed by BICR.The median age was 65 years of age (range: 32 to 86) with 51% of patients >=65 years of age and 12% of patients >=75 years of age, 23% were Asian, 72% were White, 0.3% were Black, 0.3% were American Indian or Alaska Native, 4.9% were Other, 12% were Hispanic or Latino, and 77% were male. Baseline ECOG performance status was (53%) or (46%). At baseline, 87% of patients had metastatic UC, including 20% with liver metastases, 11% had locally advanced UC, and 51% had UC histologic variants. Forty-nine (16%) in the intravenous nivolumab in combination with cisplatin-based chemotherapy arm and 43 (14%) in the cisplatin-based chemotherapy arm switched from cisplatin to carboplatin after at least one cycle of cisplatin.Efficacy results are presented in Table 59 and Figures 18 and 19.Table 59: Efficacy Results CHECKMATE-901a Based on Kaplan-Meier Estimates.b Stratified Cox proportional hazard model.c sided values from stratified log-rank test.d Assessed by BICR.Intravenous Nivolumab and Cisplatin and Gemcitabine(n=304)Cisplatin and Gemcitabine (n=304)Overall Survival (OS) Events, (%)172 (56.6)193 (63.5) Median (months) (95% CI)a 21.7(18.6, 26.4)18.9(14.7, 22.4) Hazard ratio (95% CI)b 0.78(0.63, 0.96) p-valuec 0.0171Progression-free Survival (PFS)d Events, (%)211 (69.4)191 (62.8) Median (months) (95% CI)a 7.9(7.6, 9.5)7.6(6.0, 7.8) Hazard ratio (95% CI)b 0.72(0.59, 0.88) p-valuec 0.0012Objective Response Rate (ORR)d Response rate, (%) (95% CI)175 (57.6%)(51.8, 63.2)131 (43.1%)(37.5, 48.9) Complete response rate, (%) 66 (22%)36 (12%) Partial response rate, (%)109 (36%)95 (31%)Duration of Response (DoR) Median (months) (95% CI)a 9.5(7.6, 15.1)7.3(5.7, 8.9)Figure 18: Overall Survival CHECKMATE-901Figure 19: Progression-free Survival CHECKMATE-901. oIntravenous nivolumab 360 mg and cisplatin 70 mg/m2 on Day and gemcitabine 1000 mg/m2 on Days and of 21-day cycle of 21-day cycle for up to cycles followed by single-agent intravenous nivolumab 480 mg every weeks until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, intravenous nivolumab was continued for up to years from first dose.. oCisplatin 70 mg/m2 on Day and gemcitabine 1000 mg/m2 on Days and of 21-day cycle for up to cycles, until disease progression or unacceptable toxicity.. oq-os-checkmate-901. oq-pfs-checkmate-901. Previously Treated Advanced or Metastatic Urothelial Carcinoma. The effectiveness of OPDIVO QVANTIG has been established for the treatment of patients with locally advanced or metastatic UC and disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this UC population.CHECKMATE-275CHECKMATE-275 (NCT02387996) was single-arm trial in 270 patients with locally advanced or metastatic UC who had disease progression during or following platinum-containing chemotherapy or who had disease progression within 12 months of treatment with platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients were excluded for active brain or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, and ECOG performance status >1. Patients received nivolumab mg/kg by intravenous infusion every weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every weeks for the first 48 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed ORR as assessed by IRRC using RECIST v1.1 and DOR.The median age was 66 years (range: 38 to 90), 78% were male, 86% were White. Twenty-seven percent had non-bladder urothelial carcinoma and 84% had visceral metastases. Thirty-four percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy. Twenty-nine percent of patients had received >=2 prior systemic regimens in the metastatic setting. Thirty-six percent of patients received prior cisplatin only, 23% received prior carboplatin only, and 7% were treated with both cisplatin and carboplatin in the metastatic setting. Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent of patients had hemoglobin <10 g/dL, and twenty-eight percent of patients had liver metastases at baseline. Patients were included regardless of their PD-L1 status.Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 270 patients, 46% were defined as having PD-L1 expression of >=1% (defined as >=1% of tumor cells expressing PD-L1). The remaining 54% of patients were classified as having PD-L1 expression of <1% (defined as <1% of tumor cells expressing PD-L1). Confirmed ORR in all patients and the two PD-L1 subgroups are shown in Table 60. Median time to response was 1.9 months (range: 1.6-7.2). In 77 patients who received prior systemic therapy only in the neoadjuvant or adjuvant setting, the ORR was 23.4% (95% CI: 14.5%, 34.4%).Table 60: Efficacy Results CHECKMATE-275a Estimated from the Kaplan-Meier Curve.b Not Reached.All PatientsN=270PD-L1 <1%N=146PD-L1 >=1%N=124Confirmed Overall Response Rate, (%) (95% CI)53 (19.6%)(15.1, 24.9)22 (15.1%)(9.7, 21.9)31 (25.0%)(17.7, 33.6) Complete response rate (2.6%)1 (0.7%)6 (4.8%) Partial response rate 46 (17.0%)21 (14.4%)25 (20.2%)Median Duration of Responsea (months) (range)10.3 (1.9+, 12.0+)7.6 (3.7, 12.0+)NRb (1.9+, 12.0+). 14.9Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer The effectiveness of OPDIVO QVANTIG has been established for the treatment of microsatellite instability-high or mismatch repair deficient colorectal cancer (CRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab (CHECKMATE-142, NCT02060188), and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this CRC population.OPDIVO QVANTIG is not indicated for the treatment of pediatric patients. CHECKMATE-142CHECKMATE-142 (NCT02060188) was multicenter, non-randomized, multiple parallel-cohort, open-label trial conducted in patients with locally determined dMMR or MSI-H metastatic CRC (mCRC) who had disease progression during or after prior treatment with fluoropyrimidine- oxaliplatin- or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line of treatment for metastatic disease, ECOG performance status or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression.Patients enrolled in the single agent intravenous nivolumab MSI-H mCRC cohort received nivolumab mg/kg by intravenous infusion (IV) every weeks. Patients enrolled in the intravenous nivolumab and ipilimumab MSI-H mCRC cohort received nivolumab mg/kg and ipilimumab mg/kg intravenously every weeks for doses, followed by nivolumab as single agent at dose of mg/kg as intravenous infusion every weeks. Treatment in both cohorts continued until unacceptable toxicity or radiographic progression.Tumor assessments were conducted every weeks for the first 24 weeks and every 12 weeks thereafter. Efficacy outcome measures included ORR and DOR as assessed by BICR using RECIST v1.1.A total of 74 patients were enrolled in the single-agent MSI-H mCRC intravenous nivolumab cohort. The median age was 53 years (range: 26 to 79) with 23% >=65 years of age and 5% >=75 years of age, 59% were male and 88% were White. Baseline ECOG performance status was (43%), (55%), or (1.4%) and 36% were reported to have Lynch Syndrome. Across the 74 patients, 72% received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan; 7%, 30%, 28%, 19%, and 16% received 0, 1, 2, 3, or >=4 prior lines of therapy for metastatic disease, respectively, and 42% of patients had received an anti-EGFR antibody.A total of 119 patients were enrolled in the intravenous nivolumab and ipilimumab MSI-H mCRC cohort. The median age was 58 years (range: 21 to 88), with 32% >=65 years of age and 9% >=75 years of age; 59% were male and 92% were White. Baseline ECOG performance status was (45%) and (55%), and 29% were reported to have Lynch Syndrome. Across the 119 patients, 69% had received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%, 24%, and 15% received 1, 2, 3, or >=4 prior lines of therapy for metastatic disease, respectively, and 29% had received an anti-EGFR antibody.Efficacy results for each of these single-arm cohorts are shown in Table 61.Table 61: Efficacy Results CHECKMATE-142a Minimum follow-up 33.7 months for all patients treated with intravenous nivolumab (n=74).b Minimum follow-up 27.5 months for all patients treated with intravenous nivolumab and ipilimumab (n=119).c Estimated using the Clopper-Pearson method.Intravenous Nivolumaba MSI-H/dMMR CohortIntravenous Nivolumab and Ipilimumabb MSI-H/dMMR CohortAll Patients(n=74)Prior Treatment (Fluoropyrimidine, Oxaliplatin, and Irinotecan)(n=53)All Patients(n=119)Prior Treatment (Fluoropyrimidine, Oxaliplatin, and Irinotecan)(n=82)Overall Response Rate per BICR; (%)28 (38%)17 (32%)71 (60%)46 (56%) (95% CI)c (27, 50)(20, 46)(50, 69)(45, 67) Complete Response (%)8 (11%)5 (9%)17 (14%)11 (13%) Partial Response (%)20 (27%)12 (23%)54 (45%)35 (43%)Duration of Response Proportion of responders with >=6 months response duration86%94%89%87% Proportion of responders with >=12 months response duration82%88%77%74%. 14.10Hepatocellular Carcinoma The effectiveness of OPDIVO QVANTIG has been established for the treatment of hepatocellular carcinoma in patients who have been previously treated with sorafenib and following treatment with intravenous nivolumab and ipilimumab. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this hepatocellular carcinoma population.CHECKMATE-040CHECKMATE-040 (NCT01658878) was multicenter, multiple cohort, open-label trial that evaluated the efficacy of intravenous nivolumab as single agent and in combination with ipilimumab in patients with hepatocellular carcinoma (HCC) who progressed on or were intolerant to sorafenib. Additional eligibility criteria included histologic confirmation of HCC and Child-Pugh Class cirrhosis. The trial excluded patients with active autoimmune disease, brain metastasis, history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co-infection with hepatitis virus (HBV) and hepatitis virus (HCV) or HBV and hepatitis virus (HDV); however, patients with only active HBV or HCV were eligible.Tumor assessments were conducted every weeks for 48 weeks and then every 12 weeks thereafter. The major efficacy outcome measure was confirmed overall response rate as assessed by BICR using RECIST v1.1 and modified RECIST (mRECIST) for HCC. Duration of response was also assessed.The efficacy of intravenous nivolumab in combination with ipilimumab was evaluated in 49 patients (Cohort 4) who received intravenous nivolumab mg/kg and ipilimumab mg/kg administered every weeks for doses, followed by single-agent intravenous nivolumab at 240 mg every weeks until disease progression or unacceptable toxicity. The median age was 60 years (range: 18 to 80), 88% were male, 74% were Asian, and 25% were White. Baseline ECOG performance status was (61%) or (39%). Fifty-seven (57%) percent of patients had active HBV infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The etiology for HCC was alcoholic liver disease in 16% and non-alcoholic fatty liver disease in 6% of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had extrahepatic spread; 35% had vascular invasion; and 51% had AFP levels >=400 ug/L. Prior cancer treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of patients had received or more prior systemic therapies.Efficacy results are shown in Table 62. The results for intravenous nivolumab in combination with ipilimumab in Cohort are based on minimum follow-up of 28 months. Table 62: Efficacy Results Cohort of CHECKMATE-040a Confirmed by BICR.b Confidence interval is based on the Clopper and Pearson method.Intravenous Nivolumab and Ipilimumab(Cohort 4)(n=49)Overall Response Rate per BICR,a (%), RECIST v1.116 (33%) (95% CI)b (20, 48) Complete response4 (8%) Partial response12 (24%)Duration of Response per BICR,a RECIST v1.1n=16 Range (months)4.6, 30.5+ Percent with duration >=6 months88% Percent with duration >=12 months56% Percent with duration >=24 months31%Overall Response Rate per BICR,a (%), mRECIST17 (35%) (95% CI)b (22, 50) Complete response (12%) Partial response11 (22%). 14.11Esophageal Cancer Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer. The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of resected esophageal or gastroesophageal junction cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy (CRT). Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this esophageal or gastroesophageal junction cancer population.CHECKMATE-577CHECKMATE-577 (NCT02743494) was randomized, multicenter, double-blind trial in 794 patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following concurrent chemoradiotherapy (CRT). Patients were randomized (2:1) to receive either nivolumab 240 mg or placebo by intravenous infusion over 30 minutes every weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every weeks beginning at week 17. Treatment was until disease recurrence, unacceptable toxicity, or for up to year in total duration. Enrollment required complete resection within to 16 weeks prior to randomization. The trial excluded patients who did not receive CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Randomization was stratified by tumor PD-L1 status (>=1% vs. <1% or indeterminate or non-evaluable), pathologic lymph node status (positive >=ypN1 vs. negative ypN0), and histology (squamous vs. adenocarcinoma). The major efficacy outcome measure was disease-free survival (DFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant from the primary resected site) or death, from any cause, whichever occurred first as assessed by the investigator prior to subsequent anti-cancer therapy. Patients on treatment underwent imaging for tumor recurrence every 12 weeks for years, and minimum of one scan every to 12 months for years to 5.The trial population characteristics were: median age 62 years (range: 26 to 86), 36% were >=65 years of age, 85% were male, 15% were Asian, 82% were White, and 1.1% were Black. Disease characteristics were AJCC Stage II (35%) or Stage III (65%) at initial diagnosis carcinoma, EC (60%) or GEJC (40%) at initial diagnosis, with pathologic positive lymph node status (58%) at study entry and histological confirmation of predominant adenocarcinoma (71%) or squamous cell carcinoma (29%). The baseline Tumor PD-L1 status >=1% was positive for 16% of patients and negative for 72% of patients. Baseline ECOG performance status was (58%) or (42%).CHECKMATE-577 demonstrated statistically significant improvement in DFS for patients randomized to the intravenous nivolumab arm as compared with the placebo arm. DFS benefit was observed regardless of tumor PD-L1 expression and histology.Efficacy results are shown in Table 63 and Figure 20.Table 63: Efficacy Results CHECKMATE-577a Based on stratified proportional hazards model.b Based on stratified log-rank test.Intravenous Nivolumab(n=532)Placebo(n=262)Disease-free Survival Number of events, (%)241 (45%)155 (59%) Median (months) (95% CI)22.4(16.6, 34.0)11.0(8.3, 14.3) Hazard ratioa (95% CI)0.69 (0.56, 0.85) p-valueb 0.0003Figure 20: Disease-free Survival CHECKMATE-577. oq-dfs-checkmate-577. First-line Treatment of Unresectable Advanced or Metastatic Esophageal Squamous Cell Carcinoma (ESCC) Whose Tumors Express PD-L1 (>=1). The effectiveness of OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapy has been established for the first-line treatment of unresectable advanced or metastatic ESCC. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this esophageal squamous cell carcinoma population.CHECKMATE-648CHECKMATE-648 (NCT03143153) was randomized, active-controlled, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC (squamous or adenosquamous histology). The trial enrolled patients whose tumor was evaluable for tumor cell (TC) PD-L1 expression [also called PD-L1 tumor proportion score (TPS)], which was evaluated using the PD-L1 IHC 28-8 pharmDx assay at central laboratory. retrospective scoring of patients tumor PD-L1 status using Combined Positive Score (CPS), was also conducted using the PD-L1-stained tumor specimens used for randomization. Patients were not amenable to chemoradiation or surgery with curative intent. Prior treatment with curative intent was allowed if completed more than six months prior to trial enrollment. The trial excluded patients with brain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to apparent invasion of tumor to organs adjacent to the esophageal tumor. Patients were randomized to receive one of the following treatments:oIntravenous nivolumab 240 mg on days and 15, fluorouracil 800 mg/m2/day intravenously on days through (for days), and cisplatin 80 mg/m2 intravenously on day (of 4-week cycle).oIntravenous nivolumab mg/kg every weeks in combination with ipilimumab mg/kg every weeks.oFluorouracil 800 mg/m2/day intravenously on days through (for days), and cisplatin 80 mg/m2 intravenously on day (of 4-week cycle).Patients received intravenous nivolumab until disease progression, unacceptable toxicity, or up to years. In patients who received intravenous nivolumab in combination with chemotherapy and in whom either fluorouracil and/or cisplatin were discontinued, other components of the treatment regimen were allowed to be continued. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue intravenous nivolumab as single agent.Randomization was stratified by TC PD-L1 expression (>=1% vs. <1% or indeterminate), region (East Asia vs. Rest of Asia vs. Rest of World), ECOG performance status (0 vs. 1), and number of organs with metastases (<=1 vs. >=2). The major efficacy outcome measures were OS and BICR-assessed PFS in patients with TC PD-L1 expression >=1%. Additional efficacy measures included OS in all randomized patients, BICR-assessed PFS in all randomized patients, and ORR assessed by BICR in TC PD-L1 expression >=1% and in all randomized patients. The tumor assessments per RECIST v1.1 were conducted every weeks up to and including week 48, then every 12 weeks thereafter.A total of 970 patients were randomized in CHECKMATE-648 study among whom 965 and 906 patients had quantifiable TC PD-L1 expression and CPS at baseline, respectively; 85% (824/970) had tumors with PD-L1 CPS >=1. The trial population characteristics in patients with PD-L1 CPS >=1 were median age 63 years (range: 26 to 90), 46% were >=65 years of age, 82% were male, 71% were Asian, 25% were White, and 1.2% were Black or African American. Patients had histological confirmation of squamous cell carcinoma (99%) or adenosquamous cell carcinoma (1.7%) in the esophagus. Baseline ECOG performance status was (44.0%) or (54%).A statistically significant improvement in OS was demonstrated in patients randomized to intravenous nivolumab in combination with chemotherapy and patients randomized to intravenous nivolumab in combination with ipilimumab compared with chemotherapy. An exploratory analysis of OS in patients with PD-L1 CPS <1 showed HR of 0.98 (95% CI 0.50, 1.95) for the comparison of intravenous nivolumab in combination with chemotherapy, and the exploratory analysis OS in patients with PD-L1 CPS <1 showed HR of 1.0 (95% CI 0.52, 1.94) for the comparison of intravenous nivolumab in combination with ipilimumab; these results indicate that the improvement in the ITT population was primarily attributed to the results observed in the subgroup of patients with PD-L1 CPS >=1. Efficacy results are shown in Table 64 and Figures 21 and 22.Table 64: Efficacy Results CHECKMATE-648a Assessed by BICR.b Based on stratified Cox proportional hazard model. Hazard ratios are reported for each intravenous nivolumab containing arm compared to chemotherapy within each analysis population.c Based on stratified 2-sided log-rank test.S1, S2, S3 Significant p-value compared to stopping boundary of 0.005, 0.014, and 0.015, respectively.NS: Not Statistically significant, NT: Not evaluated for statistical significance as per pre-specified hierarchical testing procedure.Intravenous Nivolumab with Cisplatin and Fluorouracil(n=158)Intravenous Nivolumab and Ipilimumab(n=158)Cisplatin and Fluorouracil(n=157)Intravenous Nivolumab with Cisplatin and Fluorouracil(n=278)Intravenous Nivolumab and Ipilimumab(n=266)Cisplatin and Fluorouracil(n=280)TC PD-L1 expression >=1%PD-L1 CPS >=1Overall Survival Deaths (%)98 (62)106 (67)121 (77)177 (64)179 (67)205 (73) Median (months) (95% CI)15.4(11.9, 19.5)13.7(11.2, 17.0)9.1(7.7, 10)13.8(12.0, 16.1)12.7(10.9, 15.5)9.8(8.8, 11.6) Hazard ratio (95% CI)b 0.54(0.41, 0.71)0.64(0.49, 0.84)-0.69(0.57, 0.85)0.76(0.62, 0.93)- p-valuec <0.0001S1 0.0010S2 ----Progression-free Survivala Disease progression or death (%)117 (74)123 (78)100 (64)201 (72)206 (77)184 (66) Median (months) (95% CI)6.9(5.7, 8.3)4.0(2.4, 4.9)4.4(2.9, 5.8)5.8(5.5, 7.0)2.8(2.6, 4.2)5.6(4.2, 5.9) Hazard ratio(95% CI)b 0.65(0.49, 0.86)1.02(0.78, 1.34)-0.8(0.7, 1.0)1.2(1.0, 1.5)- p-valuec 0.0023S3 NS----Overall Response Rate, (%)a, NT 84 (53.2)56 (35.4)31 (19.7)135 (49)74 (28)76 (27) (95% CI)(45.1, 61.1)(28.0, 43.4)(13.8, 26.8)(42.5, 54.6)(22.5, 33.6)(22.0, 32.8) Complete response (%)26 (16.5)28 (17.7)8 (5.1)39 (14)32 (12.0)18 (6.4) Partial response (%)58 (36.7)28 (17.7)23 (14.6)96 (35)42 (15.8)58 (20.7)Duration of Response (months)a Median (95% CI)8.4(6.9, 12.4)11.8(7.1, 27.4)5.7(4.4, 8.7)8.2(6.7, 11.1)11.8(7.1, 23.6)6.9(5.7, 8.2) Range1.4+, 34.61.4+, 34.5+1.4+, 31.8+1.4+, 35.9+1.4+, 34.5+1.4+, 31.8+Figure 21: Overall Survival CHECKMATE-648 (A) OS in CPS >=1 (B) OS in TC PD-L1 >=1%Figure 22: Progression-free Survival CHECKMATE-648 (A) PFS in CPS >=1 (B) PFS in TC PD-L1 >=1%. oIntravenous nivolumab 240 mg on days and 15, fluorouracil 800 mg/m2/day intravenously on days through (for days), and cisplatin 80 mg/m2 intravenously on day (of 4-week cycle).. oIntravenous nivolumab mg/kg every weeks in combination with ipilimumab mg/kg every weeks.. oFluorouracil 800 mg/m2/day intravenously on days through (for days), and cisplatin 80 mg/m2 intravenously on day (of 4-week cycle).. (A) OS in CPS >=1. (B) OS in TC PD-L1 >=1%. (A) PFS in CPS >=1. (B) PFS in TC PD-L1 >=1%. A-OS in CPS CHECKMATE 648.jpg. B-OS in TC PD L1 CHECKMATE 648.jpg. A-PFS in CPS CHECKMATE 648.jpg. B-PFS in TC PD L1 CHECKMATE 648.jpg. Previously Treated Unresectable Advanced, Recurrent or Metastatic ESCC. The effectiveness of OPDIVO QVANTIG has been established for the treatment of unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this ESCC population.ATTRACTION-3ATTRACTION-3 (NCT02569242) was multicenter, randomized (1:1), active-controlled, open-label trial in patients with unresectable advanced, recurrent, or metastatic ESCC, who were refractory or intolerant to at least one fluoropyrimidine- and platinum-based regimen. The trial enrolled patients regardless of PD-L1 status, but tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at central laboratory. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, or had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients were randomized to receive nivolumab 240 mg by intravenous infusion over 30 minutes every weeks or investigators choice of taxane chemotherapy consisting of docetaxel (75 mg/m2 intravenously every weeks) or paclitaxel (100 mg/m2 intravenously once week for weeks followed by week off).Randomization was stratified by region (Japan vs. Rest of World), number of organs with metastases (<=1 vs. >=2), and PD-L1 status (>=1% vs. <1% or indeterminate). Patients were treated until disease progression, assessed by the investigator per RECIST v1.1, or unacceptable toxicity. The tumor assessments were conducted every weeks for year, and every 12 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were ORR and PFS as assessed by the investigator using RECIST v1.1 and DOR.A total of 419 patients were randomized; 210 to the intravenous nivolumab arm and 209 to the investigators choice arm (docetaxel: 31%, paclitaxel: 69%). The trial population characteristics were: median age 65 years (range: 33 to 87), 53% were >=65 years of age, 87% were male, 96% were Asian and 4% were White. Sixty-seven percent of patients had received one prior systemic therapy regimen and 26% had received two prior systemic therapy regimens prior to enrolling in ATTRACTION-3. Baseline ECOG performance status was (50%) or (50%).ATTRACTION-3 demonstrated statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with investigators choice of taxane chemotherapy. OS benefit was observed regardless of PD-L1 expression level. OS results by PD-L1 CPS level (<1 and >=1) were not studied. The minimum follow-up was 17.6 months. Efficacy results are shown in Table 65 and Figure 23.Table 65: Efficacy Results ATTRACTION-3a Based on ITT analysis.b Based on stratified proportional hazards model.c Based on stratified log-rank test.d Based on Response Evaluable Set (RES) analysis, n=171 in intravenous nivolumab group and n=158 in investigators choice group.e Based on stratified Cochran-Mantel-Haenszel test; p-value not significant.f PFS not tested due to pre-specified hierarchical testing strategy.Intravenous Nivolumab(n=210)Docetaxel or Paclitaxel(n=209)Overall Survivala Deaths (%)160 (76%)173 (83%) Median (months) (95% CI)10.9(9.2, 13.3)8.4(7.2, 9.9) Hazard ratio (95% CI)b 0.77 (0.62, 0.96) p-valuec 0.0189Overall Response Rated 33 (19.3)34 (21.5) (95% CI)(13.7, 26.0)(15.4, 28.8) Complete response (%)1 (0.6)2 (1.3) Partial response (%)32 (18.7)32 (20.3) Median duration of response (months) (95% CI)6.9(5.4, 11.1)3.9(2.8, 4.2) p-valuee 0.6323Progression-free Survivala, Disease progression or death (%)187 (89)176 (84) Median (months) (95% CI)1.7(1.5, 2.7)3.4(3.0, 4.2) Hazard ratio (95% CI)b 1.1 (0.9, 1.3)Figure 23: Overall Survival ATTRACTION-3Of the 419 patients, 48% had PD-L1 positive ESCC, defined as >=1% of tumor cells expressing PD-L1. The remaining 52% had PD-L1 negative ESCC defined as <1% of tumor cells expressing PD-L1.In pre-specified exploratory analysis by PD-L1 status, the hazard ratio (HR) for OS was 0.69 (95% CI: 0.51, 0.94) with median survivals of 10.9 and 8.1 months for the intravenous nivolumab and investigators choice arms, respectively, in the PD-L1 positive subgroup. In the PD-L1 negative subgroup, the HR for OS was 0.84 (95% CI: 0.62, 1.14) with median survivals of 10.9 and 9.3 months for the intravenous nivolumab and investigators choice arms, respectively.. oq-os-attraction-3. 14.12Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma Whose Tumors Express PD-L1 (>=1) The effectiveness of OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapy has been established for the treatment of gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is description of the efficacy results of the adequate and well-controlled study of intravenous nivolumab in this population.CHECKMATE-649CHECKMATE-649 (NCT02872116) was randomized, multicenter, open-label trial in patients (n=1581) with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. The trial enrolled patients regardless of PD-L1 status, and tumor specimens were evaluated using the PD-L1 IHC 28-8 pharmDx assay at central laboratory (tumor cell [TC] and Combined Positive Score [CPS]). The trial excluded patients who were known human epidermal growth factor receptor (HER2) positive, or had untreated CNS metastases. Patients were randomized to receive intravenous nivolumab in combination with chemotherapy (n=789) or chemotherapy (n=792). Patients received one of the following treatments:oIntravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every weeks or mFOLFOX6 every weeks.oIntravenous nivolumab 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every weeks or CapeOX every weeks.Patients were treated until disease progression, unacceptable toxicity, or up to years. In patients who received intravenous nivolumab in combination with chemotherapy and in whom chemotherapy was discontinued, intravenous nivolumab monotherapy was allowed to be given at 240 mg every weeks, 360 mg every weeks, or 480 mg every weeks up to years after treatment initiation.Randomization was stratified by tumor cell PD-L1 status (>=1% vs. <1% or indeterminate), region (Asia vs. US vs. Rest of World), ECOG performance status (0 vs. 1), and chemotherapy regimen (mFOLFOX6 vs. CapeOX). The major efficacy outcome measures, assessed in patients with PD-L1 CPS >=5, were PFS assessed by BICR and OS. Additional efficacy outcome measures included OS and PFS in patients with PD-L1 CPS >=1 and in all randomized patients, and ORR and DOR as assessed by BICR in patients with PD-L1 CPS >=1 and >=5, and in all randomized patients. Tumor assessments were conducted per RECIST v1.1 every weeks up to and including week 48, then every 12 weeks thereafter.A total of 1581 patients were randomized in the CHECKMATE-649 study, among whom 1296 and 955 had baseline PD-L1 CPS >=1 and CPS >=5, respectively. The trial population characteristics in patients with PD-L1 CPS >=1 were: median age 62 years (range: 18 to 90), 40% were >=65 years of age, 72% were male, 23% were Asian, and 69% were White, and 1% were Black or African American. Baseline ECOG performance status was (42%) or (58%). Seventy percent of patients had adenocarcinoma tumors in the stomach, 17% in the gastroesophageal junction, and 13% in the esophagus.CHECKMATE-649 demonstrated statistically significant improvement in OS and PFS for patients with PD-L1 CPS >=5. Statistically significant improvement in OS was also demonstrated for all randomized patients and patients with PD-L1 CPS >=1. Exploratory analysis of OS in the CPS <1 population showed hazard ratio of 0.85 (95% CI: 0.63, 1.15), indicating that the improvement in the ITT population was primarily attributed to the results observed in the subgroup of patients with PD-L1 CPS >=1. The minimum follow-up was 12.1 months. Efficacy results are shown in Table 66 and Figures 24 and 25.Table 66: Efficacy Results CHECKMATE-649a Based on stratified Cox proportional hazard model.b Based on stratified log-rank test.c Assessed by BICR.d Based on confirmed response.e Not evaluated for statistical significance.Intravenous Nivolumab and mFOLFOX6or CapeOX(n=641)mFOLFOX6or CapeOX(n=655)Intravenous Nivolumab and mFOLFOX6or CapeOX(n=473)mFOLFOX6or CapeOX (n=482)PD-L1 CPS >=1PD-L1 CPS >=5Overall SurvivalDeaths (%)434 (68)492 (75)309 (65)362 (75)Median (months)(95% CI)14.0(12.6, 15.0)11.3(10.6, 12.3)14.4(13.1, 16.2)11.1(10.0, 12.1)Hazard ratio (95% CI)a 0.77 (0.68, 0.88)0.71 (0.61, 0.83)p-valueb <0.0001<0.0001Progression-free Survivalc Disease progression or death (%)454 (70.8)472 (72.1)328 (69.3)350 (72.6)Median (months)(95% CI)7.5(7.0, 8.4)6.9(6.1, 7.0)7.7(7.0, 9.2)6.0(5.6, 6.9)Hazard ratio (95% CI)a 0.74 (0.65, 0.85)0.68 (0.58, 0.79)p-valueb -e <0.0001Overall Response Rate, (%)c,d 314 (49)249 (38)237 (50)184 (38)(95% CI)(45, 53)(34, 42)(46, 55)(34, 43)Complete response (%)65 (10)42 (6)55 (12)34 (7)Partial response (%)249 (39)207 (32)182 (38)150 (31)Duration of Response (months)c,d Median(95% CI)Range8.5(7.7, 10.3)1.1+, 29.6+6.9(5.8, 7.6)1.2+, 30.8+9.5(8.1, 11.9)1.1+, 29.6+6.9(5.6, 7.9)1.2+, 30.8+Figure 24: Overall Survival (PD-L1 CPS >=1) CHECKMATE-649Figure 25: Overall Survival (PD-L1 CPS >=5) CHECKMATE-649An exploratory analysis of OS in the 44 patients with MSI-H tumors showed HR of 0.37 (95% CI: 0.16, 0.87).. oIntravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every weeks or mFOLFOX6 every weeks.. oIntravenous nivolumab 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every weeks or CapeOX every weeks.. oq-os-pd-l1-cps-greater-than-1-checkmate-649. oq-os-pd-l1-cps-greater-than-5-checkmate-649.

SPL MEDGUIDE SECTION.

Medication Guide MEDICATION GUIDEOPDIVO QVANTIG(TM) (op-DEE-voh cue-VAN-tig)(nivolumab and hyaluronidase-nvhy)injection, for subcutaneous useRead this Medication Guide before you start receiving OPDIVO QVANTIG and before each injection. There may be new information. If your healthcare provider prescribes OPDIVO QVANTIG in combination with cabozantinib, also read the Patient Information that comes with cabozantinib. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.What is the most important information should know about OPDIVO QVANTIGOPDIVO QVANTIG is medicine that may treat certain cancers by working with your immune system. OPDIVO QVANTIG can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. You may have more than one of these problems at the same time. Some of these problems may happen more often when OPDIVO QVANTIG is used in combination with another therapy.Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including:Lung problems.ocoughoshortness of breathochest painIntestinal problems.odiarrhea (loose stools) or more frequent bowel movements than usualostools that are black, tarry, sticky, or have blood or mucusosevere stomach-area (abdominal) pain or tendernessLiver problems.oyellowing of your skin or the whites of your eyesosevere nausea or vomitingopain on the right side of your stomach area (abdomen)odark urine (tea colored)obleeding or bruising more easily than normalHormone gland problems.oheadaches that will not go away or unusual headachesoeye sensitivity to lightoeye problemsorapid heartbeat oincreased sweatingoextreme tirednessoweight gain or weight lossofeeling more hungry or thirsty than usualourinating more often than usualohair lossofeeling coldoconstipationoyour voice gets deeperodizziness or faintingochanges in mood or behavior, such as decreased sex drive, irritability, or forgetfulnessKidney problems.odecrease in your amount of urineoblood in your urineoswelling of your anklesoloss of appetiteSkin problems.orashoitchingoskin blistering or peelingoswollen lymph nodesopainful sores or ulcers in mouth or nose, throat, or genital areaofever or flu-like symptomsProblems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with OPDIVO QVANTIG. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include:ochest pain, irregular heartbeat, shortness of breath or swelling of anklesoconfusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legsodouble vision, blurry vision, sensitivity to light, eye pain, changes in eyesightopersistent or severe muscle pain or weakness, muscle crampsolow red blood cells, bruisingRejection of transplanted organ or tissue. Your healthcare provider should tell you what signs and symptoms you should report and monitor you depending on the type of organ or tissue transplant that you have had.Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during treatment with OPDIVO QVANTIG. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with OPDIVO QVANTIG, if you have severe side effects.What is OPDIVO QVANTIGOPDIVO QVANTIG is prescription medicine used to treat adults with:oa type of kidney cancer that has spread called advanced renal cell carcinoma (RCC).oOPDIVO QVANTIG may be used alone as first treatment in certain people with advanced RCC, after completing combination treatment with nivolumab given into the vein (intravenous nivolumab) and ipilimumab.oOPDIVO QVANTIG may be used in combination with cabozantinib as your first treatment for advanced RCC.oOPDIVO QVANTIG may be used alone when your cancer has spread after treatment with other cancer medicines.oa type of skin cancer called melanoma.oOPDIVO QVANTIG may be used alone to treat melanoma that has spread or cannot be removed by surgery (advanced melanoma).oOPDIVO QVANTIG may be used alone to treat melanoma that has spread or cannot be removed by surgery (advanced melanoma), after completing combination treatment with intravenous nivolumab and ipilimumab.oOPDIVO QVANTIG may be used alone to help prevent Stage IIB, Stage IIC, Stage III, or Stage IV melanoma from coming back after it has been completely removed by surgery.oa type of lung cancer called non-small cell lung cancer (NSCLC).oOPDIVO QVANTIG may be used in combination with chemotherapy that contains platinum and another chemotherapy medicine before you have surgery for early-stage NSCLC.oOPDIVO QVANTIG may be used in combination with chemotherapy that contains platinum and another chemotherapy medicine before you have surgery for early-stage NSCLC:that does not have an abnormal EGFR or ALK gene, andthen OPDIVO QVANTIG may be continued alone after surgery to help prevent your lung cancer from coming back.oOPDIVO QVANTIG may be used alone when your lung cancer:has spread, andyou have tried chemotherapy that contains platinum, and it did not work or is no longer working.If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.ohead and neck cancer (squamous cell carcinoma).oOPDIVO QVANTIG may be used alone when your head and neck cancer:has come back or spread, andyou have tried chemotherapy that contains platinum and it did not work or is no longer working.ocancer of the lining of the urinary tract (urothelial carcinoma).oOPDIVO QVANTIG may be used alone to help prevent cancer of the urinary tract from coming back after it was removed by surgery.oOPDIVO QVANTIG may be used in combination with chemotherapy medicines cisplatin and gemcitabine as your first treatment when your urinary tract cancer has spread (metastatic) or cannot be removed by surgery.oOPDIVO QVANTIG may be used alone when your urinary tract cancer has spread (locally advanced or metastatic), and:you have tried chemotherapy that contains platinum, and it did not work or is no longer working, oryour cancer worsened within 12 months of treatment with chemotherapy that contains platinum, either before or after surgery to remove your cancer.oa type of colon or rectal cancer (colorectal cancer or CRC).oOPDIVO QVANTIG may be used alone and after completing combination treatment with intravenous nivolumab and ipilimumab, when your colon or rectal cancer:has spread to other parts of the body (metastatic CRC), andis microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), andyou have tried treatment with fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.oa type of liver cancer called hepatocellular carcinoma (HCC).oOPDIVO QVANTIG may be used alone if you have previously received treatment with sorafenib and after completing combination treatment with intravenous nivolumab and ipilimumab.ocancer of the tube that connects your throat to your stomach (esophageal cancer).oOPDIVO QVANTIG may be used alone to help prevent your esophageal or gastroesophageal junction cancer from coming back when:your esophageal or gastroesophageal junction cancer has been treated with chemoradiation followed by surgery to completely remove the cancer, butsome cancer cells were still present in the removed tumor or lymph nodes.oOPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum as your first treatment when your esophageal cancer:is type called squamous cell carcinoma, andcannot be removed with surgery, or has spread, andyour tumors are positive for PD-L1.oOPDIVO QVANTIG may be used alone when your esophageal cancer:is type called squamous cell carcinoma, andcannot be removed with surgery, and has come back or spread, andyou have received chemotherapy that contains fluoropyrimidine and platinum.ocancer of the stomach (gastric cancer), cancer where the esophagus joins the stomach (gastroesophageal junction cancer), and type of cancer in the esophagus called esophageal adenocarcinoma.oOPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum when your gastric, gastroesophageal junction, or esophageal cancer:cannot be removed with surgery, or has spread, andyour tumors are positive for PD-L1. It is not known if OPDIVO QVANTIG is safe and effective in children.Before receiving OPDIVO QVANTIG, tell your healthcare provider about all of your medical conditions, including if you:ohave immune system problems such as Crohns disease, ulcerative colitis, or lupusohave received an organ transplant, including corneal transplantohave received or plan to receive stem cell transplant that uses donor stem cells (allogeneic)ohave received radiation treatment to your chest area in the pastohave condition that affects your nervous system, such as myasthenia gravis or Guillain-Barre syndromeoare pregnant or plan to become pregnant. OPDIVO QVANTIG can harm your unborn baby. Females who are able to become pregnant:Your healthcare provider should do pregnancy test before you start receiving OPDIVO QVANTIG.You should use an effective method of birth control during treatment and for months after your last dose of OPDIVO QVANTIG. Talk to your healthcare provider about birth control methods that you can use during this time.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with OPDIVO QVANTIG.oare breastfeeding or plan to breastfeed. It is not known if OPDIVO QVANTIG passes into your breast milk. Do not breastfeed during treatment and for months after your last dose of OPDIVO QVANTIG.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive OPDIVO QVANTIGoYour healthcare provider will give you OPDIVO QVANTIG as an injection under the skin, in the stomach area (abdomen) or thigh, over about to minutes.oOPDIVO QVANTIG is usually given every 2, 3, or weeks, depending on the dose you are receiving. oYour healthcare provider will decide how many treatments you will receive.oYour healthcare provider will do blood tests to check you for side effects.oFor type of kidney cancer called advanced renal cell carcinoma, your healthcare provider may also prescribe you cabozantinib. Take cabozantinib exactly as your healthcare provider tells you.oIf you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.What are the possible side effects of OPDIVO QVANTIGOPDIVO QVANTIG can cause serious side effects, including:oSee What is the most important information should know about OPDIVO QVANTIGoComplications, including graft-versus-host-disease (GVHD), in people who have received bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with OPDIVO QVANTIG. Your healthcare provider will monitor you for signs of complications if you have an allogeneic stem cell transplant.The most common side effects of OPDIVO QVANTIG when used alone in people with renal cell carcinoma include:opain in muscles, bones, and jointsofeeling tiredoitchy skinorasholow thyroid hormone levelsodiarrheaocoughostomach-area (abdominal) painThe most common side effects observed with nivolumab given into the vein (intravenous nivolumab), which may be experienced with OPDIVO QVANTIG, are shown below. The most common side effects of intravenous nivolumab when used alone include:ofeeling tiredorashopain in muscles, bones, and jointsoitchy skinodiarrheaonauseaoweaknessocoughoshortness of breathoconstipation odecreased appetiteoback painoupper respiratory tract infectionofeveroheadacheostomach-area (abdominal) painovomitingourinary tract infectionThe most common side effects of intravenous nivolumab when used in combination with cabozantinib as the first treatment for advanced RCC include:odiarrheaofeeling tiredoliver problems. See What is the most important information should know about OPDIVO QVANTIGorash, redness, pain, swelling or blisters on the palms of your hands or soles of your feetomouth soresorashohigh blood pressureolow thyroid hormone levels opain in muscles, bones, and jointsodecreased appetiteonauseaochange in the sense of tasteostomach-area (abdominal) painocoughoupper respiratory tract infectionThe most common side effects of intravenous nivolumab when used in combination with platinum-containing chemotherapy and another chemotherapy medicine before having surgery for NSCLC include:onauseaoconstipationofeeling tiredodecreased appetiteorashThe most common side effects of intravenous nivolumab when used in combination with cisplatin and gemcitabine to treat urothelial cancer include:onauseaofeeling tiredopain in muscles, bones, and jointsoconstipationodecreased appetiteorashovomitingonumbness, pain, tingling or burning in your hands and feetThe most common side effects of intravenous nivolumab when used in combination with fluoropyrimidine and platinum-containing chemotherapy to treat esophageal cancer and gastric cancer include:onauseaonumbness, pain, tingling, or burning in your hands or feet odecreased appetiteofeeling tiredoconstipationomouth soresodiarrheaovomitingostomach-area (abdominal) painopain in muscles, bones, and jointsThese are not all the possible side effects of OPDIVO QVANTIG.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of OPDIVO QVANTIG.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about OPDIVO QVANTIG that is written for health professionals.What are the ingredients in OPDIVO QVANTIGActive ingredients: nivolumab and hyaluronidase-nvhyInactive ingredients: histidine, histidine hydrochloride monohydrate, methionine, pentetic acid, polysorbate 80, sucrose, and Water for Injection.Manufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA U.S. License No. 1713Halozyme Therapeutics, Inc., 12390 El Camino Real, San Diego, CA 92130, U.S. License No. 2187OPDIVO QVANTIG(TM) is trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners.For more information, call 1-855-673-4861 or go to www.Qvantig.com.This Medication Guide has been approved by the U.S. Food and Drug Administration.Issued: May 2025. ocough. oshortness of breath. ochest pain. odiarrhea (loose stools) or more frequent bowel movements than usual. ostools that are black, tarry, sticky, or have blood or mucus. osevere stomach-area (abdominal) pain or tenderness. oyellowing of your skin or the whites of your eyes. osevere nausea or vomiting. opain on the right side of your stomach area (abdomen). odark urine (tea colored). obleeding or bruising more easily than normal. oheadaches that will not go away or unusual headaches. oeye sensitivity to light. oeye problems. orapid heartbeat oincreased sweating. oextreme tiredness. oweight gain or weight loss. ofeeling more hungry or thirsty than usual. ourinating more often than usual. ohair loss. ofeeling cold. oconstipation. oyour voice gets deeper. odizziness or fainting. ochanges in mood or behavior, such as decreased sex drive, irritability, or forgetfulness. odecrease in your amount of urine. oblood in your urine. oswelling of your ankles. oloss of appetite. orash. oitching. oskin blistering or peeling. oswollen lymph nodes. opainful sores or ulcers in mouth or nose, throat, or genital area. ofever or flu-like symptoms. ochest pain, irregular heartbeat, shortness of breath or swelling of ankles. oconfusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs. odouble vision, blurry vision, sensitivity to light, eye pain, changes in eyesight. opersistent or severe muscle pain or weakness, muscle cramps. olow red blood cells, bruising. oa type of kidney cancer that has spread called advanced renal cell carcinoma (RCC).oOPDIVO QVANTIG may be used alone as first treatment in certain people with advanced RCC, after completing combination treatment with nivolumab given into the vein (intravenous nivolumab) and ipilimumab.oOPDIVO QVANTIG may be used in combination with cabozantinib as your first treatment for advanced RCC.oOPDIVO QVANTIG may be used alone when your cancer has spread after treatment with other cancer medicines.. oOPDIVO QVANTIG may be used alone as first treatment in certain people with advanced RCC, after completing combination treatment with nivolumab given into the vein (intravenous nivolumab) and ipilimumab.. oOPDIVO QVANTIG may be used in combination with cabozantinib as your first treatment for advanced RCC.. oOPDIVO QVANTIG may be used alone when your cancer has spread after treatment with other cancer medicines.. oa type of skin cancer called melanoma.oOPDIVO QVANTIG may be used alone to treat melanoma that has spread or cannot be removed by surgery (advanced melanoma).oOPDIVO QVANTIG may be used alone to treat melanoma that has spread or cannot be removed by surgery (advanced melanoma), after completing combination treatment with intravenous nivolumab and ipilimumab.oOPDIVO QVANTIG may be used alone to help prevent Stage IIB, Stage IIC, Stage III, or Stage IV melanoma from coming back after it has been completely removed by surgery.. oOPDIVO QVANTIG may be used alone to treat melanoma that has spread or cannot be removed by surgery (advanced melanoma).. oOPDIVO QVANTIG may be used alone to treat melanoma that has spread or cannot be removed by surgery (advanced melanoma), after completing combination treatment with intravenous nivolumab and ipilimumab.. oOPDIVO QVANTIG may be used alone to help prevent Stage IIB, Stage IIC, Stage III, or Stage IV melanoma from coming back after it has been completely removed by surgery.. oa type of lung cancer called non-small cell lung cancer (NSCLC).oOPDIVO QVANTIG may be used in combination with chemotherapy that contains platinum and another chemotherapy medicine before you have surgery for early-stage NSCLC.oOPDIVO QVANTIG may be used in combination with chemotherapy that contains platinum and another chemotherapy medicine before you have surgery for early-stage NSCLC:that does not have an abnormal EGFR or ALK gene, andthen OPDIVO QVANTIG may be continued alone after surgery to help prevent your lung cancer from coming back.oOPDIVO QVANTIG may be used alone when your lung cancer:has spread, andyou have tried chemotherapy that contains platinum, and it did not work or is no longer working.If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.. oOPDIVO QVANTIG may be used in combination with chemotherapy that contains platinum and another chemotherapy medicine before you have surgery for early-stage NSCLC.. oOPDIVO QVANTIG may be used in combination with chemotherapy that contains platinum and another chemotherapy medicine before you have surgery for early-stage NSCLC:that does not have an abnormal EGFR or ALK gene, andthen OPDIVO QVANTIG may be continued alone after surgery to help prevent your lung cancer from coming back.. that does not have an abnormal EGFR or ALK gene, and. then OPDIVO QVANTIG may be continued alone after surgery to help prevent your lung cancer from coming back.. oOPDIVO QVANTIG may be used alone when your lung cancer:has spread, andyou have tried chemotherapy that contains platinum, and it did not work or is no longer working.If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.. has spread, and. you have tried chemotherapy that contains platinum, and it did not work or is no longer working.. If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.. ohead and neck cancer (squamous cell carcinoma).oOPDIVO QVANTIG may be used alone when your head and neck cancer:has come back or spread, andyou have tried chemotherapy that contains platinum and it did not work or is no longer working.. oOPDIVO QVANTIG may be used alone when your head and neck cancer:has come back or spread, andyou have tried chemotherapy that contains platinum and it did not work or is no longer working.. has come back or spread, and. you have tried chemotherapy that contains platinum and it did not work or is no longer working.. ocancer of the lining of the urinary tract (urothelial carcinoma).oOPDIVO QVANTIG may be used alone to help prevent cancer of the urinary tract from coming back after it was removed by surgery.oOPDIVO QVANTIG may be used in combination with chemotherapy medicines cisplatin and gemcitabine as your first treatment when your urinary tract cancer has spread (metastatic) or cannot be removed by surgery.oOPDIVO QVANTIG may be used alone when your urinary tract cancer has spread (locally advanced or metastatic), and:you have tried chemotherapy that contains platinum, and it did not work or is no longer working, oryour cancer worsened within 12 months of treatment with chemotherapy that contains platinum, either before or after surgery to remove your cancer.. oOPDIVO QVANTIG may be used alone to help prevent cancer of the urinary tract from coming back after it was removed by surgery.. oOPDIVO QVANTIG may be used in combination with chemotherapy medicines cisplatin and gemcitabine as your first treatment when your urinary tract cancer has spread (metastatic) or cannot be removed by surgery.. oOPDIVO QVANTIG may be used alone when your urinary tract cancer has spread (locally advanced or metastatic), and:you have tried chemotherapy that contains platinum, and it did not work or is no longer working, oryour cancer worsened within 12 months of treatment with chemotherapy that contains platinum, either before or after surgery to remove your cancer.. you have tried chemotherapy that contains platinum, and it did not work or is no longer working, or. your cancer worsened within 12 months of treatment with chemotherapy that contains platinum, either before or after surgery to remove your cancer.. oa type of colon or rectal cancer (colorectal cancer or CRC).oOPDIVO QVANTIG may be used alone and after completing combination treatment with intravenous nivolumab and ipilimumab, when your colon or rectal cancer:has spread to other parts of the body (metastatic CRC), andis microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), andyou have tried treatment with fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.. oOPDIVO QVANTIG may be used alone and after completing combination treatment with intravenous nivolumab and ipilimumab, when your colon or rectal cancer:has spread to other parts of the body (metastatic CRC), andis microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), andyou have tried treatment with fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.. has spread to other parts of the body (metastatic CRC), and. is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and. you have tried treatment with fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.. oa type of liver cancer called hepatocellular carcinoma (HCC).oOPDIVO QVANTIG may be used alone if you have previously received treatment with sorafenib and after completing combination treatment with intravenous nivolumab and ipilimumab.. oOPDIVO QVANTIG may be used alone if you have previously received treatment with sorafenib and after completing combination treatment with intravenous nivolumab and ipilimumab.. ocancer of the tube that connects your throat to your stomach (esophageal cancer).oOPDIVO QVANTIG may be used alone to help prevent your esophageal or gastroesophageal junction cancer from coming back when:your esophageal or gastroesophageal junction cancer has been treated with chemoradiation followed by surgery to completely remove the cancer, butsome cancer cells were still present in the removed tumor or lymph nodes.oOPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum as your first treatment when your esophageal cancer:is type called squamous cell carcinoma, andcannot be removed with surgery, or has spread, andyour tumors are positive for PD-L1.oOPDIVO QVANTIG may be used alone when your esophageal cancer:is type called squamous cell carcinoma, andcannot be removed with surgery, and has come back or spread, andyou have received chemotherapy that contains fluoropyrimidine and platinum.. oOPDIVO QVANTIG may be used alone to help prevent your esophageal or gastroesophageal junction cancer from coming back when:your esophageal or gastroesophageal junction cancer has been treated with chemoradiation followed by surgery to completely remove the cancer, butsome cancer cells were still present in the removed tumor or lymph nodes.. your esophageal or gastroesophageal junction cancer has been treated with chemoradiation followed by surgery to completely remove the cancer, but. some cancer cells were still present in the removed tumor or lymph nodes.. oOPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum as your first treatment when your esophageal cancer:is type called squamous cell carcinoma, andcannot be removed with surgery, or has spread, andyour tumors are positive for PD-L1.. is type called squamous cell carcinoma, and. cannot be removed with surgery, or has spread, and. your tumors are positive for PD-L1.. oOPDIVO QVANTIG may be used alone when your esophageal cancer:is type called squamous cell carcinoma, andcannot be removed with surgery, and has come back or spread, andyou have received chemotherapy that contains fluoropyrimidine and platinum.. is type called squamous cell carcinoma, and. cannot be removed with surgery, and has come back or spread, and. you have received chemotherapy that contains fluoropyrimidine and platinum.. ocancer of the stomach (gastric cancer), cancer where the esophagus joins the stomach (gastroesophageal junction cancer), and type of cancer in the esophagus called esophageal adenocarcinoma.oOPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum when your gastric, gastroesophageal junction, or esophageal cancer:cannot be removed with surgery, or has spread, andyour tumors are positive for PD-L1. oOPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum when your gastric, gastroesophageal junction, or esophageal cancer:cannot be removed with surgery, or has spread, andyour tumors are positive for PD-L1. cannot be removed with surgery, or has spread, and. your tumors are positive for PD-L1. ohave immune system problems such as Crohns disease, ulcerative colitis, or lupus. ohave received an organ transplant, including corneal transplant. ohave received or plan to receive stem cell transplant that uses donor stem cells (allogeneic). ohave received radiation treatment to your chest area in the past. ohave condition that affects your nervous system, such as myasthenia gravis or Guillain-Barre syndrome. oare pregnant or plan to become pregnant. OPDIVO QVANTIG can harm your unborn baby.. Females who are able to become pregnant:Your healthcare provider should do pregnancy test before you start receiving OPDIVO QVANTIG.You should use an effective method of birth control during treatment and for months after your last dose of OPDIVO QVANTIG. Talk to your healthcare provider about birth control methods that you can use during this time.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with OPDIVO QVANTIG.. Your healthcare provider should do pregnancy test before you start receiving OPDIVO QVANTIG.. You should use an effective method of birth control during treatment and for months after your last dose of OPDIVO QVANTIG. Talk to your healthcare provider about birth control methods that you can use during this time.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with OPDIVO QVANTIG.. oare breastfeeding or plan to breastfeed. It is not known if OPDIVO QVANTIG passes into your breast milk. Do not breastfeed during treatment and for months after your last dose of OPDIVO QVANTIG.. oYour healthcare provider will give you OPDIVO QVANTIG as an injection under the skin, in the stomach area (abdomen) or thigh, over about to minutes.. oOPDIVO QVANTIG is usually given every 2, 3, or weeks, depending on the dose you are receiving. oYour healthcare provider will decide how many treatments you will receive.. oYour healthcare provider will do blood tests to check you for side effects.. oFor type of kidney cancer called advanced renal cell carcinoma, your healthcare provider may also prescribe you cabozantinib. Take cabozantinib exactly as your healthcare provider tells you.. oIf you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.. oSee What is the most important information should know about OPDIVO QVANTIG. oComplications, including graft-versus-host-disease (GVHD), in people who have received bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with OPDIVO QVANTIG. Your healthcare provider will monitor you for signs of complications if you have an allogeneic stem cell transplant.. opain in muscles, bones, and joints. ofeeling tired. oitchy skin. orash. olow thyroid hormone levels. odiarrhea. ocough. ostomach-area (abdominal) pain. ofeeling tired. orash. opain in muscles, bones, and joints. oitchy skin. odiarrhea. onausea. oweakness. ocough. oshortness of breath. oconstipation odecreased appetite. oback pain. oupper respiratory tract infection. ofever. oheadache. ostomach-area (abdominal) pain. ovomiting. ourinary tract infection. odiarrhea. ofeeling tired. oliver problems. See What is the most important information should know about OPDIVO QVANTIG. orash, redness, pain, swelling or blisters on the palms of your hands or soles of your feet. omouth sores. orash. ohigh blood pressure. olow thyroid hormone levels opain in muscles, bones, and joints. odecreased appetite. onausea. ochange in the sense of taste. ostomach-area (abdominal) pain. ocough. oupper respiratory tract infection. onausea. oconstipation. ofeeling tired. odecreased appetite. orash. onausea. ofeeling tired. opain in muscles, bones, and joints. oconstipation. odecreased appetite. orash. ovomiting. onumbness, pain, tingling or burning in your hands and feet. onausea. onumbness, pain, tingling, or burning in your hands or feet odecreased appetite. ofeeling tired. oconstipation. omouth sores. odiarrhea. ovomiting. ostomach-area (abdominal) pain. opain in muscles, bones, and joints.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING OPDIVO QVANTIG(TM) (nivolumab and hyaluronidase-nvhy) injection is sterile, preservative-free, clear to opalescent and colorless to yellow solution for subcutaneous use. It is supplied as an individually packaged single-dose vial providing 600 mg nivolumab and 10,000 units hyaluronidase per mL (120 mg/ 2,000 units per mL) (NDC-0003-6120-01).Store OPDIVO QVANTIG vials in refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light.Do not freeze or shake.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE OPDIVO QVANTIG is combination of nivolumab, programmed death receptor-1 (PD-1)-blocking antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of: Renal Cell Carcinoma (RCC)oadult patients with intermediate or poor risk advanced RCC, as first-line treatment following combination treatment with intravenous nivolumab and ipilimumab. (1.1)oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma.oadult patients with advanced RCC, as first-line treatment in combination with cabozantinib. (1.1)oadult patients with advanced RCC who have received prior anti-angiogenic therapy. (1.1)Melanomaoadult patients with unresectable or metastatic melanoma. (1.2)oadult patients with unresectable or metastatic melanoma following combination treatment with intravenous nivolumab and ipilimumab. (1.2)oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic melanoma.ofor the adjuvant treatment of adult patients with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. (1.3)Non-Small Cell Lung Cancer (NSCLC)oadult patients with resectable (tumors >=4 cm or node positive) NSCLC in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. (1.4) oadult patients with resectable (tumors >=4 cm or node positive) NSCLC and no known EGFR mutations or ALK rearrangements, for neoadjuvant treatment, in combination with platinum-doublet chemotherapy, followed by OPDIVO QVANTIG monotherapy as adjuvant treatment after surgery. (1.5) oadult patients with metastatic NSCLC and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO QVANTIG. (1.6)oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC. Squamous Cell Carcinoma of the Head and Neck (SCCHN)oadult patients with recurrent or metastatic SCCHN with disease progression on or after platinum-based therapy. (1.7)Urothelial Carcinoma (UC)oadjuvant treatment of adult patients with UC who are at high risk of recurrence after undergoing radical resection of UC. (1.8)oadult patients with unresectable or metastatic urothelial carcinoma, as first-line treatment in combination with cisplatin and gemcitabine. (1.8)oadult patients with locally advanced or metastatic UC who:ohave disease progression during or following platinum-containing chemotherapy.ohave disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.8)Colorectal Canceroadult patients with MSI-H or dMMR metastatic CRC that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan, as monotherapy or as monotherapy following combination treatment with intravenous nivolumab and ipilimumab.a (1.9) oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of MSI-H or dMMR metastatic CRC. Hepatocellular Carcinoma (HCC)oadult patients with HCC previously treated with sorafenib and following combination treatment with intravenous nivolumab and ipilimumab.a (1.10) oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of HCC. Esophageal Canceroadult patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, who have received neoadjuvant chemoradiotherapy (CRT). (1.11)oadult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) as first-line treatment in combination with fluoropyrimidine- and platinum-containing chemotherapy whose tumors express PD-L1 (>=1). (1.11) oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC. oadult patients with unresectable advanced, recurrent or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy. (1.11)Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinomaoadult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (>=1) in combination with fluoropyrimidine- and platinum-containing chemotherapy. (1.12) This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.. oadult patients with intermediate or poor risk advanced RCC, as first-line treatment following combination treatment with intravenous nivolumab and ipilimumab. (1.1)oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma.. oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma.. oadult patients with advanced RCC, as first-line treatment in combination with cabozantinib. (1.1). oadult patients with advanced RCC who have received prior anti-angiogenic therapy. (1.1). oadult patients with unresectable or metastatic melanoma. (1.2). oadult patients with unresectable or metastatic melanoma following combination treatment with intravenous nivolumab and ipilimumab. (1.2)oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic melanoma.. oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic melanoma.. ofor the adjuvant treatment of adult patients with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. (1.3). oadult patients with resectable (tumors >=4 cm or node positive) NSCLC in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. (1.4) oadult patients with resectable (tumors >=4 cm or node positive) NSCLC and no known EGFR mutations or ALK rearrangements, for neoadjuvant treatment, in combination with platinum-doublet chemotherapy, followed by OPDIVO QVANTIG monotherapy as adjuvant treatment after surgery. (1.5) oadult patients with metastatic NSCLC and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO QVANTIG. (1.6)oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC. oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC. oadult patients with recurrent or metastatic SCCHN with disease progression on or after platinum-based therapy. (1.7). oadjuvant treatment of adult patients with UC who are at high risk of recurrence after undergoing radical resection of UC. (1.8). oadult patients with unresectable or metastatic urothelial carcinoma, as first-line treatment in combination with cisplatin and gemcitabine. (1.8). oadult patients with locally advanced or metastatic UC who:ohave disease progression during or following platinum-containing chemotherapy.ohave disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.8). ohave disease progression during or following platinum-containing chemotherapy.. ohave disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.8). oadult patients with MSI-H or dMMR metastatic CRC that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan, as monotherapy or as monotherapy following combination treatment with intravenous nivolumab and ipilimumab.a (1.9) oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of MSI-H or dMMR metastatic CRC. oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of MSI-H or dMMR metastatic CRC.. oadult patients with HCC previously treated with sorafenib and following combination treatment with intravenous nivolumab and ipilimumab.a (1.10) oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of HCC. oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of HCC.. oadult patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, who have received neoadjuvant chemoradiotherapy (CRT). (1.11). oadult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) as first-line treatment in combination with fluoropyrimidine- and platinum-containing chemotherapy whose tumors express PD-L1 (>=1). (1.11) oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC. oLimitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC. oadult patients with unresectable advanced, recurrent or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy. (1.11). oadult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (>=1) in combination with fluoropyrimidine- and platinum-containing chemotherapy. (1.12) 1.1Advanced Renal Cell Carcinoma OPDIVO QVANTIG(TM), as monotherapy, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC) following treatment with intravenous nivolumab and ipilimumab combination therapy.Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma.OPDIVO QVANTIG, in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced RCC.OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with advanced RCC who have received prior anti-angiogenic therapy.. 1.2Unresectable or Metastatic Melanoma OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic melanoma.OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic melanoma following treatment with intravenous nivolumab and ipilimumab combination therapy.Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic melanoma.. 1.3Adjuvant Treatment of Melanoma OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult patients with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.. 1.4Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors >=4 cm or node positive) non-small cell lung cancer (NSCLC).. 1.5Neoadjuvant and Adjuvant Treatment of Resectable Non-Small Cell Lung Cancer OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated for the neoadjuvant treatment of adult patients with resectable (tumors >=4 cm or node positive) NSCLC and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by OPDIVO QVANTIG as monotherapy in the adjuvant setting after surgical resection.. 1.6Metastatic Non-Small Cell Lung Cancer OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO QVANTIG.Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC.. 1.7Squamous Cell Carcinoma of the Head and Neck OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.. 1.8Urothelial Carcinoma OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.OPDIVO QVANTIG, in combination with cisplatin and gemcitabine, is indicated for the first-line treatment of adult patients with unresectable or metastatic UC.OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with locally advanced or metastatic UC who:ohave disease progression during or following platinum-containing chemotherapy.ohave disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.. ohave disease progression during or following platinum-containing chemotherapy.. ohave disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.. 1.9Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer OPDIVO QVANTIG, as monotherapy or as monotherapy following treatment with intravenous nivolumab and ipilimumab combination therapy, is indicated for the treatment of adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic CRC that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of MSI-H or dMMR metastatic CRC.This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.9)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.. 1.10Hepatocellular Carcinoma OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib and following treatment with intravenous nivolumab and ipilimumab.Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with HCC.This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.10)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.. 1.11Esophageal Cancer OPDIVO QVANTIG as monotherapy, is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (>=1) [see Dosage and Administration (2.2)] .Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC.OPDIVO QVANTIG as monotherapy, is indicated for the treatment of adult patients with unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy.. 1.12Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (>=1) [see Dosage and Administration (2.2)].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is at least 600 times higher than the human dose (U/kg basis), of 10,000 once every weeks, 15,000 once every weeks, or 20,000 once every weeks, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data.

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY . 12.1Mechanism of Action Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.Hyaluronan is polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidase in OPDIVO QVANTIG acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.. 12.2Pharmacodynamics Exposure-Response RelationshipThe exposure-response relationship and time course of pharmacodynamics of OPDIVO QVANTIG have not been fully characterized.. 12.3Pharmacokinetics When comparing nivolumab exposures following OPDIVO QVANTIG to those of intravenous nivolumab in CHECKMATE-67T [see Clinical Studies (14.1)], the geometric mean ratios (GMRs) (90% CI) for time-averaged concentration (Cavg) over 28 days and at steady state were 2.10 (2.00, 2.20) and 1.98 (1.87, 2.11), respectively, and for minimum concentration (Cmin) at 28 days and at steady state were 1.60 (1.49, 1.72) and 1.77 (1.63, 1.93), respectively.Steady state was achieved by 16 weeks. The systemic accumulation ratio was 2.3.AbsorptionThe geometric mean bioavailability (CV%) of nivolumab is 74% (14%). Peak concentrations occurred by around days.DistributionThe geometric mean (CV%) volume of distribution at steady state is 6.8 (27%).EliminationNivolumab clearance decreases over time, with mean maximal reduction (CV%) from baseline values of 24.5% (47.6%), resulting in geometric mean steady-state clearance (CV%) of 8.2 mL/h (53.9%) in patients with metastatic tumors; this decrease in clearance is not considered clinically relevant. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady state.The geometric mean (CV%) elimination half-life is 25 days (78%).Specific PopulationsBody weight (35 to 153 kg), sex, eGFR (24 to 124 mL/min/1.73 m2), and performance status have no clinically significant effects on the clearance of nivolumab.. 12.6Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of OPDIVO QVANTIG or of other nivolumab products or hyaluronidase products.During the 2-year treatment period in CHECKMATE-67T [see Clinical Studies (14.1)], 23% (46/202) of patients who received OPDIVO QVANTIG developed anti-nivolumab antibodies (ADA) and 4.3% (2/46) had neutralizing antibodies against nivolumab (NAb). The corresponding incidence of ADA was 7% (15/215) and NAb was 0% (0/15) for intravenous nivolumab in the same study. The incidence of anti-hyaluronidase antibodies in CHECKMATE-67T was 8.8% (19/215); (26%) of these 19 patients developed NAb.Nivolumab clearance increased by approximately 26% in patients who received OPDIVO QVANTIG and tested positive for ADA compared to patients who tested negative for ADA; this change in clearance is not considered clinically significant. Local injection-site reactions were reported in 15% (7/46) of patients who developed ADA to nivolumab and 7% (10/155) of patients who did not develop ADA to nivolumab; however, all events were Grade or and resolved. Because of low occurrence of anti-nivolumab or anti-hyaluronidase antibodies, the effect of ADA on the effectiveness of OPDIVO QVANTIG is unknown.

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS None.. oNone. (4). oNone. (4).

DESCRIPTION SECTION.

11DESCRIPTION OPDIVO QVANTIG is fixed-combination drug product containing nivolumab and hyaluronidase (human recombinant). Nivolumab is programmed death receptor-1 (PD-1) blocking antibody. Nivolumab is an IgG4 kappa immunoglobulin that has calculated molecular mass of 146 kDa. It is expressed in recombinant Chinese Hamster Ovary (CHO) cell line.Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. Hyaluronidase (human recombinant) is glycosylated single-chain protein produced by CHO cells containing DNA plasmid encoding for soluble fragment of human hyaluronidase (PH20). Hyaluronidase (human recombinant) has molecular weight of approximately 61 kDa.OPDIVO QVANTIG (nivolumab and hyaluronidase-nvhy) injection is sterile, preservative-free, clear to opalescent, colorless to yellow solution that may contain few translucent-to-white particles, supplied in single-dose vial for subcutaneous use.Each mL single-dose vial of OPDIVO QVANTIG contains 600 mg of nivolumab and 10,000 units of hyaluronidase (human recombinant), and the inactive ingredients: histidine (7.75 mg), histidine hydrochloride monohydrate (10.5 mg), methionine (3.73 mg), pentetic acid (0.0985 mg), polysorbate 80 (2.5 mg), sucrose (428 mg), and Water for Injection, USP. The pH is 5.5 to 6.5.

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION oOPDIVO QVANTIG has different dosage and administration instructions than intravenous nivolumab products. oOPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. oOPDIVO QVANTIG is to be administered by healthcare professional only. (2.1) OPDIVO QVANTIG is for subcutaneous use only.oAdminister by subcutaneous injection over 3-5 minutes. (2.1)oRenal cell carcinomao600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3) o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks administered in combination with cabozantinib 40 mg once daily without food. (2.3)oMelanomao600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3)oNeoadjuvant treatment of resectable (tumors >=4 cm or node positive) non-small cell lung cancero900 mg/15,000 units with platinum-doublet chemotherapy on the same day every weeks for cycles. (2.3) oNeoadjuvant and adjuvant treatment of resectable non-small cell lung cancero900 mg/15,000 units with platinum-doublet chemotherapy on the same day every weeks for up to cycles, then continued as single-agent OPDIVO QVANTIG 1,200 mg/20,000 units every weeks after surgery for up to 13 cycles (~1 year). (2.3)oMetastatic non-small cell lung cancero600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3)oSquamous cell carcinoma of the head and necko600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3)oUrothelial carcinomao600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3)oFirst-line unresectable or metastatic urothelial carcinomao900 mg/15,000 units every weeks with cisplatin and gemcitabine on the same day for up to cycles, then 600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3) oColorectal cancero600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3)oHepatocellular carcinomao600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3)oEsophageal cancero600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3)o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks administered in combination with fluoropyrimidine- and platinum-containing chemotherapy. (2.3)oGastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinomao600 mg/10,000 units every weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every weeks. (2.3)o900 mg/15,000 units every weeks with fluoropyrimidine- and platinum-containing chemotherapy every weeks. (2.3)oSee full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.. oOPDIVO QVANTIG has different dosage and administration instructions than intravenous nivolumab products. oOPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. oOPDIVO QVANTIG is to be administered by healthcare professional only. (2.1) oAdminister by subcutaneous injection over 3-5 minutes. (2.1). oRenal cell carcinomao600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3) o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks administered in combination with cabozantinib 40 mg once daily without food. (2.3). o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3) o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks administered in combination with cabozantinib 40 mg once daily without food. (2.3). oMelanomao600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). oNeoadjuvant treatment of resectable (tumors >=4 cm or node positive) non-small cell lung cancero900 mg/15,000 units with platinum-doublet chemotherapy on the same day every weeks for cycles. (2.3) o900 mg/15,000 units with platinum-doublet chemotherapy on the same day every weeks for cycles. (2.3). oNeoadjuvant and adjuvant treatment of resectable non-small cell lung cancero900 mg/15,000 units with platinum-doublet chemotherapy on the same day every weeks for up to cycles, then continued as single-agent OPDIVO QVANTIG 1,200 mg/20,000 units every weeks after surgery for up to 13 cycles (~1 year). (2.3). o900 mg/15,000 units with platinum-doublet chemotherapy on the same day every weeks for up to cycles, then continued as single-agent OPDIVO QVANTIG 1,200 mg/20,000 units every weeks after surgery for up to 13 cycles (~1 year). (2.3). oMetastatic non-small cell lung cancero600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). oSquamous cell carcinoma of the head and necko600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). oUrothelial carcinomao600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). oFirst-line unresectable or metastatic urothelial carcinomao900 mg/15,000 units every weeks with cisplatin and gemcitabine on the same day for up to cycles, then 600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3) o900 mg/15,000 units every weeks with cisplatin and gemcitabine on the same day for up to cycles, then 600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3) oColorectal cancero600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). oHepatocellular carcinomao600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). oEsophageal cancero600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3)o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks administered in combination with fluoropyrimidine- and platinum-containing chemotherapy. (2.3). o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks. (2.3). o600 mg/10,000 units every weeks or 1,200 mg/20,000 units every weeks administered in combination with fluoropyrimidine- and platinum-containing chemotherapy. (2.3). oGastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinomao600 mg/10,000 units every weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every weeks. (2.3)o900 mg/15,000 units every weeks with fluoropyrimidine- and platinum-containing chemotherapy every weeks. (2.3). o600 mg/10,000 units every weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every weeks. (2.3). o900 mg/15,000 units every weeks with fluoropyrimidine- and platinum-containing chemotherapy every weeks. (2.3). oSee full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.. 2.1Important Dosage and Administration Information OPDIVO QVANTIG has different dosage and administration instructions than intravenously administered nivolumab products [see Dosage and Administration (2.5)].OPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. Do not administer intravenously. OPDIVO QVANTIG is to be administered by healthcare professional only.Adult patients currently receiving intravenous nivolumab as single agent, or in combination with chemotherapy or cabozantinib, may switch to subcutaneous OPDIVO QVANTIG at their next scheduled dose.. 2.2Patient Selection Esophageal Cancer. Select patients with unresectable advanced or metastatic ESCC for treatment with OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapy based on PD-L1 expression [see Clinical Studies (14.11)].oAn FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic ESCC is not available.. oAn FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic ESCC is not available.. Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma. Select patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma for treatment with OPDIVO QVANTIG in combination with fluoropyrimidine-and platinum-containing chemotherapy based on PD-L1 expression [see Clinical Studies (14.12)].oAn FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma is not available.. oAn FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma is not available.. 2.3Recommended Dosage The recommended dosages of OPDIVO QVANTIG as monotherapy agent are presented in Table 1.Table 1: Recommended Dosages for OPDIVO QVANTIG as Monotherapy+ Dosing recommendations for both monotherapy or following intravenous nivolumab and ipilimumab combination therapy. Administer over 3-5 minutes.IndicationRecommended OPDIVO QVANTIG DosageDuration of TherapyAdvanced renal cell carcinoma+600 mg nivolumab and 10,000 units hyaluronidase every weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every weeksUntil disease progression or unacceptable toxicityUnresectable or metastatic melanoma+Metastatic non-small cell lung cancer Squamous cell carcinoma of the head and neckLocally advanced or metastatic urothelial carcinomaMicrosatellite instability-high or mismatch repair deficient metastatic colorectal cancer+Hepatocellular carcinoma+Esophageal squamous cell carcinoma Adjuvant treatment of melanoma600 mg nivolumab and 10,000 units hyaluronidase every weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every weeksUntil disease recurrence or unacceptable toxicity for up to yearAdjuvant treatment of urothelial carcinoma Adjuvant treatment of resected esophageal or gastroesophageal junction cancerThe recommended dosages of OPDIVO QVANTIG in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with OPDIVO QVANTIG for the recommended dosage information, as appropriate. Table 2: Recommended Dosages for OPDIVO QVANTIG in Combination with Other Therapeutic Agents Administer over 3-5 minutes.IndicationRecommended OPDIVO QVANTIG DosageDuration of TherapyAdvanced renal cell carcinoma600 mg nivolumab and 10,000 units hyaluronidase every weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every weeksAdminister OPDIVO QVANTIG in combination with cabozantinib 40 mg orally once daily without foodOPDIVO QVANTIG: Until disease progression, unacceptable toxicity, or up to years Cabozantinib: Until disease progression or unacceptable toxicityNeoadjuvant treatment of resectable non-small cell lung cancer900 mg nivolumab and 15,000 units hyaluronidase with platinum-doublet chemotherapy on the same day every weeksIn combination with platinum-doublet chemotherapy for cyclesNeoadjuvant and adjuvant treatment of resectable non-small cell lung cancerNeoadjuvant: 900 mg nivolumab and 15,000 units hyaluronidase with platinum-doublet chemotherapy on the same day every weeksNeoadjuvant: in combination with platinum-doublet chemotherapy until disease progression or unacceptable toxicity, for up to cyclesAdjuvant: 1,200 mg nivolumab and 20,000 units hyaluronidase every weeksAdjuvant: following neoadjuvant therapy and surgery, administer as single agent until disease progression, recurrence, or unacceptable toxicity, for up to 13 cycles (up to year)First-line unresectable or metastatic urothelial carcinoma900 mg nivolumab and 15,000 units hyaluronidase every weeksAdminister OPDIVO QVANTIG in combination with cisplatin and gemcitabine on the same day every weeksIn combination with cisplatin and gemcitabine for up to cycles600 mg nivolumab and 10,000 units hyaluronidase every weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every weeksAfter completing up to cycles of combination therapy, administer as single agent until disease progression, unacceptable toxicity, or up to years from first doseEsophageal squamous cell carcinoma600 mg nivolumab and 10,000 units hyaluronidase every weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every weeksAdminister OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapyUntil disease progression, unacceptable toxicity, or up to yearsChemotherapy: Until disease progression or unacceptable toxicityGastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma600 mg nivolumab and 10,000 units hyaluronidase with fluoropyrimidine- and platinum-containing chemotherapy every weeksor900 mg nivolumab and 15,000 units hyaluronidase with fluoropyrimidine- and platinum-containing chemotherapy every weeksOPDIVO QVANTIG: Until disease progression, unacceptable toxicity, or up to years Chemotherapy: Until disease progression or unacceptable toxicity. 2.4Dosage Modifications No dose reduction for OPDIVO QVANTIG is recommended. In general, withhold OPDIVO QVANTIG for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue OPDIVO QVANTIG for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for OPDIVO QVANTIG or OPDIVO QVANTIG in combination with other anti-cancer agents for adverse reactions that require management different from these general guidelines are summarized in Table and Table 4.Table 3: Recommended Dosage Modifications for Adverse Reactionsa Resume in patients with complete or partial resolution (Grade to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO QVANTIG based on recommendations for hepatitis with no liver involvement. Depending on clinical severity, consider withholding for Grade endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.ALT alanine aminotransferase, AST aspartate aminotransferase, DRESS Drug Rash with Eosinophilia and Systemic Symptoms, SJS Stevens-Johnson Syndrome, TEN toxic epidermal necrolysis, ULN upper limit of normalAdverse ReactionSeverityDosage ModificationImmune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] PneumonitisGrade 2Withholda Grade or 4Permanently discontinueColitis For colitis in patients treated with combination therapy with ipilimumab, see Table 4.Grade or 3Withholda Grade 4Permanently discontinueHepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy with cabozantinib, see Table 4. AST/ALT increases to >3 and <=8 times ULN or Total bilirubin increases to >1.5 and <=3 times ULN.Withholda AST or ALT increases to >8 times ULN or Total bilirubin increases to >3 times ULN.Permanently discontinueHepatitis with tumor involvement of the liverb Baseline AST/ALT is >1 and <=3 times ULN and increases to >5 and <=10 times ULNorBaseline AST/ALT is >3 and <=5 times ULN and increases to >8 and <=10 times ULN.Withholda AST/ALT increases to >10 times ULN or Total bilirubin increases to >3 times ULN.Permanently discontinueEndocrinopathiesc Grade or 4Withhold until clinically stable or permanently discontinue depending on severityNephritis with Renal DysfunctionGrade or increased blood creatinineWithholda Grade increased blood creatininePermanently discontinueExfoliative Dermatologic ConditionsSuspected SJS, TEN, or DRESSWithhold Confirmed SJS, TEN, or DRESSPermanently discontinueMyocarditisGrades 2, 3, or 4Permanently discontinueNeurological ToxicitiesGrade 2Withholda Grade or 4Permanently discontinueTable 4: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with Combination Therapya Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO QVANTIG is withheld or discontinued when administered in combination with cabozantinib. After recovery, rechallenge with one or both of OPDIVO QVANTIG and cabozantinib may be considered. If rechallenging with cabozantinib with or without OPDIVO QVANTIG, refer to cabozantinib Prescribing Information. TreatmentAdverse ReactionSeverityDosage ModificationOPDIVO QVANTIG in combination with cabozantinibLiver enzyme elevationsALT or AST >3 times ULN but <=10 times ULN with concurrent total bilirubin <2 times ULNWithholda both OPDIVO QVANTIG and cabozantinib until adverse reactions recoverb to Grades 0-1ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin >=2 times ULNPermanently discontinuea both OPDIVO QVANTIG and cabozantinib. 2.5Preparation and Administration To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is OPDIVO QVANTIG for subcutaneous use and NOT intravenous nivolumab. Do NOT administer OPDIVO QVANTIG intravenously. OPDIVO QVANTIG should be administered by healthcare professional. Each OPDIVO QVANTIG vial is for one-time use only. It is ready-to-use solution for injection. It should not be diluted.Visually inspect for particulate matter and discoloration prior to administration. OPDIVO QVANTIG is clear to opalescent, colorless to yellow solution. Discard if the solution is discolored or contains extraneous particulate matter other than few translucent-to-white particles. Do not shake.. Preparation. No incompatibilities were observed between OPDIVO QVANTIG and polypropylene and polycarbonate syringes, or between OPDIVO QVANTIG and polyethylene, polyurethane, polyvinyl chloride, and fluorinated ethylene propylene subcutaneous administration sets.A syringe and transfer needle are needed to withdraw OPDIVO QVANTIG solution from the vial. OPDIVO QVANTIG may be injected subcutaneously using 23G-25G (3/8-5/8) hypodermic injection needle or subcutaneous administration set (eg., winged/butterfly).o600 mg nivolumab and 10,000 units hyaluronidaseAllow OPDIVO QVANTIG vial to reach room temperature, then withdraw mL of OPDIVO QVANTIG into the syringe.o900 mg nivolumab and 15,000 units hyaluronidaseAllow OPDIVO QVANTIG vials to reach room temperature, then withdraw mL from one vial and 2.5 mL from the other vial, for total volume of 7.5 mL of OPDIVO QVANTIG into single syringe.o1,200 mg nivolumab and 20,000 units hyaluronidaseAllow OPDIVO QVANTIG vials to reach room temperature, then withdraw 10 mL of OPDIVO QVANTIG into single syringe.Select the appropriate syringe label provided in the carton that matches the prescribed dose and apply to the prepared syringe.Discard partially used or empty vials of OPDIVO QVANTIG.If the dose is not to be used immediately, attach tip cap to the syringe prior to storage. To avoid clogging of the hypodermic injection needle, attach 23G-25G (3/8-5/8) hypodermic injection needle to the syringe immediately prior to administration.. o600 mg nivolumab and 10,000 units hyaluronidaseAllow OPDIVO QVANTIG vial to reach room temperature, then withdraw mL of OPDIVO QVANTIG into the syringe.. Allow OPDIVO QVANTIG vial to reach room temperature, then withdraw mL of OPDIVO QVANTIG into the syringe.. o900 mg nivolumab and 15,000 units hyaluronidaseAllow OPDIVO QVANTIG vials to reach room temperature, then withdraw mL from one vial and 2.5 mL from the other vial, for total volume of 7.5 mL of OPDIVO QVANTIG into single syringe.. Allow OPDIVO QVANTIG vials to reach room temperature, then withdraw mL from one vial and 2.5 mL from the other vial, for total volume of 7.5 mL of OPDIVO QVANTIG into single syringe.. o1,200 mg nivolumab and 20,000 units hyaluronidaseAllow OPDIVO QVANTIG vials to reach room temperature, then withdraw 10 mL of OPDIVO QVANTIG into single syringe.. Allow OPDIVO QVANTIG vials to reach room temperature, then withdraw 10 mL of OPDIVO QVANTIG into single syringe.. Storage in Syringe. Once withdrawn into the syringe, OPDIVO QVANTIG should be used immediately. If not used immediately, store the syringe:oIn the refrigerator at 2C to 8C (36F to 46F), protected from light for up to 72 hours; do not freeze, or oAt room temperature 20C to 25C (68F to 77F) for up to hours. Storage at room temperature for this duration does not require protection from light.oDiscard if storage time exceeds these limits. oIf stored in the refrigerator, allow the solution to come to room temperature before administration.. oIn the refrigerator at 2C to 8C (36F to 46F), protected from light for up to 72 hours; do not freeze, or oAt room temperature 20C to 25C (68F to 77F) for up to hours. Storage at room temperature for this duration does not require protection from light.. oDiscard if storage time exceeds these limits. oIf stored in the refrigerator, allow the solution to come to room temperature before administration.. Administration. oAdminister the full contents of the syringe into the subcutaneous tissue of of the quadrants of the abdomen, or thigh over period of to minutes.oAlternate injection sites across the quadrants of the abdomen or thighs for successive injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If the administration of OPDIVO QVANTIG is interrupted, continue administering at the same site, or at an alternate site.oDuring treatment with OPDIVO QVANTIG, do not administer other subcutaneous medications at the same site used for OPDIVO QVANTIG.. oAdminister the full contents of the syringe into the subcutaneous tissue of of the quadrants of the abdomen, or thigh over period of to minutes.. oAlternate injection sites across the quadrants of the abdomen or thighs for successive injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If the administration of OPDIVO QVANTIG is interrupted, continue administering at the same site, or at an alternate site.. oDuring treatment with OPDIVO QVANTIG, do not administer other subcutaneous medications at the same site used for OPDIVO QVANTIG.

DOSAGE FORMS & STRENGTHS SECTION.

3DOSAGE FORMS AND STRENGTHS Injection: 600 mg nivolumab and 10,000 units hyaluronidase per mL (120 mg/2,000 units per mL), as clear to opalescent, colorless to yellow solution in single-dose vial.. oInjection: 600 mg nivolumab and 10,000 units hyaluronidase per mL (120 mg/2,000 units per mL) in single-dose vial. (3). oInjection: 600 mg nivolumab and 10,000 units hyaluronidase per mL (120 mg/2,000 units per mL) in single-dose vial. (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3Females and Males of Reproductive Potential Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating OPDIVO QVANTIG [see Use in Specific Populations (8.1)].ContraceptionOPDIVO QVANTIG can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG and for months following the last dose.

GERIATRIC USE SECTION.

8.5Geriatric Use Monotherapy. Of the 248 patients who were randomized to monotherapy OPDIVO QVANTIG in clinical studies, 48% were 65 years and over and 14% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Single Agent Intravenous Nivolumab. Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and esophageal or gastroesophageal junction cancer who were randomized to single agent intravenous nivolumab in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients [see Clinical Studies (14.1, 14.2, 14.3, 14.6 14.8, 14.11 14.12)].Clinical studies in patients with recurrent head and neck SCC, or dMMR or MSI-H metastatic CRC (mCRC) who were treated with single agent intravenous nivolumab did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients [see Clinical Studies (14.7, 14.9)].. Intravenous Nivolumab in Combination with Platinum-Containing Chemotherapy. Of the 179 patients with NSCLC who were randomized to intravenous nivolumab in combination with platinum-doublet chemotherapy, 48% were 65 years old or older and 6% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years [see Clinical Studies (14.4)].Of the 229 patients with NSCLC who were randomized to intravenous nivolumab 360 mg in combination with platinum-doublet chemotherapy every weeks for up to cycles, followed by intravenous nivolumab 480 mg every weeks, 56% were 65 years old or older and 7% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years.Of the 1,110 patients with ESCC, GC, GEJC, or EAC who were randomized to intravenous nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy, 42% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14.11, 14.12)].Of the 304 patients with UC who were treated with intravenous nivolumab in combination with gemcitabine and platinum-doublet chemotherapy, 40% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age and over and younger patients. Clinical studies of intravenous nivolumab with platinum-doublet chemotherapy did not include sufficient numbers of patients aged 75 years and over to determine whether safety and effectiveness differs compared to younger patients. [see Clinical Studies (14.8)].. In Combination with Cabozantinib. Of the 320 patients with renal cell carcinoma who were treated with intravenous nivolumab in combination with cabozantinib, 41% were 65 years or older and 9% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14.1)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).Immune-Mediated Adverse ReactionsInform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of OPDIVO QVANTIG, including:oPneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].oColitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)].oHepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.1)].oEndocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.1)].oNephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions (5.1)].oSkin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions (5.1)].oOther immune-mediated adverse reactions: oAdvise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms [see Warnings and Precautions (5.1)]. oAdvise patients of the risk of solid organ transplant rejection and other transplant (including corneal graft) rejection. Advise patients to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection and other transplant (including corneal graft) rejection [see Warnings and Precautions (5.1)].Complications of Allogeneic HSCToAdvise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.2)].Embryo-Fetal ToxicityoAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. oAdvise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG and for months following the last dose [see Use in Specific Populations (8.3)].LactationoAdvise women not to breastfeed during treatment with OPDIVO QVANTIG and for months after the last dose [see Use in Specific Populations (8.2)].Manufactured by:Bristol-Myers Squibb CompanyPrinceton, NJ 08543 USAU.S. License No. 1713Halozyme Therapeutics, Inc.12390 El Camino RealSan Diego, CA 92130U.S. License No. 2187. oPneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].. oColitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)].. oHepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.1)].. oEndocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.1)].. oNephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions (5.1)].. oSkin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions (5.1)].. oOther immune-mediated adverse reactions: oAdvise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms [see Warnings and Precautions (5.1)]. oAdvise patients of the risk of solid organ transplant rejection and other transplant (including corneal graft) rejection. Advise patients to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection and other transplant (including corneal graft) rejection [see Warnings and Precautions (5.1)].. oAdvise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.2)].. oAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. oAdvise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG and for months following the last dose [see Use in Specific Populations (8.3)].. oAdvise women not to breastfeed during treatment with OPDIVO QVANTIG and for months after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2Lactation Risk SummaryThere are no data on the presence of nivolumab or hyaluronidase in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for months after the last dose of OPDIVO QVANTIG.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.Hyaluronan is polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidase in OPDIVO QVANTIG acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

NONCLINICAL TOXICOLOGY SECTION.

13NONCLINICAL TOXICOLOGY . 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is at least 600 times higher than the human dose (U/kg basis), of 10,000 once every weeks, 15,000 once every weeks, or 20,000 once every weeks, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data.. 13.2Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

OPDIVO QVANTIGTM 600 mg and 10,000 units/5 mL Representative Packaging Rx OnlyNDC 0003-6120-01OPDIVO QVANTIG(TM) (nivolumab and hyaluronidase-nvhy)injection 600 mg and 10,000 units/5 mL(120mg and 2,000 units/mL)For Subcutaneous Use OnlyAdminister SubcutaneousInjection Over to MinutesSingle-dose vial;Discard unused portion.ATTENTION: Dispense theenclosed Medication Guideto each patient.Bristol Myers Squibb nivo-sc-carton.

PEDIATRIC USE SECTION.

8.4Pediatric Use The safety and effectiveness of OPDIVO QVANTIG have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2Pharmacodynamics Exposure-Response RelationshipThe exposure-response relationship and time course of pharmacodynamics of OPDIVO QVANTIG have not been fully characterized.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics When comparing nivolumab exposures following OPDIVO QVANTIG to those of intravenous nivolumab in CHECKMATE-67T [see Clinical Studies (14.1)], the geometric mean ratios (GMRs) (90% CI) for time-averaged concentration (Cavg) over 28 days and at steady state were 2.10 (2.00, 2.20) and 1.98 (1.87, 2.11), respectively, and for minimum concentration (Cmin) at 28 days and at steady state were 1.60 (1.49, 1.72) and 1.77 (1.63, 1.93), respectively.Steady state was achieved by 16 weeks. The systemic accumulation ratio was 2.3.AbsorptionThe geometric mean bioavailability (CV%) of nivolumab is 74% (14%). Peak concentrations occurred by around days.DistributionThe geometric mean (CV%) volume of distribution at steady state is 6.8 (27%).EliminationNivolumab clearance decreases over time, with mean maximal reduction (CV%) from baseline values of 24.5% (47.6%), resulting in geometric mean steady-state clearance (CV%) of 8.2 mL/h (53.9%) in patients with metastatic tumors; this decrease in clearance is not considered clinically relevant. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady state.The geometric mean (CV%) elimination half-life is 25 days (78%).Specific PopulationsBody weight (35 to 153 kg), sex, eGFR (24 to 124 mL/min/1.73 m2), and performance status have no clinically significant effects on the clearance of nivolumab.

PREGNANCY SECTION.

8.1Pregnancy Risk SummaryBased on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], OPDIVO QVANTIG can cause fetal harm when administered to pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death (see Data). Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO QVANTIG are likely to be greater during the second and third trimesters of pregnancy. There are no available data on OPDIVO QVANTIG use in pregnant women to evaluate drug-associated risk. Advise pregnant women of the potential risk to fetus.The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.DataAnimal DataOPDIVO QVANTIG for subcutaneous injection contains nivolumab and hyaluronidase [see Description (11) ].NivolumabA central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab intravenously twice weekly from the onset of organogenesis through delivery, at exposure levels of between and 15 times higher than those observed at the clinical dose of 600 mg once every weeks, 900 mg once every weeks, or 1,200 mg once every weeks (based on AUC). Nivolumab administration resulted in non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response, and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period.HyaluronidaseIn an embryo-fetal development study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is at least 6,600 times higher than the human dose of 10,000 once every weeks, 15,000 once every weeks, or 20,000 once every weeks (U/kg basis), when administered with nivolumab. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at daily dose of 360,000 U/kg, which is at least 1,080 times higher than the human dose of 10,000 once every weeks, 15,000 once every weeks, or 20,000 once every weeks (U/kg basis), when administered with nivolumab.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1) 5/2025Dosage and Administration (2) 6/2025.

SPL UNCLASSIFIED SECTION.

1.1Advanced Renal Cell Carcinoma OPDIVO QVANTIG(TM), as monotherapy, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC) following treatment with intravenous nivolumab and ipilimumab combination therapy.Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma.OPDIVO QVANTIG, in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced RCC.OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with advanced RCC who have received prior anti-angiogenic therapy.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS . oLactation: Advise not to breastfeed. (8.2). oLactation: Advise not to breastfeed. (8.2). 8.1Pregnancy Risk SummaryBased on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], OPDIVO QVANTIG can cause fetal harm when administered to pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death (see Data). Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO QVANTIG are likely to be greater during the second and third trimesters of pregnancy. There are no available data on OPDIVO QVANTIG use in pregnant women to evaluate drug-associated risk. Advise pregnant women of the potential risk to fetus.The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.DataAnimal DataOPDIVO QVANTIG for subcutaneous injection contains nivolumab and hyaluronidase [see Description (11) ].NivolumabA central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab intravenously twice weekly from the onset of organogenesis through delivery, at exposure levels of between and 15 times higher than those observed at the clinical dose of 600 mg once every weeks, 900 mg once every weeks, or 1,200 mg once every weeks (based on AUC). Nivolumab administration resulted in non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response, and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period.HyaluronidaseIn an embryo-fetal development study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is at least 6,600 times higher than the human dose of 10,000 once every weeks, 15,000 once every weeks, or 20,000 once every weeks (U/kg basis), when administered with nivolumab. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at daily dose of 360,000 U/kg, which is at least 1,080 times higher than the human dose of 10,000 once every weeks, 15,000 once every weeks, or 20,000 once every weeks (U/kg basis), when administered with nivolumab.. 8.2Lactation Risk SummaryThere are no data on the presence of nivolumab or hyaluronidase in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for months after the last dose of OPDIVO QVANTIG.. 8.3Females and Males of Reproductive Potential Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating OPDIVO QVANTIG [see Use in Specific Populations (8.1)].ContraceptionOPDIVO QVANTIG can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG and for months following the last dose.. 8.4Pediatric Use The safety and effectiveness of OPDIVO QVANTIG have not been established in pediatric patients.. 8.5Geriatric Use Monotherapy. Of the 248 patients who were randomized to monotherapy OPDIVO QVANTIG in clinical studies, 48% were 65 years and over and 14% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Single Agent Intravenous Nivolumab. Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and esophageal or gastroesophageal junction cancer who were randomized to single agent intravenous nivolumab in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients [see Clinical Studies (14.1, 14.2, 14.3, 14.6 14.8, 14.11 14.12)].Clinical studies in patients with recurrent head and neck SCC, or dMMR or MSI-H metastatic CRC (mCRC) who were treated with single agent intravenous nivolumab did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients [see Clinical Studies (14.7, 14.9)].. Intravenous Nivolumab in Combination with Platinum-Containing Chemotherapy. Of the 179 patients with NSCLC who were randomized to intravenous nivolumab in combination with platinum-doublet chemotherapy, 48% were 65 years old or older and 6% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years [see Clinical Studies (14.4)].Of the 229 patients with NSCLC who were randomized to intravenous nivolumab 360 mg in combination with platinum-doublet chemotherapy every weeks for up to cycles, followed by intravenous nivolumab 480 mg every weeks, 56% were 65 years old or older and 7% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years.Of the 1,110 patients with ESCC, GC, GEJC, or EAC who were randomized to intravenous nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy, 42% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14.11, 14.12)].Of the 304 patients with UC who were treated with intravenous nivolumab in combination with gemcitabine and platinum-doublet chemotherapy, 40% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age and over and younger patients. Clinical studies of intravenous nivolumab with platinum-doublet chemotherapy did not include sufficient numbers of patients aged 75 years and over to determine whether safety and effectiveness differs compared to younger patients. [see Clinical Studies (14.8)].. In Combination with Cabozantinib. Of the 320 patients with renal cell carcinoma who were treated with intravenous nivolumab in combination with cabozantinib, 41% were 65 years or older and 9% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14.1)].

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS oImmune-Mediated Adverse Reactions: (5.1)oImmune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction.oMonitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. oWithhold or permanently discontinue based on severity and type of reaction. (2.4)oComplications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with PD-1/PD-L1 blocking antibody. (5.2)oEmbryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. (5.3, 8.1, 8.3)oTreatment of patients with multiple myeloma with PD-1 or PD-L1 blocking antibody in combination with thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. (5.4). oImmune-Mediated Adverse Reactions: (5.1)oImmune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction.oMonitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. oWithhold or permanently discontinue based on severity and type of reaction. (2.4). oImmune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction.. oMonitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. oWithhold or permanently discontinue based on severity and type of reaction. (2.4). oComplications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with PD-1/PD-L1 blocking antibody. (5.2). oEmbryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. (5.3, 8.1, 8.3). oTreatment of patients with multiple myeloma with PD-1 or PD-L1 blocking antibody in combination with thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. (5.4). 5.1Severe and Fatal Immune-Mediated Adverse Reactions OPDIVO QVANTIG is combination of monoclonal antibody that belongs to class of drugs that bind to either the programmed death-receptor (PD-1) or the PD-ligand (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance, and inducing immune-mediated adverse reactions, and an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ]. In general, if OPDIVO QVANTIG requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to mg/kg/day prednisone or equivalent) until improvement to Grade or less. Upon improvement to Grade or less, initiate corticosteroid taper and continue to taper over at least month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.. Immune-Mediated Pneumonitis. OPDIVO QVANTIG can cause immune-mediated pneumonitis, which is defined as requiring use of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.Immune-mediated pneumonitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade (0.8%) and Grade (2.0%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDIVO QVANTIG in 1.6% and withholding of OPDIVO QVANTIG in 1.6% of patients.Systemic corticosteroids were required in 100% (7/7) of patients with pneumonitis. Pneumonitis resolved in 27% of the patients. Of the patients in whom OPDIVO QVANTIG was withheld for pneumonitis, reinitiated OPDIVO QVANTIG after symptom improvement; of these, (50%) had recurrence of pneumonitis.. Immune-Mediated Colitis. OPDIVO QVANTIG can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.Immune-mediated colitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade (0.4%) and Grade (2.4%) adverse reactions. Colitis led to withholding of OPDIVO QVANTIG in 2.0% of patients. Systemic corticosteroids were required in 100% (7/7) of patients with colitis. Colitis resolved in 71% of the patients. Of the patients in whom OPDIVO QVANTIG was withheld for colitis, reinitiated OPDIVO QVANTIG after symptom improvement; of these, (67%) had recurrence of colitis.. Immune-Mediated Hepatitis and Hepatotoxicity. OPDIVO QVANTIG can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology. Immune-mediated hepatitis occurred in 2.4% (6/247) of patients receiving OPDIVO QVANTIG, including Grade (1.6%), and Grade (0.8%) adverse reactions. Hepatitis led to permanent discontinuation of OPDIVO QVANTIG in 0.8% and withholding of OPDIVO QVANTIG in 1.6% of patients.Systemic corticosteroids were required in 100% (6/6) of patients with hepatitis. Hepatitis resolved in 67% of the patients. Of the patients in whom OPDIVO QVANTIG was withheld for hepatitis, reinitiated OPDIVO QVANTIG after symptom improvement; of these, (50%) had recurrence of hepatitis.. Intravenous Nivolumab with Cabozantinib. Nivolumab in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade and ALT and AST elevations compared to nivolumab alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt nivolumab and cabozantinib and consider administering corticosteroids [see Dosage and Administration (2.4) ].With the combination of intravenous nivolumab and cabozantinib, Grades and increased ALT or AST were seen in 11% (35/320) of patients. ALT or AST >3 times ULN (Grade >=2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade >=2 increased ALT or AST who were rechallenged with either intravenous nivolumab (n=11) or cabozantinib (n=9) administered as single agent or with both (n=24), recurrence of Grade >=2 increased ALT or AST was observed in patients receiving intravenous nivolumab, patients receiving cabozantinib, and patients receiving both intravenous nivolumab and cabozantinib.. Immune-Mediated Endocrinopathies. Adrenal Insufficiency OPDIVO QVANTIG can cause primary or secondary adrenal insufficiency. For Grade or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ].Adrenal insufficiency occurred in 2% (5/247) of patients receiving OPDIVO QVANTIG, including Grade (0.8%) and Grade (1.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO QVANTIG in 0.4% of patients and withholding of OPDIVO QVANTIG in 0.4% of patients.Systemic corticosteroids were required in 100% (5/5) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 20% of the patients. Intravenous Nivolumab with CabozantinibAdrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received intravenous nivolumab with cabozantinib, including Grade (2.2%) and Grade (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of intravenous nivolumab and cabozantinib in 0.9% and withholding of intravenous nivolumab and cabozantinib in 2.8% of patients with RCC. Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the patients in whom intravenous nivolumab with cabozantinib was withheld for adrenal insufficiency, reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and had recurrence of adrenal insufficiency.HypophysitisOPDIVO QVANTIG can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ].Intravenous NivolumabHypophysitis occurred in 0.6% (12/1994) of patients treated with single agent intravenous nivolumab, including Grade (0.2%) and Grade (0.3%). Hypophysitis led to permanent discontinuation of intravenous nivolumab in <0.1% and withholding of intravenous nivolumab in 0.2% of patients. Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the patients in whom intravenous nivolumab was withheld for hypophysitis, reinitiated intravenous nivolumab after symptom improvement; of these, none had recurrence of hypophysitis. Thyroid DisordersOPDIVO QVANTIG can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ].ThyroiditisThyroiditis occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG, including Grade (0.4%) adverse reaction. Systemic corticosteroids were not required in the patient with thyroiditis. Thyroiditis did not resolve in this patient.HyperthyroidismHyperthyroidism occurred in 0.8% (2/247) of patients receiving OPDIVO QVANTIG, including Grade (0.4%) adverse reactions. Systemic corticosteroids were not required in patients with hyperthyroidism. Hyperthyroidism resolved in 50% of the patients.Hypothyroidism Hypothyroidism occurred in 9% (23/247) of patients receiving OPDIVO QVANTIG, including Grade (5.7%) adverse reactions. Hypothyroidism led to withholding of OPDIVO QVANTIG in 0.8% of patients.Systemic corticosteroids were not required in patients with hypothyroidism. Hypothyroidism resolved in 4.3% of the 23 patients. Of the patient in whom OPDIVO QVANTIG was withheld for hypothyroidism, OPDIVO QVANTIG was not reinitiated after symptom improvement.Type Diabetes Mellitus, which can present with Diabetic KetoacidosisMonitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ].Grade diabetes occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG. No patients with diabetes required systemic corticosteroids. Diabetes did not resolve in this patient.. Immune-Mediated Nephritis with Renal Dysfunction. OPDIVO QVANTIG can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology.Grade immune-mediated nephritis and renal dysfunction occurred in 1.2% (3/247) of patients receiving OPDIVO QVANTIG. Immune-mediated nephritis and renal dysfunction led to withholding of OPDIVO QVANTIG in 1.2% of patients.Systemic corticosteroids were required in 100% (3/3) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 100% of the patients. Of the patients in whom OPDIVO QVANTIG was withheld for nephritis or renal dysfunction, reinitiated OPDIVO QVANTIG after symptom improvement without recurrence of nephritis or renal dysfunction.. Immune-Mediated Dermatologic Adverse Reactions. OPDIVO QVANTIG can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ].Immune-mediated rash occurred in 7% (17/247) of patients, including Grade (0.8%) and Grade (2.8%) adverse reactions. Immune-mediated rash led to withholding of OPDIVO QVANTIG in 1.2% of patients.Systemic corticosteroids were required in 47% (8/17) of patients with immune-mediated rash. Rash resolved in 77% of the 17 patients. Of the patients in whom OPDIVO QVANTIG was withheld for immune-mediated rash, all reinitiated OPDIVO QVANTIG after symptom improvement; of these, all (100%) had recurrence of immune-mediated rash.. Other Immune-Mediated Adverse Reactions. The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO QVANTIG or intravenous nivolumab as single agent or in combination with chemotherapy or immunotherapy, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.Cardiac/Vascular: Myocarditis, pericarditis, vasculitisNervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathyOcular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision lossGastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitisMusculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumaticEndocrine: HypoparathyroidismOther (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.. 5.2Complications of Allogeneic Hematopoietic Stem Cell Transplantation Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause) [see Adverse Reactions (6.1)]. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.. 5.3Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO QVANTIG can cause fetal harm when administered to pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].. 5.4Increased Mortality in Patients with Multiple Myeloma when Nivolumab Is Added to Thalidomide Analogue and Dexamethasone In randomized clinical trials in patients with multiple myeloma, the addition of PD-1 blocking antibody, including intravenous nivolumab, to thalidomide analogue plus dexamethasone, use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with PD-1 or PD-L1 blocking antibody in combination with thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.