ADVERSE REACTIONS SECTION.

6 ADVERSE 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)].oInfusion-related reactions [see Warnings and Precautions (5.2)].. oSevere and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)].. oInfusion-related reactions [see Warnings and Precautions (5.2)].. Most common adverse reactions (>=20%) with YERVOY as single agent are fatigue, diarrhea, pruritus, rash, nausea, and headache. (6.1) Most common adverse reactions (>=20%) with YERVOY in combination with nivolumab are fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness. (6.1) Most common adverse reactions (>=20%) with YERVOY in combination with nivolumab and platinum-doublet chemotherapy are fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. (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.. 6.1 Clinical 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The data described in the Warnings and Precautions section reflect exposure to YERVOY mg/kg as single agent (or in combination with an investigational gp100 peptide vaccine) in 511 patients in Study MDX010-20; YERVOY mg/kg administered with nivolumab mg/kg in 1,362 patients in CHECKMATE-214, CHECKMATE-142, CHECKMATE-227, and CHECKMATE-743; YERVOY mg/kg administered with nivolumab mg/kg in 456 patients enrolled in CHECKMATE-067, CHECKMATE-040, and another randomized trial; and to YERVOY mg/kg, administered in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA.. Unresectable or Metastatic Melanoma. The safety of YERVOY was evaluated in 643 previously treated patients with unresectable or metastatic melanoma in Study MDX010-20 [see Clinical Studies (14.1)]. Study MDX010-20 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Patients received YERVOY mg/kg by intravenous infusion for doses as single agent (n=131), YERVOY with an investigational gp100 peptide vaccine (n=380), or gp100 peptide vaccine as single agent (n=132). Patients in the trial received median of doses (range: to doses).The trial population characteristics were: median age 57 years (range: 19 to 90), 59% male, 94% White, and baseline ECOG performance status (56%).YERVOY was discontinued for adverse reactions in 10% of patients. Table presents adverse reactions from Study MDX010-20.Table 4: Selected Adverse Reactions (>=5%) in Patients Receiving YERVOY with Difference Between Arms of >5% for All Grades and >1% for Grades to Compared to gp100 Peptide Vaccine in Study MDX010-20Adverse ReactionsYERVOY mg/kg n=131YERVOY mg/kg and gp100n=380gp100n=132All Grades (%)Grade3 to (%)All Grades(%)Grade3 to (%)All Grades (%)Grade3 to (%)General and Administration-Site Conditions Fatigue417345313Gastrointestinal Diarrhea325374201 Colitis855320Dermatologic Pruritus31021<1110 Rash29225280. Unresectable or Metastatic Melanoma: In Combination with Nivolumab. The safety of YERVOY, administered with nivolumab 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 (14.1)]. 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:oYERVOY mg/kg by intravenous infusion over 90 minutes with nivolumab mg/kg by intravenous infusion every weeks for doses followed by nivolumab as single agent at dose of mg/kg by intravenous infusion every weeks (YERVOY and nivolumab arm; n=313), oroNivolumab mg/kg by intravenous infusion every weeks (nivolumab arm; n=313), oroYERVOY mg/kg by intravenous infusion over 90 minutes every weeks for up to doses (YERVOY arm; n=311).The median duration of exposure to nivolumab was 2.8 months (range: day to 36.4 months) for the YERVOY and nivolumab arm. In the YERVOY and nivolumab arm, 39% were exposed to nivolumab for >=6 months and 30% exposed for >1 year.Serious adverse reactions (74%), adverse reactions leading to permanent discontinuation (47%) or to dosing delays (58%), and Grade or adverse reactions (72%) occurred in patients treated with YERVOY and nivolumab.The most frequent (>=10%) serious adverse reactions in the YERVOY and nivolumab arm were diarrhea (13%), colitis (10%), and pyrexia (10%). The most frequent adverse reactions leading to discontinuation of both drugs in the YERVOY and nivolumab arm were colitis (10%), diarrhea (8%), increased ALT (4.8%), increased AST (4.5%), and pneumonitis (1.9%).The most common (>=20%) adverse reactions in the YERVOY and nivolumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. Tables and summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.Table 5: Adverse Reactions Occurring in >=10% of Patients on the YERVOY and Nivolumab Arm or the Nivolumab Arm and at Higher Incidence than in the YERVOY Arm (Between Arm Difference of >=5% All Grades or >=2% Grades 3-4) CHECKMATE-067Toxicity was graded per NCI CTCAE v4. Includes asthenia and fatigue. 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. Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. Includes hypertension and blood pressure increased.Adverse ReactionYERVOY andNivolumab(n=313)Nivolumab(n=313)YERVOY(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 Vomiting313.8201.0171.6Skin and Subcutaneous Tissue Rashb 536401.9423.5 Vitiligo90100.350Musculoskeletal and Connective Tissue Musculoskeletal painc 322.6423.8361.9 Arthralgia210.3211.0160.3Metabolism 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 YERVOY with nivolumab: 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 6: Laboratory Abnormalities Worsening from Baselinea Occurring in >=20% of Patients Treated with YERVOY with Nivolumab or Single-Agent Nivolumab and at Higher Incidence than in the YERVOY 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: YERVOY and nivolumab (range: 75 to 297); nivolumab (range: 81 to 306); YERVOY (range: 61 to 301)Laboratory AbnormalityYERVOY andNivolumabNivolumabYERVOYAll Grades (%)Grade3-4 (%)All Grades (%)Grade3-4 (%)All Grades (%)Grade3-4 (%)Chemistry Increased ALT 5516253.0292.7 Hyperglycemia 535467260 Increased AST 5213293.7291.7 Hyponatremia4510223.3267 Increased lipase43223212247 Increased alkaline phosphatase416272.0232.0 Hypocalcemia311.1150.7200.7 Increased amylase2710192.7151.6 Increased creatinine 262.7190.7171.3Hematology Anemia522.7412.6416 Lymphopenia395414.9294.0. oYERVOY mg/kg by intravenous infusion over 90 minutes with nivolumab mg/kg by intravenous infusion every weeks for doses followed by nivolumab as single agent at dose of mg/kg by intravenous infusion every weeks (YERVOY and nivolumab arm; n=313), or. oNivolumab mg/kg by intravenous infusion every weeks (nivolumab arm; n=313), or. oYERVOY mg/kg by intravenous infusion over 90 minutes every weeks for up to doses (YERVOY arm; n=311).. Adjuvant Treatment of Melanoma. The safety of YERVOY was evaluated in Study E1609, an open-label, multicenter, randomized trial for the adjuvant treatment of patients with completely resected node positive cutaneous melanoma [see Clinical Studies (14.2)]. Patients received YERVOY mg/kg intravenously every weeks for doses followed by mg/kg every 12 weeks for up to additional doses, or high-dose interferon-2b (HDI). Among patients who received YERVOY, 55% were exposed for months or longer and 42% were exposed for greater than year.Fatal adverse reactions occurred in 1.4% of patients who received YERVOY, including gastric perforation (0.2%), and cardiac arrest (0.2%). Permanent discontinuation of YERVOY due to an adverse reaction occurred in 35% of patients.The most common adverse reactions (>=20%) in the YERVOY arm were fatigue, diarrhea, rash, pruritus, nausea, and headache. Table summarizes adverse reactions in E1609.Table 7: Adverse Reactions (>10%) in Patients Receiving YERVOY mg/kg in E1609Adverse ReactionYERVOY mg/kgn=516HDIn=520All Grades (%)Grade to (%)All Grades (%)Grade to (%)General disorders and administration site conditions Fatigue5638722 Decreased appetite140.6532.1 Pyrexia100310.8Gastrointestinal Diarrhea4910340.8 Nausea291.2664.2 Abdominal Pain19190.4 Vomiting110.6262.3 Colitis10810.4Dermatologic Rash464181 Pruritus412150Nervous System Disorders Headache252453Endocrine Endocrine disorders, other194.120 Hypothyroidism110.6100.2Adrenal insufficiency1020.60. Other Clinical Experience. Across clinical studies in which patients received YERVOY as single agent at doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence <1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.. Advanced Renal Cell Carcinoma: In Combination with Nivolumab. The safety of YERVOY in combination with nivolumab was evaluated in 1082 patients with previously untreated advanced RCC in CHECKMATE-214 [see Clinical Studies (14.3)]. Patients received YERVOY mg/kg with nivolumab mg/kg intravenously every weeks for doses followed by nivolumab as single agent at dose of mg/kg every weeks (n=547) or sunitinib 50 mg orally daily for first weeks of each 6-week cycle (n=535). The median duration of treatment was 7.9 months (range: day to 21.4+ months) in YERVOY and nivolumab arm. In this trial, 57% of patients in the YERVOY and nivolumab arm were exposed to treatment for greater than months and 38% of patients were exposed to treatment for greater than year.Serious adverse reactions occurred in 59% of patients receiving YERVOY with nivolumab. The most frequent serious adverse reactions reported in >=2% of patients treated with YERVOY and nivolumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In patients who received YERVOY with nivolumab, study therapy was discontinued for adverse reactions in 31% and delayed for adverse reactions in 54%.The most common adverse reactions (>=20%) in the YERVOY and nivolumab arm were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, vomiting, dyspnea, and decreased appetite. Table summarizes adverse reactions in CHECKMATE-214.Table 8: Adverse Reactions (>15%) in Patients Receiving YERVOY and Nivolumab in 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 ReactionYERVOY mg/kg and Nivolumabn=547Sunitinibn=535Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)General and Administration Site Conditions Fatiguea 5886913 Pyrexia250.7170.6 Edemab 160.5170.6Skin and Subcutaneous Tissue Rashc 393.7251.1 Pruritus/generalized pruritus330.5110Gastrointestinal Diarrhea384.6586 Nausea302.0431.5 Vomiting200.9282.1 Abdominal pain 191.6241.9 Constipation170.4180Musculoskeletal and Connective Tissue Musculoskeletal paind 374.0402.6 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 summarizes the laboratory abnormalities in CHECKMATE-214.Table 9: Laboratory Abnormalities (>15%) Worsening from Baseline in Patients Receiving YERVOY and Nivolumab in 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: nivolumab and YERVOY group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients).Laboratory AbnormalityYERVOY mg/kg and Nivolumaba Sunitiniba Grades 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 phosphatase292.0321.0 Hyperkalemia292.4282.9 Hypocalcemia210.4350.6 Hypomagnesemia160.4261.6Hematology Anemia433.0649 Lymphopenia3656314In addition, among patients with TSH <= ULN at baseline, lower proportion of patients experienced treatment-emergent elevation of TSH ULN in the YERVOY with nivolumab group compared to the sunitinib group (31% and 61%, respectively).. MSI-H or dMMR Metastatic Colorectal Cancer. Treatment of MSI -H or dMMR mCRC: In Combination with Nivolumab The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-8HW, randomized, open-label, three arm trial in immunotherapy naive patients with MSI-H or dMMR mCRC [see Clinical Studies (14.4)]. Patients received one of the following:oYERVOY mg/kg every weeks and nivolumab 240 mg every weeks for maximum of doses, then nivolumab 480 mg every weeks.oNivolumab 240 mg every weeks for doses, then nivolumab 480 mg every weeks.oInvestigators choice chemotherapy: mFOLFOX or FOLFIRI [see Clinical Studies (14.4)].In the YERVOY and nivolumab arm, the median duration of exposure to YERVOY was 2.1 months (range day to 3.7 months); patients received median of doses (range 1-4). The median duration of treatment in the YERVOY and nivolumab arm was 20.5 months (range: day to 35.9 months); 70% were exposed to treatment for >6 months, and 63% were exposed for >1 year. The median duration of treatment was 16.4 months (range: day to 36 months) in the nivolumab-only arm; 64% were exposed to treatment for >6 months, and 54% were exposed for >1 year.Serious adverse reactions occurred in 46% of patients receiving YERVOY in combination with nivolumab, and 39% of patients receiving nivolumab alone. The most frequent serious adverse reactions reported in >=1% of patients who received YERVOY with nivolumab were adrenal insufficiency (2.8%), hypophysitis (2.8%), diarrhea (2.0%), abdominal pain (2.0%), small intestinal obstruction (2.0%), pneumonia (1.7%), acute kidney injury (1.4%), immune-mediated enterocolitis (1.4%), pneumonitis (1.4%), colitis (1.1%), large intestinal obstruction (1.1%), and urinary tract infection (1.1%). The most frequent serious adverse reactions reported in >1% of patients who received OPDIVO, as single agent, were intestinal obstruction (2.3%), acute kidney injury (1.7%), COVID-19 (1.7%), abdominal pain (1.4%), diarrhea (1.4%), ileus (1.4%), subileus (1.4%), pulmonary embolism (1.4%), adrenal insufficiency (1.1%) and pneumonia (1.1%).Fatal adverse reactions occurred in (0.6%) patients who received YERVOY in combination with nivolumab; these included myocarditis, and pneumonitis (1 each).YERVOY and/or nivolumab were permanently discontinued in 19% of patients receiving the combination. The most frequent adverse reactions (>1%) leading to permanent discontinuation were adrenal insufficiency (1.4%), immune-mediated enterocolitis (1.1%), and pneumonitis (1.1%). Nivolumab was permanently discontinued in 13% of patients receiving single agent nivolumab. Adverse reactions leading to the delay of YERVOY and/or nivolumab occurred in 48% of patients receiving the combination; single agent nivolumab was delayed in 37% of patients due to adverse reactions.The most common adverse reactions reported in >=20% of patients treated with YERVOY in combination with nivolumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions reported in >=20% of patients treated with nivolumab as single agent, were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain. Tables 10 and 11 summarize the adverse reactions and selected laboratory abnormalities, for YERVOY in combination with nivolumab and nivolumab arms respectively, in CHECKMATE-8HW.Table 10: Adverse Reactions in >=10% in Patient and Difference Between Arms of >5% for All Grades in CHECKMATE-8HWToxicity was graded per NCI CTCAE v5.a Includes colitis, diarrhea, enterocolitis, immune-mediated enterocolitisAdverse ReactionYERVOY and Nivolumab(n=352)Nivolumab(n=351)All Grades (%)Grades or (%)All Grades (%)Grades or (%)Gastrointestinal Diarrheaa354.5303.4Skin and Subcutaneous Tissue Pruritus 300230Musculoskeletal and Connective Tissue Arthralgia200.6150.6Endocrine Hypothyroidism180.6100 Hyperthyroidism12050Table 11: Laboratory Values Worsening from Baselinea in >=10% of Patients and Difference Between Arms of >5% for All Grades CHECKMATE-8HWa Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 108 to 343 patients) or nivolumab group (range: 102 to 348 patients).Laboratory Abnormalitya YERVOY and Nivolumab(n=352)Nivolumab(n=351)All Grades (%)Grades 3-or (%)All Grades (%)Grades or -4 (%)Hematology Lymphocytes decreased305374 Neutrophils decreased211.7120.6Chemistry Lipase increased44103211 Amylase increased414.6335 ALT increased393.5321.4 AST increased383.2291.4 Sodium decreased363.2302.3 Creatinine increased 322251.4 Potassium increased291.2350.9 Glucose decreased170120. oYERVOY mg/kg every weeks and nivolumab 240 mg every weeks for maximum of doses, then nivolumab 480 mg every weeks.. oNivolumab 240 mg every weeks for doses, then nivolumab 480 mg every weeks.. oInvestigators choice chemotherapy: mFOLFOX or FOLFIRI [see Clinical Studies (14.4)].. Hepatocellular Carcinoma: In Combination with Nivolumab. Unresectable or Metastatic Hepatocellular Carcinoma (HCC) The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-9DW, randomized, open-label trial in adult patients with unresectable or metastatic HCC [see Clinical Studies (14.5)]. Patients received YERVOY in combination with nivolumab (n=332) or investigators choice of lenvatinib (n=275) or sorafenib (n=50) at the following dosage:oYERVOY mg/kg administered intravenously over 30 minutes in combination with nivolumab mg/kg administered intravenously over 30 minutes every weeks, for maximum of doses, followed by single agent nivolumab at 480 mg administered intravenously over 30 minutes every weeks, oroInvestigators choice:oLenvatinib mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight >=60 kg), oroSorafenib 400 mg orally twice daily In the YERVOY and nivolumab arm, the median duration of exposure to nivolumab was 4.7 months (range: <0.1 to 24.4 months), 45% were exposed for >6 months and 30% were exposed for >1 year. Serious adverse reactions occurred in 53% of patients treated with YERVOY in combination with nivolumab. The most frequent non-liver-related serious adverse reactions reported in >=2% were diarrhea/colitis (4.5%), gastrointestinal hemorrhage (3%), and rash (2.4%).Liver-related serious adverse reactions occurred in 17% of patients treated with YERVOY in combination with nivolumab, including Grade 3-4 events in 16% of patients. The most frequently reported all grade liver-related serious adverse reactions occurring in >=1% of patients were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2.4%), ascites (2.4%), and hepatotoxicity (1.2%).Fatal adverse reactions occurred in 12 (3.6%) patients who received YERVOY in combination with nivolumab; these included (1.2%) patients who died due to immune-mediated or autoimmune hepatitis and (1.2%) patients who died of hepatic failure.Permanent discontinuation due to an adverse reaction occurred in 27% of patients treated with YERVOY in combination with nivolumab. Adverse reactions leading to permanent discontinuation in >1% of patients included immune-mediated hepatitis (1.8%), diarrhea/colitis (1.8%), and hepatic failure (1.2%). Dosage interruptions due to an adverse reaction occurred in 62% of patients treated with YERVOY in combination with nivolumab. Adverse reactions which required dosage interruption in >5% of patients included increased AST (13%), increased ALT (11%), and diarrhea/colitis (8%).The most common (>20%) adverse reactions were rash, pruritus, fatigue, and diarrhea.Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9DW.Table 12: Adverse Reactions Occurring in >=10% of YERVOY in combination with Nivolumab-Treated Patients CHECKMATE-9DWToxicity was graded per NCI CTCAE v5a Represents composite of multiple related terms.Adverse ReactionYERVOY and Nivolumab(n=332)Lenvatinib or Sorafenib(n=325)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Skin and Subcutaneous Tissue Rasha 363.6151.2 Pruritus341.570.3General Fatiguea 332.4394 Pyrexiaa 150.691.5 Edemaa 131.2131.5Gastrointestinal Diarrhea256393.4 Abdominal paina 141.2272.5 Nausea100.3160.9Musculoskeletal and Connective Tissue Musculoskeletal paina 170.6230.3 Arthralgia120.3130.6Metabolism and Nutrition Decreased appetite161.2281.8Endocrine Hypothyroidisma 140270 Hyperthyroidism110.61.50Respiratory, Thoracic and Mediastinal Cougha 13080Clinically important adverse reactions reported in <10% of patients who received YERVOY with nivolumab were hyperglycemia (8%), adrenal insufficiency (4.2%), pneumonitis (2.7%), and pancreatitis (2.4%).Table 13: Laboratory Values Worsening from Baselinea Occurring in >=20% of YERVOY in combination with Nivolumab-Treated Patients CHECKMATE-9DWa Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 168 to 331 patients) and lenvatinib or sorafenib group (range: 145 to 315 patients).Laboratory AbnormalityYERVOY and Nivolumab(n=332)Lenvatinib or Sorafenib(n=325)Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Chemistry Increased AST62295114 Increased ALT6117469 Increased lipase5816395 Decreased albumin480.9570.6 Hyponatremia456423.8 Hyperglycemia4415322.1 Increased bilirubin4410448 Increased amylase416261 Increased alkaline phosphatase361.2385 Hypocalcemia290.9460 Increased creatinine262.4230.6 Hypokalemia212.1202.6Hematology Anemia445403.8 Lymphopenia406.1408 Thrombocytopenia274444.8 Neutropenia244323.5. oYERVOY mg/kg administered intravenously over 30 minutes in combination with nivolumab mg/kg administered intravenously over 30 minutes every weeks, for maximum of doses, followed by single agent nivolumab at 480 mg administered intravenously over 30 minutes every weeks, or. oInvestigators choice:oLenvatinib mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight >=60 kg), oroSorafenib 400 mg orally twice daily oLenvatinib mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight >=60 kg), or. oSorafenib 400 mg orally twice daily. Previously Treated Hepatocellular Carcinoma The safety of YERVOY mg/kg in combination with nivolumab mg/kg was evaluated in subgroup of 49 patients with HCC and Child-Pugh Class cirrhosis who progressed on or were intolerant to sorafenib enrolled in Cohort of CHECKMATE-040. YERVOY and nivolumab were administered every weeks for four doses, followed by single-agent nivolumab 240 mg every weeks until disease progression or unacceptable toxicity.During the YERVOY and nivolumab combination period, 33 of 49 (67%) patients received all four planned doses of YERVOY and nivolumab. During the entire treatment period, the median duration of exposure to YERVOY was 2.1 months (range: to 4.5 months) and to nivolumab was 5.1 months (range: to 35+ 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.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.Table 14 summarizes the adverse reactions and Table 15 summarizes the laboratory abnormalities of YERVOY in combination with nivolumab in CHECKMATE-040.Table 14: Adverse Reactions Occurring in >=10% of Patients Receiving YERVOY in Combination with Nivolumab in Cohort of CHECKMATE-040Adverse ReactionYERVOY and Nivolumab(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 receiving YERVOY with nivolumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%).Table 15: Select Laboratory Abnormalities (>=10%) Worsening from Baseline in Patients Receiving YERVOY in Combination with Nivolumab in Cohort of CHECKMATE-040Laboratory AbnormalityYERVOY and Nivolumab(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 YERVOY with nivolumab, 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.. First-line Treatment of Metastatic NSCLC: In Combination with Nivolumab The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-227, randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.6)]. The trial excluded patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients received YERVOY mg/kg by intravenous infusion over 30 minutes every weeks and nivolumab mg/kg by intravenous infusion over 30 minutes every weeks or platinum-doublet chemotherapy every weeks for cycles. The median duration of therapy in YERVOY and nivolumab-treated patients was 4.2 months (range: day to 25.5 months): 39% of patients received YERVOY and nivolumab for >6 months and 23% of patients received YERVOY and nivolumab for >1 year. The population characteristics were: median age 64 years (range: 26 to 87); 48% were >=65 years of age, 76% White, and 67% male. Baseline ECOG performance status was (35%) or (65%), 85% were former/current smokers, 11% had brain metastases, 28% had squamous histology and 72% had non-squamous histology.Serious adverse reactions occurred in 58% of patients. YERVOY and nivolumab were discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.The most frequent (>=2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. The most common (>=20%) adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus.Tables 16 and 17 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.Table 16: Adverse Reactions in >=10% of Patients Receiving YERVOY and Nivolumab CHECKMATE-227a Includes fatigue and asthenia. Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, and periorbital edema. Includes autoimmune dermatitis, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, granulomatous dermatitis, rash generalized, drug eruption, dyshidrotic eczema, eczema, exfoliative rash, nodular rash, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption. Includes pruritus and pruritus generalized. Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, and pain in extremity. Includes colitis, colitis microscopic, colitis ulcerative, diarrhea, enteritis infectious, enterocolitis, enterocolitis infectious, and enterocolitis viral. Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. Includes dyspnea and dyspnea exertional. Includes cough and productive cough. Includes alanine aminotransferase increased, aspartate aminotransferase increased, autoimmune hepatitis, blood bilirubin increased, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatitis, hepatitis E, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test abnormal, liver function test increased, transaminases increased. Includes autoimmune thyroiditis, blood thyroid stimulating hormone increased, hypothyroidism, primary hypothyroidism, thyroiditis, and tri-iodothyronine free decreased. Contains blood thyroid stimulating hormone decreased, hyperthyroidism, and tri-iodothyronine free increased. Includes lower respiratory tract infection, lower respiratory tract infection bacterial, lung infection, pneumonia, pneumonia adenoviral, pneumonia aspiration, pneumonia bacterial, pneumonia klebsiella, pneumonia influenzal, pneumonia viral, atypical pneumonia, organizing pneumonia.Adverse ReactionYERVOY and Nivolumab(n=576)Platinum-Doublet Chemotherapy(n=570)All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)General Fatiguea 446424.4 Pyrexia180.5110.4 Edemab 140.2120.5Skin and Subcutaneous Tissue Rashc 344.7100.4 Pruritusd 210.53.30Metabolism and Nutrition Decreased appetite312.3261.4Musculoskeletal and Connective Tissue Musculoskeletal paine 271.9160.7 Arthralgia130.92.50.2Gastrointestinal Diarrhea/colitisf 263.6160.9 Nausea211.0422.5 Constipation180.3270.5 Vomiting131.0182.3 Abdominal paing 100.290.7Respiratory, Thoracic, and Mediastinal Dyspneah 264.3162.1 Coughi 230.2130Hepatobiliary Hepatitisj 219101.2Endocrine Hypothyroidismk 160.51.20 Hyperthyroidisml 1000.50Infections and Infestations Pneumoniam 13784.0Nervous System Headache110.560Other clinically important adverse reactions in CHECKMATE-227 were:Skin and Subcutaneous Tissue: urticaria, alopecia, erythema multiforme, vitiligoGastrointestinal: stomatitis, pancreatitis, gastritisMusculoskeletal and Connective Tissue: arthritis, polymyalgia rheumatica, rhabdomyolysisNervous System: peripheral neuropathy, autoimmune encephalitisBlood and Lymphatic System: eosinophiliaEye Disorders: blurred vision, uveitisCardiac: atrial fibrillation, myocarditisTable 17: Laboratory Values Worsening from Baselinea Occurring in >=20% of Patients on YERVOY and Nivolumab CHECKMATE-227a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 494 to 556 patients) and chemotherapy group (range: 469 to 542 patients).Laboratory AbnormalityYERVOY and NivolumabPlatinum-doublet ChemotherapyGrades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Hematology Anemia463.67814 Lymphopenia4656015Chemistry Hyponatremia4112264.9 Increased AST395260.4 Increased ALT367270.7 Increased lipase3514143.4 Increased alkaline phosphatase343.8200.2 Increased amylase289181.9 Hypocalcemia281.7171.3 Hyperkalemia273.4220.4 Increased creatinine220.9170.2. First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Nivolumab and Platinum-Doublet Chemotherapy The safety of YERVOY in combination with nivolumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Clinical Studies (14.6)]. Patients received either YERVOY mg/kg administered every weeks in combination with nivolumab 360 mg administered every weeks and platinum-doublet chemotherapy administered every weeks for cycles; or platinum-doublet chemotherapy administered every weeks for cycles. The median duration of therapy in YERVOY in combination with nivolumab and platinum-doublet chemotherapy was months (range: day to 19 months): 50% of patients received YERVOY and nivolumab for >6 months and 13% of patients received YERVOY and nivolumab for >1 year. Serious adverse reactions occurred in 57% of patients who were treated with YERVOY in combination with nivolumab and platinum-doublet chemotherapy. The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. Study therapy with YERVOY in combination with nivolumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction. The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.Tables 18 and 19 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.Table 18: Adverse Reactions in >10% of Patients Receiving YERVOY and Nivolumab and Platinum-Doublet Chemotherapy CHECKMATE-9LAToxicity was graded per NCI CTCAE v4. Includes fatigue and asthenia. Includes myalgia, back pain, pain in extremity, musculoskeletal pain, bone pain, flank pain, muscle spasms, musculoskeletal chest pain, musculoskeletal disorder, osteitis, musculoskeletal stiffness, non-cardiac chest pain, arthralgia, arthritis, arthropathy, joint effusion, psoriatic arthropathy, synovitis. Includes colitis, ulcerative colitis, diarrhea, and enterocolitis. Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain. Includes acne, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, generalized exfoliative dermatitis, eczema, keratoderma blennorrhagica, palmar-plantar erythrodysesthesia syndrome, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, urticaria. Includes pruritus and generalized pruritus. Includes cough, productive cough, and upper-airway cough syndrome. Includes dyspnea, dyspnea at rest, and exertional dyspnea. Includes autoimmune thyroiditis, increased blood thyroid stimulating hormone, hypothyroidism, thyroiditis, and decreased free tri-iodothyronine. Includes dizziness, vertigo and positional vertigoAdverse ReactionYERVOY and Nivolumab and Platinum-Doublet Chemotherapy(n=358)Platinum-Doublet Chemotherapy(n=349)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)General Fatiguea 495404.9 Pyrexia140.6100.6Musculoskeletal and Connective Tissue Musculoskeletal painb 394.5272.0Gastrointestinal Nausea321.7410.9 Diarrheac 316181.7 Constipation210.6230.6 Vomiting182.0171.4 Abdominal paind 120.6110.9Skin and Subcutaneous Tissue Rashe 304.7100.3 Pruritusf 210.82.90 Alopecia110.8100.6Metabolism and Nutrition Decreased appetite282.0221.7Respiratory, Thoracic and Mediastinal Coughg 190.6150.9 Dyspneah 184.7143.2Endocrine Hypothyroidismi 190.33.40Nervous System Headache110.670 Dizzinessj 110.660Table 19: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on YERVOY and Nivolumab and Platinum-Doublet Chemotherapy CHECKMATE-9LAa Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab and platinum-doublet chemotherapy group (range: 197 to 347 patients) and platinum-doublet chemotherapy group (range: 191 to 335 patients).Laboratory AbnormalityYERVOY and Nivolumab and Platinum-Doublet ChemotherapyPlatinum-Doublet ChemotherapyGrades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)Hematology Anemia7097416 Lymphopenia4164011 Neutropenia40154215 Leukopenia3610409 Thrombocytopenia234.3245Chemistry Hyperglycemia457422.6 Hyponatremia3710277 Increased ALT344.3241.2 Increased lipase3112102.2 Increased alkaline phosphatase311.2260.3 Increased amylase307191.3 Increased AST303.5220.3 Hypomagnesemia291.2330.6 Hypocalcemia261.4221.8 Increased creatinine261.2230.6 Hyperkalemia221.7212.1. First-line Treatment of Unresectable Malignant Pleural Mesothelioma: In Combination with Nivolumab. The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-743, randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see Clinical Studies (14.7)]. Patients received either YERVOY mg/kg over 30 minutes by intravenous infusion every weeks and nivolumab mg/kg over 30 minutes by intravenous infusion every weeks for up to years; or platinum-doublet chemotherapy for up to cycles. The median duration of therapy in YERVOY and nivolumab-treated patients was 5.6 months (range: to 26.2 months); 48% of patients received YERVOY and nivolumab for >6 months and 24% of patients received YERVOY and nivolumab for >1 year.Serious adverse reactions occurred in 54% of patients who were treated with YERVOY in combination with nivolumab. The most frequent (>=2%) serious adverse reactions were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.Both YERVOY and nivolumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction. An additional 4.7% of patients permanently discontinued YERVOY alone due to adverse reactions.The most common (>=20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.Table 20: Adverse Reactions in >=10% of Patients Receiving YERVOY and Nivolumab CHECKMATE-743a Includes fatigue and asthenia. Includes pyrexia and tumor-associated fever. Includes edema, generalized edema, peripheral edema, and peripheral swelling. Includes musculoskeletal pain, back pain, bone pain, flank pain, involuntary muscle contractions, muscle spasms, muscle twitching, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, polymyalgia rheumatica, and spinal pain. Includes rash, acne, acneiform dermatitis, allergic dermatitis, atopic dermatitis, autoimmune dermatitis, bullous dermatitis, contact dermatitis, dermatitis, drug eruption, dyshidrotic eczema, eczema, erythematous rash, exfoliative rash, generalized exfoliative dermatitis, generalized rash, granulomatous dermatitis, keratoderma blennorrhagica, macular rash, maculopapular rash, morbilliform rash, nodular rash, papular rash, psoriasiform dermatitis, pruritic rash, pustular rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, toxic skin eruption, and urticaria. Includes pruritus, allergic pruritus, and generalized pruritus. Includes diarrhea, colitis, enteritis, infectious enteritis, enterocolitis, infectious enterocolitis, microscopic colitis, ulcerative colitis, and viral enterocolitis. Includes abdominal pain, abdominal discomfort, abdominal tenderness, gastrointestinal pain, lower abdominal pain, and upper abdominal pain. Includes dyspnea, dyspnea at rest, and exertional dyspnea. Includes cough, productive cough, and upper-airway cough syndrome. Includes hypothyroidism, autoimmune thyroiditis, decreased free tri-iodothyronine, increased blood thyroid stimulating hormone, primary hypothyroidism, thyroiditis, and autoimmune hypothyroidism. Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. Includes pneumonia, lower respiratory tract infection, lung infection, aspiration pneumonia, and Pneumocystis jirovecii pneumonia.Adverse ReactionYERVOY and Nivolumab(n=300)Chemotherapy(n=284)All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)General Fatiguea 434.3456 Pyrexiab 181.34.60.7 Edemac 17080Musculoskeletal and Connective Tissue Musculoskeletal paind 383.3171.1 Arthralgia131.01.10Skin and Subcutaneous Tissue Rashe 342.7110.4 Pruritusf 211.01.40Gastrointestinal Diarrheag 326121.1 Nausea240.7432.5 Constipation190.3300.7 Abdominal painh 151100.7 Vomiting140182.1Respiratory, Thoracic, and Mediastinal Dyspneai 272.3163.2 Coughj 230.790Metabolism and Nutrition Decreased appetite241.0251.4Endocrine Hypothyroidismk 1501.40Infections and Infestations Upper respiratory tract infectionl 120.370 Pneumoniam 104.04.22.1Table 21: Laboratory Values Worsening from Baselinea Occurring in >=20% of Patients on YERVOY and Nivolumab CHECKMATE-743a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 109 to 297 patients) and chemotherapy group (range: 90 to 276 patients).Laboratory AbnormalityYERVOY and NivolumabChemotherapyGrades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Chemistry Hyperglycemia533.7341.1 Increased AST387170 Increased ALT377150.4 Increased lipase341390.8 Hyponatremia328212.9 Increased alkaline phosphatase313.1120 Hyperkalemia304.1160.7 Hypocalcemia280160 Increased amylase265130.9 Increased creatinine200.3200.4Hematology Lymphopenia4385714 Anemia432.47515. First-line Treatment of Unresectable Advanced or Metastatic ESCC: In Combination with Nivolumab. The safety of YERVOY in combination with nivolumab 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 (14.8)]. Patients received one of the following treatments:oYERVOY mg/kg every weeks in combination with nivolumab 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 YERVOY and nivolumab, the median duration of exposure was 2.8 months (range: to 24 months).Serious adverse reactions occurred in 69% of patients receiving YERVOY in combination with nivolumab. The most frequent serious adverse reactions reported in >=2% of patients who received YERVOY with nivolumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4.0%), 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 YERVOY in combination with nivolumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome. YERVOY and/or nivolumab were discontinued in 23% of patients and delayed in 46% of patients for an adverse reaction. The most common adverse reactions reported in >=20% of patients treated with YERVOY in combination with nivolumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation.Tables 22 and 23 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648.Table 22: Adverse Reactions in >=10% of Patients Receiving YERVOY and Nivolumab CHECKMATE-648Adverse ReactionYERVOY and Nivolumab(n=322)Cisplatin and 5-FU(n=304)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Toxicity was graded per NCI CTCAE v4. 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. Includes tumor associated fever. Includes asthenia and malaise. Includes aphthous ulcer, mouth ulceration, and mucosal inflammation. Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper. Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, and spinal pain. Includes organizing pneumonia, pneumonia bacterial, and pneumonia pseudomonal. Includes productive cough.Skin and Subcutaneous Tissue Rasha 313.170 Pruritis170.93.60General Fatiguec 282.5414.9 Pyrexiab 230.9120.3Gastrointestinal Nausea220.6562.6 Diarrhea221.9202.0 Constipation200.3431.0 Vomiting151.6193.0 Dysphagia125124.9 Stomatitisd 110.6353.0 Abdominal paine 100.9110.7Metabolism and Nutrition Decreased appetite174.0506Musculoskeletal and Connective Tissue Musculoskeletal painf 140.680.3Infections and Infestations Pneumoniag 148102.6Endocrine Hypothyroidism1400.30Respiratory, Thoracic and Mediastinal Coughh 130.3130.3Investigations Weight decreased121.9111.0Table 23: Laboratory Values Worsening from Baselinea Occurring in >=10% of Patients on YERVOY and Nivolumab CHECKMATE-648Laboratory Abnormality YERVOY and Nivolumab(n=322)Cisplatin and 5-FU(n=304)Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 59 to 307 patients) or Cisplatin and 5-FU group (range: 56 to 283 patients).Hematology Anemia5276614 Lymphopenia5013448 Neutropenia131.34813 Thrombocytopenia121.0292.8Chemistry Hyponatremia4511408 Hyperglycemia434.3360.8 Increased AST396111.4 Increased ALT33680.7 Hypocalcemia320230.7 Increased alkaline phosphatase313.3150 Hyperkalemia231.6240.7 Hypokalemia195176 Hypercalcemia152.080 Hypoglycemia151.270 Increased creatinine150.7310.7 Hypomagnesemia150251.8. oYERVOY mg/kg every weeks in combination with nivolumab 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).. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of YERVOY. 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.Blood and lymphatic system disorders: hemophagocytic lymphohistiocytosis (HLH)Immune System: graft-versus-host disease, solid organ transplant rejectionSkin and Subcutaneous Tissue: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Unresectable or Metastatic Melanoma The efficacy of YERVOY was investigated in Study MDX010-20, randomized (3:1:1), double-blind, double-dummy trial (NCT00094653) that included patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. The trial enrolled only patients with HLA-A20201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine. The trial excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Patients were randomized to YERVOY administered at dose of mg/kg as an intravenous infusion every weeks for doses with an investigational peptide vaccine with incomplete Freunds adjuvant gp100 administered at dose of mg peptide by deep subcutaneous injection every weeks for doses; gp100 administered at dose of mg by deep subcutaneous injection every weeks for doses as single agent with placebo; or YERVOY administered at dose of mg/kg by intravenous infusion every weeks for doses with placebo. The major efficacy outcome measure was overall survival (OS) in the YERVOY and gp100 arm compared to that in the single-agent gp100 arm. Secondary efficacy outcome measures were OS in the YERVOY and gp100 arm compared to the YERVOY arm, OS in the YERVOY arm compared to the gp100 arm, best overall response rate (BORR) as assessed by the investigator at week 24 between each of the trial arms, and duration of response. Assessment of tumor response was conducted at weeks 12 and 24, and every months thereafter. Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively.A total of 676 patients were randomized, 403 to YERVOY and gp100 arm, 137 to YERVOY single agent arm and 136 to gp100 single agent arm. Of the randomized patients, 61%, 59%, and 54% in the YERVOY and gp100, YERVOY, and gp100 arms, respectively, were male. Twenty-nine percent were >=65 years of age, the median age was 57 years, 71% had M1c stage, 12% had history of previously treated brain metastasis, 98% had ECOG performance status of and 1, 23% had received aldesleukin, and 38% had elevated LDH level. Sixty-one percent of patients randomized to either YERVOY-containing arm received all planned doses. The median duration of follow-up was 8.9 months.The efficacy results are shown in Table 25 and Figure 1.Table 25: Efficacy Results for Study MDX010-20a Not adjusted for multiple comparisons. Not ReachedYERVOY mg/kg n=137YERVOY mg/kg and gp100 n=403gp100 n=136Overall SurvivalMedian in months (95% CI)10 (8.0, 13.8)10 (8.5, 11.5)6 (5.5, 8.7)Hazard ratio (vs. gp100) (95% CI)0.66 (0.51, 0.87)0.68 (0.55, 0.85)p-valuep=0.0026a p=0.0004Hazard ratio (vs. YERVOY) (95% CI)1.04 (0.83, 1.30)Best Overall Response Rate (BORR) (95% CI)10.9%(6.3%, 17.4%)5.7%(3.7%, 8.4%)1.5%(0.2%, 5.2%)Median duration of response in monthsNRb 11.5NRb Figure 1: Kaplan-Meier Curves for Overall Survival in Study MDX010-20. Previously Untreated Metastatic Melanoma: In Combination with Nivolumab. CHECKMATE-067 (NCT01844505) was multicenter, randomized (1:1:1), double-blind trial in which 945 patients with previously untreated, unresectable or metastatic melanoma were randomized to one of the following arms: YERVOY and nivolumab, nivolumab, or YERVOY. 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:oYERVOY mg/kg with nivolumab mg/kg intravenously every weeks for doses, followed by nivolumab as single agent at dose of mg/kg by intravenous infusion every weeks (YERVOY and nivolumab arm),oNivolumab mg/kg by intravenous infusion every weeks (nivolumab arm), oroYERVOY mg/kg intravenously every weeks for doses followed by placebo every weeks (YERVOY 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 nivolumab-containing arm as compared with the YERVOY arm. The trial was not designed to assess whether adding YERVOY to nivolumab improves PFS or OS compared to nivolumab as single agent. Efficacy results are shown in Table 26 and Figure 2.Table 26: 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. Based on stratified proportional hazards model. Based on stratified log-rank test. 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. p-value is compared with 0.005 of the allocated alpha for final PFS treatment comparisons. Based on the stratified Cochran-Mantel-Haenszel test.+ Censored observationYERVOY andNivolumab (n=314)Nivolumab (n=316)YERVOY(n=315)Overall Survivala Deaths (%)128 (41)142 (45)197 (63) Hazard ratiob (vs. YERVOY) (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. YERVOY) (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 2: Overall Survival CHECKMATE-067Based on minimum follow-up of 48 months, the median OS was not reached (95% CI: 38.2, NR) in the YERVOY and nivolumab arm. The median OS was 36.9 months (95% CI: 28.3, NR) in the nivolumab arm and 19.9 months (95% CI: 16.9, 24.6) in the YERVOY arm.Based on minimum follow-up of 28 months, the median PFS was 11.7 months (95% CI: 8.9, 21.9) in the YERVOY and nivolumab arm, 6.9 months (95% CI: 4.3, 9.5) in the nivolumab arm, and 2.9 months (95% CI: 2.8, 3.2) in the YERVOY arm. Based on minimum follow-up of 28 months, the proportion of responses lasting >=24 months was 55% in the YERVOY and nivolumab arm, 56% in the nivolumab arm, and 39% in the YERVOY arm.. oYERVOY mg/kg with nivolumab mg/kg intravenously every weeks for doses, followed by nivolumab as single agent at dose of mg/kg by intravenous infusion every weeks (YERVOY and nivolumab arm),. oNivolumab mg/kg by intravenous infusion every weeks (nivolumab arm), or. oYERVOY mg/kg intravenously every weeks for doses followed by placebo every weeks (YERVOY arm). yervoy-os-checkmate-067. yervoy-os-mdx010-20. 14.2 Adjuvant Treatment of Melanoma The efficacy of YERVOY was evaluated in Study E1609 (NCT01274338), an open-label, multicenter, randomized trial for the adjuvant treatment of cutaneous melanoma in patients with completely resected node positive disease (either clinically detectable or any size with ulceration or mitosis >=1/mm2), in transit metastasis, satellites, or metastatic disease. The trial excluded patients with history of prior therapy for melanoma and autoimmune disease requiring steroid treatment. Patients were randomized to receive one of the following regimens: oYERVOY mg/kg intravenously every weeks for doses, followed by the same dose every 12 weeks for up to additional doses, oHigh-dose interferon -2b (HDI) intravenously at 20 million units/m2 per day, days per week, for weeks (induction), followed by 10 million units/m2 per day SC every other day, days per week, for 48 weeks (maintenance), or oYERVOY 10 mg/kg intravenously every weeks for doses, followed by the same dose every 12 weeks for up to additional doses.Randomization was stratified by AJCC 7th edition stage (IIIB, IIIC, M1a, or M1b). Tumor assessments were conducted every months in patients <2 years from study entry, then every months in patients 2-5 years from study entry, and every 12 months in patients >5 years from study entry for up to 20 years. Treatment continued for maximum of 60 weeks with ipilimumab or 52 weeks with HDI, or until unacceptable toxic effects, disease progression, or withdrawal of consent. The major efficacy outcome measures were investigator-assessed recurrence-free survival (RFS) by imaging (for CNS lesions) or imaging and positive cytology or histology (for non-CNS lesions) and overall survival (OS). Only the efficacy results for the recommended starting dose of mg/kg YERVOY are described below.A total of 1051 patients were randomized to YERVOY mg/kg (n=523) and HDI (n=528). The median age was 54 years (range: 18 to 83), 62% were male, 97% were white, 0.3% were Asian, and 0.4% were Black. Regarding disease stage, 53% had Stage IIIB, 40% had Stage IIIC (with no in-transit metastases), and 7% had Stage IV disease. The efficacy results are in Table 27 and Figure 3.Table 27: Efficacy Results for E1609a Two-sided p-value from log-rank test stratified by AJCC stage. YERVOY mg/kgn=523HDI n=528Overall SurvivalNumber of deaths (%)130 (25)134 (25)Hazard ratio (95% CI)0.78 (0.61, 0.99)p-value (stratified log-ranka)0.0445-year OS Rates (95% CI)72 (68, 76)67(62, 71)Recurrence-Free SurvivalNumber of events (%)246 (47)232 (44)Median in years (95% CI) 4.5(2.7, NULL)2.5(1.8, 3.5)Hazard ratio (95% CI)0.85 (0.71, 1.02)Figure 3: Kaplan-Meier Curves for Overall Survival with Ipilimumab mg/kg vs. HDI in Study E1609. oYERVOY mg/kg intravenously every weeks for doses, followed by the same dose every 12 weeks for up to additional doses, oHigh-dose interferon -2b (HDI) intravenously at 20 million units/m2 per day, days per week, for weeks (induction), followed by 10 million units/m2 per day SC every other day, days per week, for 48 weeks (maintenance), or oYERVOY 10 mg/kg intravenously every weeks for doses, followed by the same dose every 12 weeks for up to additional doses.. kmc-os-ipili-e1609. 14.3 Advanced Renal Cell Carcinoma The efficacy of YERVOY with nivolumab was evaluated in CHECKMATE-214 (NCT02231749), randomized (1:1), open-label study 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 randomized to nivolumab mg/kg and YERVOY mg/kg administered intravenously every weeks for doses followed by nivolumab mg/kg every two weeks or to sunitinib administered orally 50 mg daily for the first weeks of each 6-week cycle. Treatment continued until disease progression or unacceptable toxicity. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and region. The major efficacy outcome measures were OS, PFS (IRRC-assessed), and confirmed ORR (IRRC-assessed) in intermediate/poor risk patients. Intermediate/poor risk patients had at least or more of prognostic risk factors as per the IMDC criteria: less than one year from time of initial RCC diagnosis to randomization, Karnofsky performance status (KPS) <80%, hemoglobin less than the lower limit of normal, corrected calcium >10 mg/dL, platelet count >ULN, and absolute neutrophil count >ULN.A total of 847 patients were randomized, 425 to YERVOY with nivolumab and 422 to sunitinib. The 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.Efficacy results from CHECKMATE-214 are presented in Table 28 and Figure 4. In intermediate/poor risk patients, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to YERVOY and nivolumab arm as compared with sunitinib arm. OS benefit was observed regardless of PD-L1 expression level. The trial did not demonstrate statistically significant improvement in PFS.Table 28: Efficacy Results for CHECKMATE-214a Based on stratified proportional hazards model. Based on stratified log-rank test. p-value is compared to alpha 0.002 in order to achieve statistical significance. Based on the stratified DerSimonian-Laird test. p-value is compared to alpha 0.001 in order to achieve statistical significance. Not Significant at alpha level of 0.009.Efficacy ParameterIntermediate/Poor-RiskYERVOY mg/kg and Nivolumabn=425Sunitinibn=422Overall Survival Number of deaths140 (32.9%)188 (44.5%) Median in monthsNE25.9 Hazard ratio (99.8% CI)a 0.63 (0.44, 0.89) p-valueb,c <0.0001Confirmed Objective Response Rate (95% CI)41.6% (36.9%, 46.5%)26.5% (22.4%, 31.0%) Complete Response40 (9.4%)5 (1.2%) Partial Response137 (32.2%)107 (25.4%) Median duration of response in months (95% CI)NE (21.8, NE)18.2 (14.8, NE) p-valued,e <0.0001Progression-free Survival Number of events (progression or death)228 (53.6%)228 (54.0%) Median in months11.68.4 Hazard ratio (99.1% CI)a 0.82 (0.64, 1.05) p-valueb NSf Figure 4: Kaplan-Meier Curves for Overall Survival (Intermediate/Poor Risk Population) in CHECKMATE-214CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to nivolumab and YERVOY (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 nivolumab and YERVOY compared to sunitinib has hazard ratio of 1.45 (95% CI: 0.75, 2.81). The efficacy of nivolumab and YERVOY in previously untreated renal cell carcinoma with favorable risk disease has not been established.. yervoy-os-checkmate-214. 14.4 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer Treatment of MSI-H or dMMR mCRC In Combination with Nivolumab. CHECKMATE-8HW (NCT03143153) was randomized, 3-arm, open-label trial in immunotherapy-naive patients across all lines of therapy with unresectable or metastatic CRC with known tumor MSI-H or dMMR (MSI-H/dMMR) status as determined in accordance with local standard of practice using PCR, NGS or IHC, assays. Central assessment of MSI-H status using PCR (Idylla MSI) test and dMMR status using IHC (Omnis MMR) test was conducted retrospectively on patient tumor specimens used for local MSI-H/dMMR status determination. Patients with confirmed MSI-H/dMMR status by either central test comprised the primary study population.The trial excluded patients with brain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroids or immunosuppressants, or had been treated with checkpoint inhibitors.Patients were randomized to receive one of the following treatments:oYERVOY mg/kg every weeks and nivolumab 240 mg every weeks for maximum of doses, then nivolumab 480 mg every weeksoNivolumab 240 mg every weeks for doses, then nivolumab 480 mg every weeks.oInvestigators choice chemotherapyomFOLFOX6 (oxaliplatin, leucovorin, and FU) with or without either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and FU 400 mg/m2 bolus followed by FU 2400 mg/m2 over 46 hours every weeks. Bevacizumab mg/kg or cetuximab 500 mg/m2 administered prior to mFOLFOX6 every weeks.oFOLFIRI (irinotecan, leucovorin, and FU) with or without either bevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2, and FU 400 mg/m2 bolus and FU 2400 mg/m2 over 46 hours every weeks. Bevacizumab mg/kg on or cetuximab 500 mg/m2 administered prior to FOLFIRI every weeks. Randomization was stratified by tumor location (right vs left) and by prior lines of therapy (0, 1, 2L+). Patients randomized to the chemotherapy arm could receive YERVOY plus nivolumab combination upon progression assessed by BICR. Study treatment was administered until disease progression, unacceptable toxicity, or for up to years for patients who received YERVOY plus nivolumab or nivolumab monotherapy. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue nivolumab as single agent. Nivolumab with or without YERVOY could be administered beyond RECIST 1.1-assessed progressive disease if there was clinical benefit as determined by investigator and therapy was tolerated. Tumor assessments per RECIST v1.1 were conducted every weeks for the first 24 weeks, then every weeks thereafter up until week 96, then every 16 weeks thereafter up until week 144, and then every 24 weeks.The evaluation of efficacy relied on the comparison of patients with centrally confirmed MSI-H/dMMR mCRC randomized to YERVOY in combination with nivolumab versus chemotherapy in the first-line (1L) setting and the comparison of patients with centrally confirmed MSI-H/dMMR mCRC randomized to YERVOY in combination with nivolumab vs nivolumab in all lines setting.The major efficacy outcome measure was BICR-assessed PFS per RECIST 1.1. Additional efficacy measures included ORR and duration of response assessed by BICR and OS.The baseline characteristics of the total of 839 patients randomized were: the median age was 63 years (range: 20 to 87), with 46% >=65 years of age and 14% >=75 years of age; 50% were male and 87% were White, 9.3% were Asian, 1.5% Black or African American, and 2.3% other race; 9.2% were Hispanic or Latino, 50% Not Hispanic or Latino, 41% ethnicity unknown. Baseline ECOG performance status was (52%) and (48%); number of prior lines of therapy was (56%) and (24%), and >=2 (19%); tumor location was right-sided or left-sided for 69% and 31% of patients. The baseline characteristics in patients with centrally confirmed MSI-H/dMMR is consistent with all randomized patients.. oYERVOY mg/kg every weeks and nivolumab 240 mg every weeks for maximum of doses, then nivolumab 480 mg every weeks. oNivolumab 240 mg every weeks for doses, then nivolumab 480 mg every weeks.. oInvestigators choice chemotherapyomFOLFOX6 (oxaliplatin, leucovorin, and FU) with or without either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and FU 400 mg/m2 bolus followed by FU 2400 mg/m2 over 46 hours every weeks. Bevacizumab mg/kg or cetuximab 500 mg/m2 administered prior to mFOLFOX6 every weeks.oFOLFIRI (irinotecan, leucovorin, and FU) with or without either bevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2, and FU 400 mg/m2 bolus and FU 2400 mg/m2 over 46 hours every weeks. Bevacizumab mg/kg on or cetuximab 500 mg/m2 administered prior to FOLFIRI every weeks. omFOLFOX6 (oxaliplatin, leucovorin, and FU) with or without either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and FU 400 mg/m2 bolus followed by FU 2400 mg/m2 over 46 hours every weeks. Bevacizumab mg/kg or cetuximab 500 mg/m2 administered prior to mFOLFOX6 every weeks.. oFOLFIRI (irinotecan, leucovorin, and FU) with or without either bevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2, and FU 400 mg/m2 bolus and FU 2400 mg/m2 over 46 hours every weeks. Bevacizumab mg/kg on or cetuximab 500 mg/m2 administered prior to FOLFIRI every weeks.. First Line YERVOY in combination with nivolumab Among 303 patients in the first-line setting were randomly assigned to YERVOY in combination with nivolumab (202) and to chemotherapy (101), 171 and 84 patients had centrally confirmed MSI-H/dMMR status in YERVOY in combination with nivolumab arm and chemotherapy arm, respectively. In the 1L setting, 200 of 202 patients assigned to receive YERVOY in combination with nivolumab and 88 of 101 patients assigned to received chemotherapy received at least dose of study treatment. Among the 88 patients who received chemotherapy, 58% and 42% of patients received oxaliplatin-containing regimens and irinotecan-containing regimens, respectively, and 66 (75%) patients received targeted agent, either bevacizumab (64%) or cetuximab (11%). The BICR-assessed PFS efficacy results for patients with centrally confirmed MSI-H/dMMR randomized to the YERVOY and nivolumab arm compared with chemotherapy in the 1L setting are presented in Table 29 and Figure 5. The comparative results of ORR and OS between arms were not available at the time of the PFS analysis due to statistical testing strategy.Table 29: Efficacy Results CHECKMATE-8HWNR: Not Reached; NE: Not Estimable.Minimum follow-up was 6.1 months at data cutoff date 12Oct2023. Based on log-rank test stratified by the same factors as used in the Cox proportional hazards model. The p-value threshold for statistical significance was 0.0209.b Based on Kaplan-Meier estimates.c HR from Cox proportional hazards model stratified by tumor sidedness (left vs right) per IRTYERVOY and Nivolumab(n=171)Chemotherapy (n=84)Progression-free SurvivalDisease progression or death (%)48 (28)52 (62)Median in monthsb (95% CI)NR(38.4, NE)5.8(4.4, 7.8)Hazard ratioc (95% CI)0.21 (0.14, 0.32)p-valuea <0.0001Figure 5: Progression-free Survival, (First line YERVOY nivolumab vs Chemotherapy)- CHECKMATE-8HWAll Lines YERVOY in combination with nivolumabAmong 707 patients across all treatment lines who were randomly assigned to YERVOY in combination with nivolumab (354) and to nivolumab (353) single agent, 296 and 286 patients had centrally confirmed MSI-H/dMMR status in the YERVOY in combination with nivolumab arm and in the nivolumab arm, respectively. Patients receiving at least dose of study treatment included 352 of 354 patients randomized to OPDIVO in combination with ipilimumab, and 351 of 353 patients randomized to single agent OPDIVO.The BICR-assessed PFS and ORR efficacy results for patients with centrally confirmed MSI-H/dMMR randomized to the YERVOY in combination with nivolumab compared with nivolumab single agent across all treatment lines setting are presented in Table 30 and Figure 6. At the time of PFS analysis OS between arms were not available due to statistical testing strategy.Table 30: Efficacy Results All Lines CHECKMATE-8HWNR: Not Reached; NE: Not Estimable.Minimum follow-up was 16.7 months at data cutoff date 28Aug2024. Based on log-rank test stratified by the same factors as used in the Cox proportional hazards model. The p-value threshold for statistical significance was 0.0095.b Based on Kaplan-Meier estimates.c HR from Cox proportional hazards model stratified by tumor sidedness (left vs right) and prior lines of therapy (0, 1, >=2) per IRT.d Based on Cochran-Mantel-Haenszel test stratified by the same factors as used in the Cox proportional hazards model. The p-value threshold for statistical significance was 0.006.YERVOY and Nivolumab (n=296)Nivolumab(n=286)Progression-free SurvivalDisease progression or death (%)101 (34)136 (48)Median (months)b (95% CI)NR(53.82, NE)39.3(22.1, NE)Hazard ratioc (95% CI)0.62 (0.48, 0.81)p-valuea 0.0003Objective Response Rate (ORR)Response Rate, (%)(95% CI)209 (71%)(65, 76)165 (58%)(52, 63)Complete Response Rate, (%)90 (30%)80 (28%)Partial Response, (%)119 (40%)65 (30%)p-valued 0.0011Figure 6: Progression-free Survival (All lines (YERVOY Nivolumab vs Nivolumab)- CHECKMATE-8HW. pfs-first-line-checkmate-8hw. pfs-all-lines-checkmate-8hw. 14.5 Hepatocellular Carcinoma Treatment of Unresectable or Metastatic Hepatocellular Carcinoma (HCC). CHECKMATE-9DW (NCT04039607) was randomized (1:1), open-label trial in adults (18 years of age or older) with unresectable or metastatic HCC. Patients had histologically confirmed HCC, Child Pugh Class A, ECOG performance status or 1, and no prior systemic therapy for advanced disease. Esophagogastroduodenoscopy was not mandated prior to enrollment. The trial excluded patients with active autoimmune disease, brain or leptomeningeal metastases, history of hepatic encephalopathy (within 12 months of randomization), platelet count <60,000, clinically significant ascites, medical conditions requiring systemic immunosuppression, infection with HIV, or active co-infection with hepatitis virus (HBV) and hepatitis virus (HCV) or HBV and hepatitis virus (HDV).Patients were randomized to receive either: oYERVOY mg/kg administered intravenously over 30 minutes in combination with nivolumab mg/kg administered intravenously over 30 minutes every weeks, for maximum of doses, followed by single agent nivolumab at 480 mg administered intravenously over 30 minutes every weeks, oroInvestigators choice:oLenvatinib mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight >=60 kg), oroSorafenib 400 mg orally twice daily Randomization was stratified by etiology (HBV vs. HCV vs. non-viral), macrovascular invasion and/or extrahepatic spread (present or absent), and alpha-fetoprotein levels (>=400 or <400 ng/mL). Study treatment for YERVOY in combination with nivolumab continued until disease progression, unacceptable toxicity, or up to years. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue nivolumab as single agent. Treatment beyond RECIST 1.1 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 and week 16, then every weeks up to 48 weeks, and then every 12 weeks thereafter until disease progression, treatment discontinuation, or initiation of subsequent therapy. The primary efficacy outcome measure was OS in all randomized patients. Additional efficacy measures included BICR-assessed ORR and DOR based on RECIST 1.1 criteria. total of 668 patients were randomized to receive YERVOY in combination with nivolumab (n=335) or investigators choice (n=333) of lenvatinib or sorafenib. In the investigator arm, 85% and 15% of treated patients received lenvatinib or sorafenib, respectively. The trial population characteristics were: median age was 66 years (range: 20 to 89), with 53% >=65 years old; 82% male; 53% White, 44% Asian, 2.2% Black; 12% Hispanic or Latino, 48% Not Hispanic or Latino, 40% not reported. Baseline ECOG performance status was (71%) or (29%). Thirty-four percent (34%) of patients had HBV infection, 28% had HCV infection, and 36% had no evidence of HBV or HCV infection. Nineteen percent (19%) of patients had alcoholic liver disease and 11% had non-alcoholic fatty liver disease. The majority of patients had BCLC stage (73%) disease at baseline, 19% had stage B, and 6% had stage A. Patients with Child-Pugh scores of 5, 6, and were 77%, 20%, and 3%, respectively; patient with Child Pugh was enrolled. total of 54% of patients had extrahepatic spread; 25% had macrovascular invasion; and 33% had AFP levels >=400 ug/L.CHECKMATE-9DW demonstrated statistically significant improvement in OS and ORR. The minimum follow-up was 26.8 months. Efficacy results are shown in Table 31 and Figure 7.Table 31: Efficacy Results CHECKMATE-9DWa Based on stratified Cox proportional hazard model.b Based on 2-sided stratified log-rank test. Boundary for statistical significance: p-value <=0.0257c Assessed by BICR using RECIST 1.1d Based on 2-sided stratified Cochran-Mantel-Haenszel test. Boundary for statistical significance: p-value <=0.025e NR: Not Reached+ Censored observationYERVOY and Nivolumab(n=335)Lenvatinib or Sorafenib (n=333)Overall SurvivalDeaths (%)194 (58%)228 (68%)Median (months)(95% CI)23.7(18.8, 29.4)20.6(17.5, 22.5)Hazard ratio (95% CI) 0.79 (0.65, 0.96)p-value 0.0180Overall Response Rate, (%)c 121 (36.1)44 (13.2)(95% CI)(31.0, 41.5)(9.8, 17.3)p-value <0.0001Complete response (%)23 (6.9)6 (1.8)Partial response (%)98 (29.3)38 (11.4)Duration of Response (months) cMedian(95% CI)30.4(21.2, NRe)12.9(10.2, 31.2)Range1.5+, 36.9+2.1+, 32.5+Figure 7: Overall Survival CHECKMATE-9DW. oYERVOY mg/kg administered intravenously over 30 minutes in combination with nivolumab mg/kg administered intravenously over 30 minutes every weeks, for maximum of doses, followed by single agent nivolumab at 480 mg administered intravenously over 30 minutes every weeks, or. oInvestigators choice:oLenvatinib mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight >=60 kg), oroSorafenib 400 mg orally twice daily oLenvatinib mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight >=60 kg), or. oSorafenib 400 mg orally twice daily. yervoy-os-checkmate-9dw. Previously Treated Hepatocellular Carcinoma. CHECKMATE-040 (NCT01658878) was multicenter, multiple cohort, open-label trial conducted in patients with 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.The efficacy of YERVOY mg/kg in combination with nivolumab mg/kg was evaluated in Cohort of CHECKMATE-040. total of 49 patients received the combination regimen, which was administered every weeks for four doses, followed by single-agent 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 percent (57%) 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 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 alfa-fetoprotein (AFP) levels >=400 ug/L. Prior 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 32.Table 32: Efficacy Results Cohort of CHECKMATE-040a Confirmed by BICR. Confidence interval is based on the Clopper and Pearson method.YERVOY and Nivolumab(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%). 14.6 Metastatic Non-Small Cell Lung Cancer First-line Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC) Expressing PD-L1 (>=1%): In Combination with Nivolumab. CHECKMATE-227 (NCT02477826) was randomized, open-label, multi-part trial in patients with metastatic or recurrent NSCLC. The study included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer [ASLC] classification), ECOG performance status or 1, and no prior anticancer therapy. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least weeks prior to enrolment, and either off corticosteroids, or on stable or decreasing dose of <10 mg daily prednisone equivalents.Primary efficacy results were based on Part 1a of the study, which was limited to patients with PD-L1 tumor expression >=1%. Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at central laboratory. Randomization was stratified by tumor histology (non-squamous versus squamous). The evaluation of efficacy relied on the comparison between: oYERVOY mg/kg administered intravenously over 30 minutes every weeks in combination with nivolumab mg/kg administered intravenously over 30 minutes every weeks; oroPlatinum-doublet chemotherapyChemotherapy regimens consisted of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) or pemetrexed (500 mg/m2) and carboplatin (AUC or 6) for non-squamous NSCLC or gemcitabine (1000 or 1250 mg/m2) and cisplatin (75 mg/m2) or gemcitabine (1000 mg/m2) and carboplatin (AUC 5) (gemcitabine was administered on Days and of each cycle) for squamous NSCLC.Study treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Treatment continued beyond disease progression if patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse event attributed to YERVOY were permitted to continue nivolumab as single agent. Tumor assessments were performed every weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.In Part 1a, total of 793 patients were randomized to receive either YERVOY in combination with nivolumab (n=396) or platinum-doublet chemotherapy (n=397). The median age was 64 years (range: 26 to 87) with 49% of patients >=65 years and 10% of patients >=75 years, 76% White, and 65% male. Baseline ECOG performance status was (34%) or (65%), 50% with PD-L1 >=50%, 29% with squamous and 71% with non-squamous histology, 10% had brain metastases, and 85% were former/current smokers.The study demonstrated statistically significant improvement in OS for PD-L1 >=1% patients randomized to the YERVOY and nivolumab arm compared to platinum-doublet chemotherapy arm. The OS results are presented in Table 33 and Figure 8.Table 33: Efficacy Results (PD-L1 >=1%) CHECKMATE-227 Part 1aa Kaplan-Meier estimate. Based on stratified Cox proportional hazard model.YERVOY and Nivolumab(n=396)Platinum-Doublet Chemotherapy(n=397)Overall Survival Events (%)258 (65%)298 (75%) Median (months)a (95% CI)17.1(15, 20.1)14.9(12.7, 16.7) Hazard ratio (95% CI)b 0.79 (0.67, 0.94) Stratified log-rank p-value0.0066Figure 8: Overall Survival (PD-L1 >=1%) CHECKMATE-227BICR-assessed PFS showed HR of 0.82 (95% CI: 0.69, 0.97), with median PFS of 5.1 months (95% CI: 4.1, 6.3) in the YERVOY and nivolumab arm and 5.6 months (95% CI: 4.6, 5.8) in the platinum-doublet chemotherapy arm. The BICR-assessed confirmed ORR was 36% (95% CI: 31, 41) in the YERVOY and nivolumab arm and 30% (95% CI: 26, 35) in the platinum-doublet chemotherapy arm. Median duration of response observed in the YERVOY and nivolumab arm was 23.2 months and 6.2 months in the platinum-doublet chemotherapy arm.. oYERVOY mg/kg administered intravenously over 30 minutes every weeks in combination with nivolumab mg/kg administered intravenously over 30 minutes every weeks; or. oPlatinum-doublet chemotherapy. yervoy-os-checkmate-227. First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Nivolumab and Platinum-Doublet Chemotherapy. CHECKMATE-9LA (NCT03215706) was randomized, open-label trial in patients with metastatic or recurrent NSCLC. The trial included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification [IASLC]), ECOG performance status or 1, and no prior anticancer therapy (including EGFR and ALK inhibitors) for metastatic disease. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with stable brain metastases were eligible for enrollment. Patients were randomized 1:1 to receive either:oYERVOY mg/kg administered intravenously over 30 minutes every weeks, nivolumab 360 mg administered intravenously over 30 minutes every weeks, and platinum-doublet chemotherapy administered intravenously every weeks for cycles, oroplatinum-doublet chemotherapy administered every weeks for cycles.Platinum-doublet chemotherapy consisted of either carboplatin (AUC or 6) and pemetrexed 500 mg/m2, or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC. Patients with non-squamous NSCLC in the control arm could receive optional pemetrexed maintenance therapy. Stratification factors for randomization were tumor PD-L1 expression level (>=1% versus <1% or non-quantifiable), histology (squamous versus non-squamous), and sex (male versus female). Study treatment continued until disease progression, unacceptable toxicity, or for up to years. Treatment could continue beyond disease progression if patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue nivolumab as single agent as part of the study. Tumor assessments were performed every weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.A total of 719 patients were randomized to receive either YERVOY in combination with nivolumab and platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy (n=358). The median age was 65 years (range: 26 to 86) with 51% of patients >=65 years and 10% of patients >=75 years. The majority of patients were White (89%) and male (70%). Baseline ECOG performance status was (31%) or (68%), 57% had tumors with PD-L1 expression >=1% and 37% had tumors with PD-L1 expression that was <1%, 32% had tumors with squamous histology and 68% had tumors with non-squamous histology, 17% had CNS metastases, and 86% were former or current smokers.The study demonstrated statistically significant benefit in OS, PFS, and ORR. Efficacy results from the prespecified interim analysis when 351 events were observed (87% of the planned number of events for final analysis) are presented in Table 34.Table 34: Efficacy Results CHECKMATE-9LAa Based on stratified Cox proportional hazard model. p-value is compared with the allocated alpha of 0.033 for this interim analysis. p-value is compared with the allocated alpha of 0.0252 for this interim analysis. Kaplan-Meier estimate. Confidence interval based on the Clopper and Pearson Method. p-value is compared with the allocated alpha of 0.025 for this interim analysis.YERVOY and Nivolumab and Platinum-Doublet Chemotherapy(n=361)Platinum-Doublet Chemotherapy(n=358)Overall Survival Events (%)156 (43.2)195 (54.5) Median (months) (95% CI)14.1(13.2, 16.2)10.7(9.5, 12.5) Hazard ratio (96.71% CI)a 0.69 (0.55, 0.87) Stratified log-rank p-valueb 0.0006Progression-free Survival per BICR Events (%)232 (64.3)249 (69.6) Hazard ratio (97.48% CI)a 0.70 (0.57, 0.86) Stratified log-rank p-valuec 0.0001 Median (months)d (95% CI)6.8(5.6, 7.7)5.0(4.3, 5.6)Overall Response Rate per BICR (%)3825 (95% CI)e (33, 43)(21, 30) Stratified CMH test p-valuef 0.0003Duration of Response per BICR Median (months) (95% CI)d 10.0(8.2, 13.0)5.1(4.3, 7.0)With an additional 4.6 months of follow-up the hazard ratio for overall survival was 0.66 (95% CI: 0.55, 0.80) and median survival was 15.6 months (95% CI: 13.9, 20.0) and 10.9 months (95% CI: 9.5, 12.5) for patients receiving YERVOY and nivolumab and platinum-doublet chemotherapy or platinum-doublet chemotherapy, respectively (Figure 9).Figure 9: Overall Survival CHECKMATE-9LA. oYERVOY mg/kg administered intravenously over 30 minutes every weeks, nivolumab 360 mg administered intravenously over 30 minutes every weeks, and platinum-doublet chemotherapy administered intravenously every weeks for cycles, or. oplatinum-doublet chemotherapy administered every weeks for cycles.. yervoy-os-checkmate-9la. 14.7 Malignant Pleural Mesothelioma CHECKMATE-743 (NCT02899299) was randomized, open-label trial in patients with unresectable malignant pleural mesothelioma. The trial included patients with histologically confirmed and previously untreated malignant pleural mesothelioma with no palliative radiotherapy within 14 days of initiation of therapy. Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial. Patients were randomized 1:1 to receive either:oYERVOY mg/kg over 30 minutes by intravenous infusion every weeks and nivolumab mg/kg over 30 minutes by intravenous infusion every weeks for up to years, orocisplatin 75 mg/m2 and pemetrexed 500 mg/m2, or carboplatin AUC and pemetrexed 500 mg/m2 administered every weeks for cycles. Stratification factors for randomization were tumor histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and sex (male vs. female). Study treatment continued for up to years, or until disease progression or unacceptable toxicity. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue nivolumab as single agent. Treatment could continue beyond disease progression if patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Tumor assessments were performed every weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR utilizing modified RECIST criteria.A total of 605 patients were randomized to receive either YERVOY in combination with nivolumab (n=303) or chemotherapy (n=302). The median age was 69 years (range: 25 to 89), with 72% of patients >=65 years and 26% >=75 years; 85% were White, 11% were Asian, and 77% were male. Baseline ECOG performance status was (40%) or (60%), 35% had Stage III and 51% had Stage IV disease, 75% had epithelioid and 25% had non-epithelioid histology, 75% had tumors with PD-L1 expression >=1%, and 22% had tumors with PD-L1 expression <1%.The trial demonstrated statistically significant improvement in OS for patients randomized to YERVOY in combination with nivolumab compared to chemotherapy. Efficacy results from the prespecified interim analysis are presented in Table 35 and Figure 10.Table 35: Efficacy Results CHECKMATE-743a At the time of the interim analysis, 419 deaths (89% of the deaths needed for the final analysis) had occurred. Kaplan-Meier estimate. Stratified Cox proportional hazard model. p-value is compared with the allocated alpha of 0.0345 for this interim analysis. Based on confirmed response by BICR.YERVOY and Nivolumab(n=303)Chemotherapy(n=302)Overall Survivala Events (%)200 (66)219 (73) Median (months)b (95% CI)18.1(16.8, 21.5)14.1(12.5, 16.2) Hazard ratio (95% CI)c 0.74 (0.61, 0.89) Stratified log-rank p-valued 0.002Progression-free Survival Events (%)218 (72)209 (69) Hazard ratio (95% CI)c 1.0 (0.82, 1.21) Median (months)b (95% CI)6.8(5.6, 7.4)7.2(6.9, 8.1)Overall Response Ratee 40%43% (95% CI)(34, 45)(37, 49)Duration of Response Median (months)a (95% CI)11.0(8.1, 16.5)6.7(5.3, 7.1)Figure 10: Overall Survival CHECKMATE-743In prespecified exploratory analysis based on histology, in the subgroup of patients with epithelioid histology, the hazard ratio (HR) for OS was 0.85 (95% CI: 0.68, 1.06), with median OS of 18.7 months in the YERVOY and nivolumab arm and 16.2 months in the chemotherapy arm. In the subgroup of patients with non-epithelioid histology, the HR for OS was 0.46 (95% CI: 0.31, 0.70), with median OS of 16.9 months in the YERVOY and nivolumab arm and 8.8 months in the chemotherapy arm.. oYERVOY mg/kg over 30 minutes by intravenous infusion every weeks and nivolumab mg/kg over 30 minutes by intravenous infusion every weeks for up to years, or. ocisplatin 75 mg/m2 and pemetrexed 500 mg/m2, or carboplatin AUC and pemetrexed 500 mg/m2 administered every weeks for cycles. yervoy-os-checkmate-743. 14.8 Esophageal Cancer CHECKMATE-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. Patients were not amenable to chemoradiation or surgery with curative intent. 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. 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:oYERVOY mg/kg every weeks in combination with nivolumab 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 were treated until disease progression, unacceptable toxicity, or up to years. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue 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 649 patients were randomized in Arms and of the CHECKMATE-648 study, among whom 644 and 601 patients had quantifiable TC PD-L1 expression and CPS at baseline, respectively; 84% (546/649) 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 81), 45% were >=65 years of age, 84% were male, 71% were Asian, 25% were White, and 1.6% were Black or African American. Patients had histological confirmation of squamous cell carcinoma (99%) or adenosquamous cell carcinoma (1.3%) in the esophagus. Baseline ECOG performance status was (46%) or (54%).A statistically significant improvement in OS was demonstrated in patients randomized to YERVOY in combination with nivolumab compared with chemotherapy; however, an exploratory analysis of OS in patients with PD-L1 CPS <1 showed HR of 1.0 (95% CI 0.52, 1.94), including 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 36 and Figures 11 and 12.Table 36: Efficacy Results Arms and of CHECKMATE-648a Assessed by BICR. Based on stratified Cox proportional hazard model. Hazard ratios are reported for each nivolumab- containing arm compared to chemotherapy within each analysis population. Based on stratified 2-sided log-rank test. S1 Significant p-value compared to stopping boundary of 0.014. NS: Not Statistically significant, NT: Not evaluated for statistical significance as per pre-specified hierarchical testing procedure.YERVOY and Nivolumab(n=158)Cisplatin and Fluorouracil (n=157)YERVOY and Nivolumab(n=266)Cisplatin and Fluorouracil (n=280)TC PD-L1 expression >=1%PD-L1 CPS >=1Overall Survival Deaths (%)106 (67)121 (77)179 (67)205 (73)Median (months)(95% CI)13.7(11.2, 17.0)9.1(7.7, 10)12.7(10.9, 15.5)9.8(8.8, 11.6)Hazard ratio (95% CI)b 0.64(0.49, 0.84)0.76(0.62, 0.93)p-valuec 0.0010S1 -Progression-free Survivala Disease progression or death (%)123 (78)100 (64)206 (77)184 (66) Median (months)(95% CI)4.0 (2.4, 4.9)4.4(2.9, 5.8)2.8(2.6, 4.2)5.6(4.2, 5.9)Hazard ratio (95% CI)b 1.02(0.78, 1.34)1.2(1.0, 1.5)p-valuec NS-Overall Response Rate, (%)a, NT 56 (35.4)31 (19.7)74 (28)76 (27)(95% CI)(28.0, 43.4)(13.8, 26.8)(22.5, 33.6)(22.0, 32.8)Complete response (%)28 (17.7)8 (5.1)32 (12.0)18 (6.4)Partial response (%)28 (17.7)23 (14.6)42 (15.8)58 (20.7)Median(95% CI)11.8(7.1, 27.4)5.7(4.4, 8.7)11.8(7.1, 23.6)6.9(5.7, 8.2)Range1.4+, 34.5+1.4+, 31.8+1.4+, 34.5+1.4+, 31.8+Figure 11: Overall Survival CHECKMATE-648(A) OS in TC PD-L1 >=1%(B) OS in PD-L1 CPS >=1Figure 12: Progression-free Survival CHECKMATE-648(A) PFS in TC PD-L1 >=1%(B) PFS in PD-L1 CPS >=1. oYERVOY mg/kg every weeks in combination with nivolumab 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).. yervoy-os-checkmate-648-a. yervoy-os-checkmate-648-b. yervoy-pfs-checkmate-648-a. yervoy-pfs-checkmate-648-b.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies, and the genotoxic potential of ipilimumab has not been evaluated.Fertility studies have not been performed with ipilimumab.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. CTLA-4 is negative regulator of T-cell activity. Ipilimumab is monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to general increase in T-cell responsiveness, including the anti-tumor immune response.. 12.3 Pharmacokinetics. The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every weeks for doses. The PK of ipilimumab is linear in the dose range of 0.3 mg/kg to 10 mg/kg. Following administration of YERVOY every weeks, the systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean minimum concentration (Cmin) at steady state was 19.4 mcg/mL at mg/kg and 58.1 mcg/mL at 10 mg/kg every weeks.EliminationThe mean (percent coefficient of variation) terminal half-life (t1/2) was 15.4 days (34%) and then mean (percent coefficient of variation) clearance (CL) was 16.8 mL/h (38%). The CL of ipilimumab was unchanged in presence of anti-ipilimumab antibodies.Specific PopulationsThe CL of ipilimumab increased with increasing body weight supporting the recommended body weight (mg/kg) based dosing. The following factors had no clinically important effect on the CL of ipilimumab: age (range: 23 to 88 years), sex, performance status, renal impairment (glomerular filtration rate >=15 mL/min/1.73 m2), mild hepatic impairment (total bilirubin [TB] >1 to 1.5 times the upper limit of normal [ULN] or AST ULN), previous cancer therapy, and baseline lactate dehydrogenase (LDH) levels. The effect of race was not examined due to limited data available in non-White racial groups. YERVOY has not been studied in patients with moderate (TB >1.5 to times ULN and any AST) or severe (TB >3 times ULN and any AST) hepatic impairment.Pediatric Patients The exposures of ipilimumab in pediatric patients 12 years and older are comparable to those in adult patients at the recommended dosage.Drug Interaction StudiesIpilimumab with NivolumabWhen YERVOY mg/kg was administered with nivolumab mg/kg every weeks, the CL of ipilimumab was unchanged compared to when YERVOY was administered alone.When YERVOY mg/kg every weeks was administered in combination with nivolumab mg/kg every weeks, the CL of ipilimumab was unchanged compared to ipilimumab administered alone and the CL of nivolumab was increased by 29% compared to nivolumab administered alone.When YERVOY mg/kg every weeks was administered in combination with nivolumab mg/kg every weeks, the CL of ipilimumab increased by 30% compared to YERVOY administered alone and the CL of nivolumab was unchanged compared to nivolumab administered alone.When YERVOY mg/kg every weeks was administered in combination with nivolumab 360 mg every weeks and chemotherapy, the CL of ipilimumab increased by 22% compared to YERVOY administered alone and the CL of nivolumab was unchanged compared to nivolumab administered alone.. 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of YERVOY or of other ipilimumab products.Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma tested positive for treatment-emergent binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay had substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Seven (4.9%) of 144 patients receiving ipilimumab developed anti-ipilimumab antibodies and (4.5%) of 156 patients receiving placebo for the adjuvant treatment of melanoma tested positive for anti-ipilimumab antibodies using an ECL assay with improved drug tolerance. No patients tested positive for neutralizing antibodies. No infusion-related reactions occurred in patients who tested positive for anti-ipilimumab antibodies.Of the 499 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-214 and CHECKMATE-142, 27 (5.4%) were positive for anti-ipilimumab antibodies; there were no patients with neutralizing antibodies against ipilimumab. There was no evidence of increased incidence of infusion reactions to YERVOY in patients with anti-ipilimumab antibodies.Of 483 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-227 Part 1, 8.5% were positive for treatment-emergent anti-ipilimumab antibodies. No patients had neutralizing antibodies against ipilimumab. In Part of the same study, of 491 patients evaluable for anti-nivolumab antibodies, 36.7% were positive for anti-nivolumab antibodies and 1.4% had neutralizing antibodies against nivolumab.Of 305 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-9LA, 8% were positive for anti-ipilimumab antibodies and 1.6% were positive for anti-ipilimumab neutralizing antibodies. There was no evidence of increased incidence of infusion reactions to YERVOY in patients with anti-ipilimumab antibodies. Of 308 patients evaluable for anti-nivolumab antibodies in CHECKMATE-9LA, 34% were positive for anti-nivolumab antibodies and 2.6% had neutralizing antibodies against nivolumab.Of 271 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-743, 13.7% were positive for anti-ipilimumab antibodies and 0.4% were positive for anti-ipilimumab neutralizing antibodies. Of 269 patients evaluable for anti-nivolumab antibodies in CHECKMATE-743, 25.7% were positive for anti-nivolumab antibodies and 0.7% had neutralizing antibodies against nivolumab.Anti-drug antibody and neutralizing antibody responses were monitored throughout the treatment period where the benefit to risk ratio was assessed. Incidence of anti-drug antibodies and neutralizing antibodies are presented in Table 24.Table 24: YERVOY Anti-Drug Antibody (ADA) and Neutralizing Antibody (NAb) Incidencea Details of each treatment regimen are described in Section 14 [see Clinical Studies (14)].b NAb incidence is reported among the subset of patients positive for ADA.ADA treatment-emergent anti-ipilimumab antibodies, NAb neutralizing antibodies, HCC hepatocellular carcinoma, RCC renal cell carcinoma, CRC colorectal cancer, NSCLC non-small cell lung cancer.Treatment Regimena Indication(s)ADANAbb YERVOY as single agentMelanoma1.1%(11/1024)0(0/11)Adjuvant Melanoma4.9(7/144)0(0/7)YERVOY with nivolumab for doses followed by nivolumab as single agentMelanoma8.4%(33/391)3%(1/33)HCC5.3%(13/244)0(0/13)RCC and CRC5.4%(27/499)0%(0/27)YERVOY with nivolumabMalignant Pleural Mesothelioma13.7%(37/271)2.7%(1/37)NSCLC8.5%(41/483)0(0/41)YERVOY with nivolumab and cycles of platinum-doublet chemotherapyNSCLC7.5%(23/305)21.7%(5/23). Effects of Anti-Drug Antibodies. Presence of treatment-emergent anti-ipilimumab antibodies did not affect ipilimumab clearance after administration of ipilimumab as monotherapy or in combination with nivolumab. These anti-drug antibody-associated pharmacokinetic changes were not considered to be clinically significant. There was no identified clinically significant effect of anti-drug antibodies on incidence of infusion-related reactions. In hepatocellular carcinoma, there was no identified clinically significant effect of anti-drug antibodies on efficacy for ipilimumab in combination with nivolumab. For other indications, the effects of anti-drug antibodies on effectiveness have not been fully characterized.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. Ipilimumab is human cytotoxic T-lymphocyte antigen (CTLA-4)-blocking antibody. Ipilimumab is recombinant IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.YERVOY (ipilimumab) injection, for intravenous use is sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution, which may contain small amount of visible translucent-to-white, amorphous ipilimumab particulates. It is supplied in single-dose vials of 50 mg/10 mL or 200 mg/40 mL. Each milliliter contains mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at pH of 7.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oAdminister by intravenous infusion after dilution based upon recommended infusion rate for each indication. (2)oUnresectable or Metastatic Melanoma:YERVOY mg/kg every weeks for maximum of doses. (2.2)YERVOY mg/kg immediately following nivolumab mg/kg on the same day, every weeks for doses. After completing doses of the combination, administer nivolumab as single agent as recommended in the Full Prescribing Information for nivolumab. (2.2)oAdjuvant Treatment of Melanoma: YERVOY mg/kg every weeks for doses, followed by mg/kg every 12 weeks for up to additional doses. (2.2)oAdvanced Renal Cell Carcinoma: YERVOY mg/kg immediately following nivolumab mg/kg on the same day, every weeks for doses. After completing doses of the combination, administer nivolumab as single agent as recommended in Full Prescribing Information for nivolumab. (2.2)oTreatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in combination with nivolumab:Adult and pediatric patients weighing 40 kg or greater: YERVOY mg/kg immediately following nivolumab 240 mg on the same day every weeks for maximum of doses. After completing the combination, administer nivolumab as single agent as recommended in Full Prescribing Information for nivolumab. (2.2)Pediatric patients weighing less than 40 kg: YERVOY mg/kg immediately following nivolumab mg/kg on the same day every weeks for maximum of doses. After completing the combination, administer nivolumab as single agent as recommended in Full Prescribing Information for nivolumab. (2.2)oHepatocellular Carcinoma: YERVOY mg/kg intravenously over 30 minutes immediately following nivolumab mg/kg intravenously over 30 minutes on the same day, every weeks for up to doses. After completing up to doses of the combination, administer nivolumab as single agent as recommended in Full Prescribing Information for nivolumab. (2.2)oMetastatic non-small cell lung cancer:YERVOY mg/kg every weeks with nivolumab 360 mg every weeks. (2.2)YERVOY mg/kg every weeks with nivolumab 360 mg every weeks and cycles of platinum-doublet chemotherapy. (2.2)oMalignant pleural mesothelioma: YERVOY mg/kg every weeks with nivolumab 360 mg every weeks. (2.2)oEsophageal squamous cell carcinoma: YERVOY mg/kg every weeks with nivolumab mg/kg every weeks or 360 mg every weeks. (2.2) oSee full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. oAdminister by intravenous infusion after dilution based upon recommended infusion rate for each indication. (2). oUnresectable or Metastatic Melanoma:YERVOY mg/kg every weeks for maximum of doses. (2.2)YERVOY mg/kg immediately following nivolumab mg/kg on the same day, every weeks for doses. After completing doses of the combination, administer nivolumab as single agent as recommended in the Full Prescribing Information for nivolumab. (2.2). YERVOY mg/kg every weeks for maximum of doses. (2.2). YERVOY mg/kg immediately following nivolumab mg/kg on the same day, every weeks for doses. After completing doses of the combination, administer nivolumab as single agent as recommended in the Full Prescribing Information for nivolumab. (2.2). oAdjuvant Treatment of Melanoma: YERVOY mg/kg every weeks for doses, followed by mg/kg every 12 weeks for up to additional doses. (2.2). oAdvanced Renal Cell Carcinoma: YERVOY mg/kg immediately following nivolumab mg/kg on the same day, every weeks for doses. After completing doses of the combination, administer nivolumab as single agent as recommended in Full Prescribing Information for nivolumab. (2.2). oTreatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in combination with nivolumab:Adult and pediatric patients weighing 40 kg or greater: YERVOY mg/kg immediately following nivolumab 240 mg on the same day every weeks for maximum of doses. After completing the combination, administer nivolumab as single agent as recommended in Full Prescribing Information for nivolumab. (2.2)Pediatric patients weighing less than 40 kg: YERVOY mg/kg immediately following nivolumab mg/kg on the same day every weeks for maximum of doses. After completing the combination, administer nivolumab as single agent as recommended in Full Prescribing Information for nivolumab. (2.2). Adult and pediatric patients weighing 40 kg or greater: YERVOY mg/kg immediately following nivolumab 240 mg on the same day every weeks for maximum of doses. After completing the combination, administer nivolumab as single agent as recommended in Full Prescribing Information for nivolumab. (2.2). Pediatric patients weighing less than 40 kg: YERVOY mg/kg immediately following nivolumab mg/kg on the same day every weeks for maximum of doses. After completing the combination, administer nivolumab as single agent as recommended in Full Prescribing Information for nivolumab. (2.2). oHepatocellular Carcinoma: YERVOY mg/kg intravenously over 30 minutes immediately following nivolumab mg/kg intravenously over 30 minutes on the same day, every weeks for up to doses. After completing up to doses of the combination, administer nivolumab as single agent as recommended in Full Prescribing Information for nivolumab. (2.2). oMetastatic non-small cell lung cancer:YERVOY mg/kg every weeks with nivolumab 360 mg every weeks. (2.2)YERVOY mg/kg every weeks with nivolumab 360 mg every weeks and cycles of platinum-doublet chemotherapy. (2.2). YERVOY mg/kg every weeks with nivolumab 360 mg every weeks. (2.2). YERVOY mg/kg every weeks with nivolumab 360 mg every weeks and cycles of platinum-doublet chemotherapy. (2.2). oMalignant pleural mesothelioma: YERVOY mg/kg every weeks with nivolumab 360 mg every weeks. (2.2). oEsophageal squamous cell carcinoma: YERVOY mg/kg every weeks with nivolumab mg/kg every weeks or 360 mg every weeks. (2.2) oSee full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. 2.1 Patient Selection Information on FDA-approved tests for patient selection is available at:https://www.fda.gov/CompanionDiagnostics. Non-Small Cell Lung Cancer. oSelect patients with metastatic NSCLC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.6)].. oSelect patients with metastatic NSCLC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.6)].. Esophageal Cancer. oSelect patients with unresectable or advanced or metastatic ESCC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.8)].oAn FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic ESCC is not available. oSelect patients with unresectable or advanced or metastatic ESCC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.8)].. oAn FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic ESCC is not available. 2.2 Recommended Dosage. The recommended dosages of YERVOY as single agent are presented in Table 1.Administer YERVOY as 30-minute intravenous infusion [see Preparation and Administration (2.4)].Table 1: Recommended Dosages for YERVOY as Single AgentIndicationRecommended YERVOY DosageDuration of TherapyUnresectable or metastatic melanoma3 mg/kg every weeksMaximum of dosesAdjuvant treatment of melanoma3 mg/kg every weeksfollowed by mg/kg every 12 weeksEvery weeks up to maximum of dosesEvery 12 weeks for up to additional dosesThe recommended dosages of YERVOY in combination with other therapeutic agents are presented in Table 2. Administer YERVOY on the same day as other therapeutic agents. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with YERVOY for recommended dosage information, as appropriate.Table 2: Recommended Dosages of YERVOY in Combination with Other Therapeutic Agents Refer to the Prescribing Information for the agents administered in combination with YERVOY for recommended dosing information, as appropriate. Refer to the Prescribing Information for nivolumab for dosage information after completing use in combination with YERVOY.IndicationRecommended YERVOY DosageDuration of TherapyUnresectable or metastatic melanoma3 mg/kg every weekswith nivolumab mg/kgIn combination with nivolumab for maximum of doses or until unacceptable toxicity, whichever occurs earlier.After completing doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity.+Advanced renal cell carcinoma1 mg/kg every weekswith nivolumab mg/kgIn combination with nivolumabfor maximum of doses.After completing doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity.+ Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancerAdult patients and pediatric patients age 12 years and older and weighing 40 kg or more:1 mg/kg every weekswith nivolumab 240 mg In combination with nivolumabfor maximum of doses.+After completing doses of combination therapy, administer nivolumab as single agent until disease progression, unacceptable toxicity, or up to years.+ Pediatric patients age 12 years and older and weighing less than 40 kg: mg/kg every weekswith nivolumab mg/kgHepatocellular carcinoma3 mg/kg every weekswith nivolumab mg/kgIn combination with nivolumabfor maximum of doses.After completing maximum of doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity.+ Metastatic non-small cell lung cancer expressing PD-L11 mg/kg every weekswith nivolumab 360 mg every weeksIn combination with nivolumab until disease progression, unacceptable toxicity, or up to years in patients without disease progression.+ Metastatic or recurrent non-small cell lung cancer1 mg/kg every weekswith nivolumab 360 mg every weeksand histology-based platinum-doubletchemotherapy every weeksIn combination with nivolumab until disease progression, unacceptable toxicity, or up to years in patients without disease progression.+ cycles of histology-based platinum-doublet chemotherapyMalignant pleural mesothelioma1 mg/kg every weekswith nivolumab 360 mg every weeksIn combination with nivolumab until disease progression, unacceptable toxicity, or up to years in patients without disease progression.+ Esophageal squamous cell carcinoma1 mg/kg every weeks with nivolumab mg/kg every weeks or 360 mg every weeksIn combination with nivolumab until disease progression, unacceptable toxicity, or up to years.. 2.3 Recommended Dosage Modifications for Adverse Reactions. No dose reduction for YERVOY is recommended. In general, withhold YERVOY for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue YERVOY for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, persistent moderate (Grade 2) or severe (Grade 3) reactions lasting 12 weeks or longer after last YERVOY dose (excluding endocrinopathy), 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 YERVOY or YERVOY in combination with nivolumab for adverse reactions that require management different from these general guidelines are summarized in Table 3.When YERVOY is administered in combination with nivolumab, withhold or permanently discontinue both YERVOY and nivolumab for toxicity.Table 3: Recommended Dosage Modifications for Adverse ReactionsALT 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 normal Based on Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Resume in patients with complete or partial resolution (Grade or 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/ALT are less than or equal to ULN at baseline, withhold or permanently discontinue YERVOY based on recommendations for hepatitis with no liver involvement. This guidance is only applicable to HCC patients who are being treated with YERVOY in combination with nivolumab. Depending on clinical severity, consider withholding for Grade endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.Adverse ReactionSeverityDosage ModificationsImmune-Mediated Adverse Reactions [See Warnings and Precautions (5.1)] ColitisGrade 2Withholda Grade or Permanently discontinue Hepatitis with no tumor involvement of the liveror Hepatitis with tumor involvement of the liver/non-HCCAST or ALT increases to more than times and up to times the ULNor Total bilirubin increases to more than 1.5 times and up to times the ULNWithholda AST or ALT more than times the ULN or Total bilirubin more than times the ULN Permanently discontinueHepatitis with tumor involvement of the liverb/HCCc Baseline AST/ALT is more than and up to times ULN and increases to more than and up to 10 times ULNorBaseline AST/ALT is more than and up to times ULN and increases to more than and up to 10 times ULN.Withholda AST/ALT increases to more than 10 times ULNorTotal bilirubin increases to more than times ULN.Permanently discontinueExfoliative Dermatologic ConditionsSuspected SJS, TEN, or DRESSWithholdConfirmed SJS, TEN, or DRESSPermanently discontinueEndocrinopathiesd Grades or 4Withhold until clinically stable or permanently discontinue depending on severityPneumonitisGrade Withholda Grade or Permanently discontinueNephritis with Renal DysfunctionGrade or increased blood creatinineWithholda Grade increased blood creatininePermanently discontinueNeurological ToxicitiesGrade 2Withholda Grade or 4Permanently discontinueMyocarditis Grade 2, or Permanently discontinueOphthalmologicGrade 2, 3, or that does not improve to Grade within weeks while receiving topical therapy or that requires systemic treatmentPermanently discontinue Other Adverse ReactionsInfusion-Related Reactions [see Warnings and Precautions (5.2)] Grade or 2Interrupt or slow the rate of infusionGrade or 4Permanently discontinue. 2.4 Preparation and Administration. oDo not shake product.oVisually inspect for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles.. oDo not shake product.. oVisually inspect for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles.. Preparation of Solution. oAllow the vial(s) to stand at room temperature for approximately minutes prior to preparation of infusion.oWithdraw the required volume of YERVOY and transfer into an intravenous bag.oDilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to final concentration ranging from mg/mL to mg/mL. Mix diluted solution by gentle inversion. oAfter preparation, store the diluted solution either refrigerated at 2C to 8C (36F to 46F) or at room temperature of 20C to 25C (68F to 77F) for no more than 24 hours from the time of preparation to the time of infusion.oDiscard partially used or empty vials of YERVOY.. oAllow the vial(s) to stand at room temperature for approximately minutes prior to preparation of infusion.. oWithdraw the required volume of YERVOY and transfer into an intravenous bag.. oDilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to final concentration ranging from mg/mL to mg/mL. Mix diluted solution by gentle inversion. oAfter preparation, store the diluted solution either refrigerated at 2C to 8C (36F to 46F) or at room temperature of 20C to 25C (68F to 77F) for no more than 24 hours from the time of preparation to the time of infusion.. oDiscard partially used or empty vials of YERVOY.. Administration. oDo not co-administer other drugs through the same intravenous line.oFlush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose.oAdminister diluted YERVOY solution by intravenous infusion over 30 minutes through an intravenous line containing sterile, non-pyrogenic, low-protein-binding in-line filter.oWhen administered in combination with nivolumab, infuse nivolumab first followed by YERVOY on the same day. oWhen administered with nivolumab and platinum-doublet chemotherapy, infuse nivolumab first followed by YERVOY and then platinum-doublet chemotherapy on the same day. oUse separate infusion bags and filters for each infusion.. oDo not co-administer other drugs through the same intravenous line.. oFlush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose.. oAdminister diluted YERVOY solution by intravenous infusion over 30 minutes through an intravenous line containing sterile, non-pyrogenic, low-protein-binding in-line filter.. oWhen administered in combination with nivolumab, infuse nivolumab first followed by YERVOY on the same day. oWhen administered with nivolumab and platinum-doublet chemotherapy, infuse nivolumab first followed by YERVOY and then platinum-doublet chemotherapy on the same day. oUse separate infusion bags and filters for each infusion.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 50 mg/10 mL (5 mg/mL) and 200 mg/40 mL (5 mg/mL) as clear to slightly opalescent, colorless to pale-yellow solution in single-dose vial.. oInjection: 50 mg/10 mL (5 mg/mL) and 200 mg/40 mL (5 mg/mL) in single-dose vial. (3). oInjection: 50 mg/10 mL (5 mg/mL) and 200 mg/40 mL (5 mg/mL) in single-dose vial. (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential Pregnancy Testing. Verify pregnancy status in females of reproductive potential prior to initiating YERVOY [see Use in Specific Populations (8.1)].. Contraception. YERVOY 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 YERVOY and for months following the last dose.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Single AgentOf the 511 patients treated with YERVOY in Study MDX010-20 (unresectable or metastatic melanoma), 28% were 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients.In Combination with NivolumabOf the 314 patients randomized to YERVOY administered with nivolumab in CHECKMATE-067, 41% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients.Of the 576 patients randomized to YERVOY mg/kg every weeks with nivolumab mg/kg every weeks in CHECKMATE-227 (NSCLC), 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received YERVOY with nivolumab (18%). Of the 396 patients in the primary efficacy population (PD-L1 >=1%) randomized to YERVOY mg/kg every weeks with nivolumab mg/kg every weeks in CHECKMATE-227, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Clinical Studies (14.6)].Of the 303 patients randomized to YERVOY mg/kg every weeks in combination with nivolumab mg/kg every weeks in CHECKMATE-743 (malignant pleural mesothelioma), 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation rate due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received YERVOY with nivolumab (54% and 28%, respectively). For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and discontinuation due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to YERVOY in combination with nivolumab.Of the 550 patients randomized to YERVOY mg/kg with nivolumab in CHECKMATE-214 (renal cell carcinoma), 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was observed between these patients and younger patients. In geriatric patients with intermediate or poor risk, no overall difference in effectiveness was observed.Of the 354 patients with dMMR or MSI-H metastatic CRC (mCRC) who were randomized to YERVOY in combination with nivolumab, 44% were 65 years or older and 14% were 75 years or older. Of the 353 patients randomized to nivolumab, as single agent, 45% were 65 years or older and 13% were 75 years or older. There was higher incidence of any Grade or adverse reactions (55%) in patients aged 65 years or older receiving YERVOY in combination with nivolumab compared to those younger than 65 receiving the combination (42%). There was higher incidence of adverse reactions leading to discontinuation in patients aged 65 years or older receiving YERVOY in combination with nivolumab (23%) compared to those younger than 65 receiving the combination (15%). No overall differences in effectiveness were reported between elderly patients and younger patients receiving YERVOY in combination with nivolumab [see Clinical Studies (14.4)].Of the 335 patients with unresectable hepatocellular carcinoma who were randomized to YERVOY in combination with nivolumab, 52% were 65 years or older and 14% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients.Of the 49 patients who received YERVOY mg/kg with nivolumab in Cohort of CHECKMATE-040 (previously treated hepatocellular carcinoma), 29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical studies of YERVOY in combination with nivolumab did not include sufficient numbers of patients with hepatocellular carcinoma aged 65 and over to determine whether they respond differently from younger patients.Of the 325 patients who received YERVOY mg/kg every weeks in combination with nivolumab mg/kg every weeks in CHECKMATE-648 (ESCC), 43% were 65 years old or older and 7% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was higher discontinuation rate due to adverse reactions in patients aged 75 years or older (38%) relative to all patients who received YERVOY with nivolumab (23%). For patients aged 75 years or older who received chemotherapy, the discontinuation rate due to adverse reactions was 33% relative to 23% for all patients. Study CA184-029 (adjuvant treatment of melanoma) and CHECKMATE-142 (metastatic colorectal cancer) did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.In Combination with Nivolumab and Platinum-Doublet ChemotherapyOf the 361 patients randomized to YERVOY mg/kg every weeks in combination with nivolumab 360 mg every weeks and platinum-doublet chemotherapy every weeks (for cycles) in CHECKMATE-9LA (NSCLC), 51% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was higher discontinuation rate due to adverse reactions in patients aged 75 years or older (43%) relative to all patients who received YERVOY with nivolumab and chemotherapy (24%). For patients aged 75 years or older who received chemotherapy only, the discontinuation rate due to adverse reactions was 16% relative to all patients who had discontinuation rate of 13%. Based on an updated analysis for overall survival, of the 361 patients randomized to YERVOY in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA, the hazard ratio for overall survival was 0.61 (95% CI: 0.47, 0.80) in the 176 patients younger than 65 years compared to 0.73 (95% CI: 0.56, 0.95) in the 185 patients 65 years or older.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. YERVOY (ipilimumab) injection is sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution. YERVOY is available as follows:Carton ContentsNDCOne 50 mg/10 mL (5 mg/mL), single-dose vialNDC 0003-2327-11One 200 mg/40 mL (5 mg/mL), single-dose vialNDC 0003-2328-22Store YERVOY under refrigeration at 2C to 8C (36F to 46F). Protect YERVOY from light by storing in the original carton until time of use. Do not freeze or shake.

IMMUNOGENICITY.

12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of YERVOY or of other ipilimumab products.Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma tested positive for treatment-emergent binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay had substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Seven (4.9%) of 144 patients receiving ipilimumab developed anti-ipilimumab antibodies and (4.5%) of 156 patients receiving placebo for the adjuvant treatment of melanoma tested positive for anti-ipilimumab antibodies using an ECL assay with improved drug tolerance. No patients tested positive for neutralizing antibodies. No infusion-related reactions occurred in patients who tested positive for anti-ipilimumab antibodies.Of the 499 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-214 and CHECKMATE-142, 27 (5.4%) were positive for anti-ipilimumab antibodies; there were no patients with neutralizing antibodies against ipilimumab. There was no evidence of increased incidence of infusion reactions to YERVOY in patients with anti-ipilimumab antibodies.Of 483 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-227 Part 1, 8.5% were positive for treatment-emergent anti-ipilimumab antibodies. No patients had neutralizing antibodies against ipilimumab. In Part of the same study, of 491 patients evaluable for anti-nivolumab antibodies, 36.7% were positive for anti-nivolumab antibodies and 1.4% had neutralizing antibodies against nivolumab.Of 305 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-9LA, 8% were positive for anti-ipilimumab antibodies and 1.6% were positive for anti-ipilimumab neutralizing antibodies. There was no evidence of increased incidence of infusion reactions to YERVOY in patients with anti-ipilimumab antibodies. Of 308 patients evaluable for anti-nivolumab antibodies in CHECKMATE-9LA, 34% were positive for anti-nivolumab antibodies and 2.6% had neutralizing antibodies against nivolumab.Of 271 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-743, 13.7% were positive for anti-ipilimumab antibodies and 0.4% were positive for anti-ipilimumab neutralizing antibodies. Of 269 patients evaluable for anti-nivolumab antibodies in CHECKMATE-743, 25.7% were positive for anti-nivolumab antibodies and 0.7% had neutralizing antibodies against nivolumab.Anti-drug antibody and neutralizing antibody responses were monitored throughout the treatment period where the benefit to risk ratio was assessed. Incidence of anti-drug antibodies and neutralizing antibodies are presented in Table 24.Table 24: YERVOY Anti-Drug Antibody (ADA) and Neutralizing Antibody (NAb) Incidencea Details of each treatment regimen are described in Section 14 [see Clinical Studies (14)].b NAb incidence is reported among the subset of patients positive for ADA.ADA treatment-emergent anti-ipilimumab antibodies, NAb neutralizing antibodies, HCC hepatocellular carcinoma, RCC renal cell carcinoma, CRC colorectal cancer, NSCLC non-small cell lung cancer.Treatment Regimena Indication(s)ADANAbb YERVOY as single agentMelanoma1.1%(11/1024)0(0/11)Adjuvant Melanoma4.9(7/144)0(0/7)YERVOY with nivolumab for doses followed by nivolumab as single agentMelanoma8.4%(33/391)3%(1/33)HCC5.3%(13/244)0(0/13)RCC and CRC5.4%(27/499)0%(0/27)YERVOY with nivolumabMalignant Pleural Mesothelioma13.7%(37/271)2.7%(1/37)NSCLC8.5%(41/483)0(0/41)YERVOY with nivolumab and cycles of platinum-doublet chemotherapyNSCLC7.5%(23/305)21.7%(5/23). Effects of Anti-Drug Antibodies. Presence of treatment-emergent anti-ipilimumab antibodies did not affect ipilimumab clearance after administration of ipilimumab as monotherapy or in combination with nivolumab. These anti-drug antibody-associated pharmacokinetic changes were not considered to be clinically significant. There was no identified clinically significant effect of anti-drug antibodies on incidence of infusion-related reactions. In hepatocellular carcinoma, there was no identified clinically significant effect of anti-drug antibodies on efficacy for ipilimumab in combination with nivolumab. For other indications, the effects of anti-drug antibodies on effectiveness have not been fully characterized.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. YERVOY is human cytotoxic T-lymphocyte antigen (CTLA-4)-blocking antibody indicated for:MelanomaoTreatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older as single agent or in combination with nivolumab. (1.1)oAdjuvant treatment of adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than mm who have undergone complete resection, including total lymphadenectomy. (1.2)Renal Cell Carcinoma (RCC)oTreatment of adult patients with intermediate or poor risk advanced renal cell carcinoma, as first-line treatment in combination with nivolumab. (1.3)Colorectal CanceroTreatment of adults and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) in combination with nivolumab. (1.4)Hepatocellular Carcinomaoadult patients with unresectable or metastatic hepatocellular carcinoma (HCC) as first-line treatment in combination with nivolumab. (1.5)oin combination with nivolumab in adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib. (1.5)Non-Small Cell Lung Cancer (NSCLC)oTreatment of adult patients with metastatic non-small cell lung cancer expressing PD-L1 (>=1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab. (1.6) oTreatment of adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with nivolumab and cycles of platinum-doublet chemotherapy. (1.6)Malignant Pleural MesotheliomaoTreatment of adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with nivolumab. (1.7)Esophageal CanceroTreatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma, as first line treatment in combination with nivolumab whose tumors express PD-L1 (>=1). (1.8) oTreatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older as single agent or in combination with nivolumab. (1.1). oAdjuvant treatment of adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than mm who have undergone complete resection, including total lymphadenectomy. (1.2). oTreatment of adult patients with intermediate or poor risk advanced renal cell carcinoma, as first-line treatment in combination with nivolumab. (1.3). oTreatment of adults and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) in combination with nivolumab. (1.4). oadult patients with unresectable or metastatic hepatocellular carcinoma (HCC) as first-line treatment in combination with nivolumab. (1.5). oin combination with nivolumab in adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib. (1.5). oTreatment of adult patients with metastatic non-small cell lung cancer expressing PD-L1 (>=1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab. (1.6) oTreatment of adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with nivolumab and cycles of platinum-doublet chemotherapy. (1.6). oTreatment of adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with nivolumab. (1.7). oTreatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma, as first line treatment in combination with nivolumab whose tumors express PD-L1 (>=1). (1.8) 1.1 Unresectable or Metastatic Melanoma YERVOY, as single agent or in combination with nivolumab, is indicated for the treatment of unresectable or metastatic melanoma in adult and pediatric patients 12 years and older.. 1.2 Adjuvant Treatment of Melanoma YERVOY is indicated for the adjuvant treatment of adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than mm who have undergone complete resection, including total lymphadenectomy.. 1.3 Advanced Renal Cell Carcinoma YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC).. 1.4 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer oYERVOY, in combination with nivolumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).. oYERVOY, in combination with nivolumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).. 1.5 Hepatocellular Carcinoma oYERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC).oYERVOY, in combination with nivolumab, is indicated for the treatment of adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib.. oYERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC).. oYERVOY, in combination with nivolumab, is indicated for the treatment of adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib.. 1.6 Metastatic Non-Small Cell Lung Cancer YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (>=1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations.YERVOY, in combination with nivolumab and cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations.. 1.7 Malignant Pleural Mesothelioma YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.. 1.8 Esophageal Cancer YERVOY, in combination with nivolumab, 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 (2.1)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Immune-Mediated Adverse Reactions. Advise patients that YERVOY can cause immune-mediated adverse reactions including the following [see Warnings and Precautions (5.1)]:oImmune-Mediated Diarrhea or Colitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of diarrhea or colitis.oImmune-Mediated Hepatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatitis.oImmune-Mediated Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately if they develop new rash.oImmune-Mediated Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus.oImmune-Mediated Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening symptoms of pneumonitis.oImmune-Mediated Nephritis with Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.Infusion-Related ReactionsoAdvise patients who are receiving YERVOY of the potential risk of an infusion-related reaction [see Warnings and Precautions (5.2)].. oImmune-Mediated Diarrhea or Colitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of diarrhea or colitis.. oImmune-Mediated Hepatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatitis.. oImmune-Mediated Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately if they develop new rash.. oImmune-Mediated Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus.. oImmune-Mediated Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening symptoms of pneumonitis.. oImmune-Mediated Nephritis with Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.. oAdvise patients who are receiving YERVOY of the potential risk of an infusion-related reaction [see Warnings and Precautions (5.2)].. Embryo-Fetal Toxicity. oAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.3)]. oAdvise females of reproductive potential to use effective contraception during treatment with YERVOY and for months after the last dose [see Use in Specific Populations (8.3)].oAdvise patients who may have been exposed to YERVOY during pregnancy to contact Bristol-Myers Squibb at 1-844-593-7869 [see Use in Specific Populations (8.1)].. oAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.3)]. oAdvise females of reproductive potential to use effective contraception during treatment with YERVOY and for months after the last dose [see Use in Specific Populations (8.3)].. oAdvise patients who may have been exposed to YERVOY during pregnancy to contact Bristol-Myers Squibb at 1-844-593-7869 [see Use in Specific Populations (8.1)].. Lactation. oAdvise women not to breastfeed during treatment with YERVOY and for months after the last dose [see Use in Specific Populations (8.2)].. oAdvise women not to breastfeed during treatment with YERVOY 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. 1713[print code].

LACTATION SECTION.

8.2 Lactation Risk Summary. There are no data on the presence of YERVOY in human milk or its effects on the breastfed child or milk production. In monkeys, ipilimumab was present in milk (see Data). Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with YERVOY and for months following the last dose.. Data. In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at 3 mg/kg dose, ipilimumab was present in milk at concentrations of 0.1 mcg/mL and 0.4 mcg/mL, representing ratio of up to 0.3% of the steady-state serum concentration of the drug.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. CTLA-4 is negative regulator of T-cell activity. Ipilimumab is monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to general increase in T-cell responsiveness, including the anti-tumor immune response.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies, and the genotoxic potential of ipilimumab has not been evaluated.Fertility studies have not been performed with ipilimumab.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

YERVOY 50 mg/10 mL Representative Packaging See How Supplied section for complete list of available packages of YERVOY.NDC 0003-2327-11Rx onlyYERVOY(R) (ipilimumab)Injection50 mg/10 mL(5 mg/mL)For Intravenous Infusion OnlySingle-use vial; Discard unused portionDISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENTBristol-Myers Squibb. yervoy-50mg-carton-serialized.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of YERVOY have been established in pediatric patients aged 12 years and older for the following indications: as single agent and in combination with nivolumab for unresectable or metastatic melanoma, in combination with nivolumab for the treatment of MSI-H or dMMR unresectable and metastatic CRC, and in combination with nivolumab for MSI-H or dMMR mCRC that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Use of YERVOY for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma or MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients. Ipilimumab exposures in pediatric patients 12 years and older are comparable to that of adults, and the courses of melanoma and MSI-H or dMMR mCRC are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.4)].The safety and effectiveness of YERVOY have not been established in pediatric patients younger than 12 years old with unresectable or metastatic melanoma or MSI-H or dMMR mCRC.The safety and effectiveness of YERVOY have not been established in pediatric patients for the adjuvant treatment of melanoma or for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, metastatic non-small cell lung cancer, malignant pleural mesothelioma and esophageal cancer.In dose-finding trial (NCT01445379), 33 patients aged to 21 years (median 13 years) with relapsed or refractory solid tumors were evaluated including unresectable stage IIIc or stage IV melanoma (12), progressive or refractory sarcomas (17), renal or bladder carcinoma (3), and neuroblastoma (1). No responses in the patients with non-melanoma solid tumors and no new safety signals were observed in pediatric patients in this study.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every weeks for doses. The PK of ipilimumab is linear in the dose range of 0.3 mg/kg to 10 mg/kg. Following administration of YERVOY every weeks, the systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean minimum concentration (Cmin) at steady state was 19.4 mcg/mL at mg/kg and 58.1 mcg/mL at 10 mg/kg every weeks.EliminationThe mean (percent coefficient of variation) terminal half-life (t1/2) was 15.4 days (34%) and then mean (percent coefficient of variation) clearance (CL) was 16.8 mL/h (38%). The CL of ipilimumab was unchanged in presence of anti-ipilimumab antibodies.Specific PopulationsThe CL of ipilimumab increased with increasing body weight supporting the recommended body weight (mg/kg) based dosing. The following factors had no clinically important effect on the CL of ipilimumab: age (range: 23 to 88 years), sex, performance status, renal impairment (glomerular filtration rate >=15 mL/min/1.73 m2), mild hepatic impairment (total bilirubin [TB] >1 to 1.5 times the upper limit of normal [ULN] or AST ULN), previous cancer therapy, and baseline lactate dehydrogenase (LDH) levels. The effect of race was not examined due to limited data available in non-White racial groups. YERVOY has not been studied in patients with moderate (TB >1.5 to times ULN and any AST) or severe (TB >3 times ULN and any AST) hepatic impairment.Pediatric Patients The exposures of ipilimumab in pediatric patients 12 years and older are comparable to those in adult patients at the recommended dosage.Drug Interaction StudiesIpilimumab with NivolumabWhen YERVOY mg/kg was administered with nivolumab mg/kg every weeks, the CL of ipilimumab was unchanged compared to when YERVOY was administered alone.When YERVOY mg/kg every weeks was administered in combination with nivolumab mg/kg every weeks, the CL of ipilimumab was unchanged compared to ipilimumab administered alone and the CL of nivolumab was increased by 29% compared to nivolumab administered alone.When YERVOY mg/kg every weeks was administered in combination with nivolumab mg/kg every weeks, the CL of ipilimumab increased by 30% compared to YERVOY administered alone and the CL of nivolumab was unchanged compared to nivolumab administered alone.When YERVOY mg/kg every weeks was administered in combination with nivolumab 360 mg every weeks and chemotherapy, the CL of ipilimumab increased by 22% compared to YERVOY administered alone and the CL of nivolumab was unchanged compared to nivolumab administered alone.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary. Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], YERVOY can cause fetal harm when administered to pregnant woman. There is insufficient human data for YERVOY exposure in pregnant women. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in dose-related manner (see Data). The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to fetus. Report pregnancies to Bristol-Myers Squibb at 1-844-593-7869.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal Data In combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every weeks from the onset of organogenesis in the first trimester through parturition. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at dose of mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality. In addition, developmental abnormalities were identified in the urogenital system of infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the humans exposure based on area under the curve at dose of mg/kg). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/- heterozygous offspring. Mated CTLA-4+/- heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-). The CTLA-4-/- homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by weeks of age, and all died by to weeks of age with massive lymphoproliferation and multiorgan tissue destruction.

RECENT MAJOR CHANGES SECTION.

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

SPL MEDGUIDE SECTION.

MEDICATION GUIDEYERVOY(R) (yur-voi)(ipilimumab)injectionRead this Medication Guide before you start receiving YERVOY and before each infusion. There may be new information. If your healthcare provider prescribes YERVOY in combination with nivolumab, also read the Medication Guide that comes with nivolumab. 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 YERVOYYERVOY is medicine that may treat certain cancers by working with your immune system. YERVOY 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 life-threatening and can lead to death. You may have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended. Some of these problems may happen more often when YERVOY is used in combination with nivolumab.Call or see your healthcare provider right away if you develop any new or worse signs or symptoms, including:Intestinal 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 normalSkin problems.orashoitchingoskin blistering or peelingopainful sores in mouth or nose, throat, or genital areaHormone gland problems.oheadache that will not go away or unusual headachesoeye sensitivity to lightoeye problemsorapid heartbeatoincreased 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 forgetfulnessLung problems.onew or worsening coughoshortness of breathochest painKidney problems.odecrease in your amount of urineoblood in your urineoswelling of your anklesoloss of appetiteEye problems. oblurry vision, double vision, or other vision problemsoeye pain or rednessProblems 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 YERVOY. Call or see your healthcare provider right away for any new or worsening signs or symptoms.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, bruisingGetting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with YERVOY. 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 YERVOY if you have severe side effects.What is YERVOYYERVOY is prescription medicine used:oto treat kind of skin cancer called melanoma.oYERVOY may be used alone or in combination with nivolumab in adults and children 12 years of age and older when melanoma has spread or cannot be removed by surgery.oYERVOY may be used alone in adults to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.oin adults with kidney cancer (renal cell carcinoma). YERVOY may be used in combination with nivolumab in certain people when their cancer has spread.oin adults and children 12 years of age and older, with type of colon or rectal cancer (colorectal cancer).oYERVOY may be used in combination with nivolumab when your colon or rectal cancer:cannot be removed with surgery, or has spread, andis microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).oin adults with liver cancer (hepatocellular carcinoma).oYERVOY may be used in combination with nivolumab as your first treatment when your liver cancer:cannot be removed by surgery, orhas spread.oYERVOY may be used in combination with nivolumab when your liver cancer:cannot be removed by surgery, orhas spread, andyou have received prior treatment with sorafenib.oin adults with type of lung cancer called non-small cell lung cancer (NSCLC).oYERVOY may be used in combination with nivolumab as your first treatment for NSCLC:when your lung cancer has spread to other parts of your body (metastatic), andyour tumors are positive for PD-L1, but do not have an abnormal EGFR or ALK gene.oYERVOY may be used in combination with nivolumab and cycles of chemotherapy that contains platinum and another chemotherapy medicine, as the first treatment of your NSCLC when your lung cancer:has spread or grown, or comes back, andyour tumor does not have an abnormal EGFR or ALK gene.oin adults with type of cancer that affects the lining of the lungs and chest wall called malignant pleural mesothelioma.oYERVOY may be used in combination with nivolumab as your first treatment for malignant pleural mesothelioma that cannot be removed by surgery.oin adults with cancer of the tube that connects your throat to your stomach (esophageal cancer).oYERVOY may be used in combination with nivolumab as your first treatment when your esophageal cancer:is type called squamous cell carcinoma, andcannot be removed with surgery (advanced), or has spread to the other parts of the body (metastatic), andyour tumors are positive for PD-L1.It is not known if YERVOY is safe and effective in children younger than 12 years of age with melanoma that has spread or cannot be removed by surgery, or with MSI-H or dMMR metastatic colorectal cancer.It is not known if YERVOY is safe and effective in children for the treatment of any other cancers.Before you receive YERVOY, tell your healthcare provider about all your medical conditions, including if you:ohave immune system problems such as ulcerative colitis, Crohns disease, or lupusohave received an organ transplantohave received or plan to receive stem cell transplant that uses donor stem cells (allogeneic) ohave condition that affects your nervous system, such as myasthenia gravis or Guillain-Barre syndromeoare pregnant or plan to become pregnant. YERVOY can harm your unborn baby. Females who are able to become pregnant:oYour healthcare provider will give you pregnancy test before you start treatment with YERVOY.oYou should use an effective method of birth control during treatment and for months after your last dose of YERVOY. Talk to your healthcare provider about birth control methods that you can use during this time.oTell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with YERVOY. You or your healthcare provider should contact Bristol-Myers Squibb at 1-844-593-7869 as soon as you become aware of pregnancy.oare breastfeeding or plan to breastfeed. It is not known if YERVOY passes into your breast milk. Do not breastfeed during treatment and for months after your last dose of YERVOY.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive YERVOYoYour healthcare provider will give you YERVOY into your vein through an intravenous (IV) line.oYERVOY is usually given over 30 minutes. oIf you are receiving YERVOY as treatment for melanoma that has been removed by surgery to help prevent it from coming back, YERVOY will be given over 30 minutes.oIn combination with nivolumab, YERVOY is usually given every weeks for up to doses. After that, nivolumab alone is usually given every or weeks.oFor NSCLC that has spread to other parts of your body, YERVOY is given every weeks and nivolumab is given every weeks for up to years. Your healthcare provider will determine if you will also need to receive chemotherapy every weeks for cycles.oFor malignant pleural mesothelioma that cannot be removed by surgery, YERVOY is given every weeks and nivolumab is given every weeks for up to years.oWhen YERVOY is used in combination with nivolumab for esophageal squamous cell carcinoma (ESCC), YERVOY is given every weeks and nivolumab is given every or weeks for up to years.oYour healthcare provider will decide how many treatments you will need.oYour healthcare provider will do blood tests before starting and during treatment with YERVOY.oIf you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.What are the possible side effects of YERVOYYERVOY can cause serious side effects, including:oSee What is the most important information should know about YERVOYoSevere infusion-related reactions. Tell your healthcare provider or nurse right away if you get these symptoms during an infusion of YERVOY:ochills or shakingoitching or rashoflushingoshortness of breath or wheezingodizzinessofeel like passing outofeveroback or neck painoComplications, 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 YERVOY. Your healthcare provider will monitor you for these complications.The most common side effects of YERVOY when used alone include:ofeeling tiredodiarrheaonauseaoitchingorashovomitingoheadacheoweight lossofeverodecreased appetiteodifficulty falling or staying asleepThe most common side effects of YERVOY when used in combination with nivolumab include:ofeeling tiredodiarrheaorashoitchingonauseaopain in muscles, bones, and jointsofeverocoughodecreased appetiteovomitingostomach-area (abdominal) painoshortness of breathoupper respiratory tract infectionoheadacheolow thyroid hormone levels (hypothyroidism)oconstipationodecreased weightodizzinessThe most common side effects of YERVOY when used in combination with nivolumab and chemotherapy include:ofeeling tiredopain in muscles, bones, and jointsonauseaodiarrheaorashodecreased appetiteoconstipationoitchingThese are not all of the possible side effects of YERVOY.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 YERVOY.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. If you would like more information about YERVOY, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about YERVOY that is written for health professionals.What are the ingredients of YERVOYActive ingredient: ipilimumabInactive ingredients: diethylene triamine pentaacetic acid (DTPA), mannitol, polysorbate 80 (vegetable origin), sodium chloride, tris hydrochloride, and Water for InjectionManufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA U.S. License No. 1713YERVOY(R) is trademark of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.For more information, call 1-800-321-1335This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: May 2025. 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. orash. oitching. oskin blistering or peeling. opainful sores in mouth or nose, throat, or genital area. oheadache 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. onew or worsening cough. oshortness of breath. ochest pain. odecrease in your amount of urine. oblood in your urine. oswelling of your ankles. oloss of appetite. oblurry vision, double vision, or other vision problems. oeye pain or redness. 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. oto treat kind of skin cancer called melanoma.oYERVOY may be used alone or in combination with nivolumab in adults and children 12 years of age and older when melanoma has spread or cannot be removed by surgery.oYERVOY may be used alone in adults to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.. oYERVOY may be used alone or in combination with nivolumab in adults and children 12 years of age and older when melanoma has spread or cannot be removed by surgery.. oYERVOY may be used alone in adults to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.. oin adults with kidney cancer (renal cell carcinoma). YERVOY may be used in combination with nivolumab in certain people when their cancer has spread.. oin adults and children 12 years of age and older, with type of colon or rectal cancer (colorectal cancer).oYERVOY may be used in combination with nivolumab when your colon or rectal cancer:cannot be removed with surgery, or has spread, andis microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).. oYERVOY may be used in combination with nivolumab when your colon or rectal cancer:cannot be removed with surgery, or has spread, andis microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).. cannot be removed with surgery, or has spread, and. is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).. oin adults with liver cancer (hepatocellular carcinoma).oYERVOY may be used in combination with nivolumab as your first treatment when your liver cancer:cannot be removed by surgery, orhas spread.oYERVOY may be used in combination with nivolumab when your liver cancer:cannot be removed by surgery, orhas spread, andyou have received prior treatment with sorafenib.. oYERVOY may be used in combination with nivolumab as your first treatment when your liver cancer:cannot be removed by surgery, orhas spread.. cannot be removed by surgery, or. has spread.. oYERVOY may be used in combination with nivolumab when your liver cancer:cannot be removed by surgery, orhas spread, andyou have received prior treatment with sorafenib.. cannot be removed by surgery, or. has spread, and. you have received prior treatment with sorafenib.. oin adults with type of lung cancer called non-small cell lung cancer (NSCLC).oYERVOY may be used in combination with nivolumab as your first treatment for NSCLC:when your lung cancer has spread to other parts of your body (metastatic), andyour tumors are positive for PD-L1, but do not have an abnormal EGFR or ALK gene.oYERVOY may be used in combination with nivolumab and cycles of chemotherapy that contains platinum and another chemotherapy medicine, as the first treatment of your NSCLC when your lung cancer:has spread or grown, or comes back, andyour tumor does not have an abnormal EGFR or ALK gene.. oYERVOY may be used in combination with nivolumab as your first treatment for NSCLC:when your lung cancer has spread to other parts of your body (metastatic), andyour tumors are positive for PD-L1, but do not have an abnormal EGFR or ALK gene.. when your lung cancer has spread to other parts of your body (metastatic), and. your tumors are positive for PD-L1, but do not have an abnormal EGFR or ALK gene.. oYERVOY may be used in combination with nivolumab and cycles of chemotherapy that contains platinum and another chemotherapy medicine, as the first treatment of your NSCLC when your lung cancer:has spread or grown, or comes back, andyour tumor does not have an abnormal EGFR or ALK gene.. has spread or grown, or comes back, and. your tumor does not have an abnormal EGFR or ALK gene.. oin adults with type of cancer that affects the lining of the lungs and chest wall called malignant pleural mesothelioma.oYERVOY may be used in combination with nivolumab as your first treatment for malignant pleural mesothelioma that cannot be removed by surgery.. oYERVOY may be used in combination with nivolumab as your first treatment for malignant pleural mesothelioma that cannot be removed by surgery.. oin adults with cancer of the tube that connects your throat to your stomach (esophageal cancer).oYERVOY may be used in combination with nivolumab as your first treatment when your esophageal cancer:is type called squamous cell carcinoma, andcannot be removed with surgery (advanced), or has spread to the other parts of the body (metastatic), andyour tumors are positive for PD-L1.. oYERVOY may be used in combination with nivolumab as your first treatment when your esophageal cancer:is type called squamous cell carcinoma, andcannot be removed with surgery (advanced), or has spread to the other parts of the body (metastatic), andyour tumors are positive for PD-L1.. is type called squamous cell carcinoma, and. cannot be removed with surgery (advanced), or has spread to the other parts of the body (metastatic), and. your tumors are positive for PD-L1.. ohave immune system problems such as ulcerative colitis, Crohns disease, or lupus. ohave received an organ transplant. ohave received or plan to receive stem cell transplant that uses donor stem cells (allogeneic) ohave condition that affects your nervous system, such as myasthenia gravis or Guillain-Barre syndrome. oare pregnant or plan to become pregnant. YERVOY can harm your unborn baby.. Females who are able to become pregnant:oYour healthcare provider will give you pregnancy test before you start treatment with YERVOY.oYou should use an effective method of birth control during treatment and for months after your last dose of YERVOY. Talk to your healthcare provider about birth control methods that you can use during this time.oTell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with YERVOY. You or your healthcare provider should contact Bristol-Myers Squibb at 1-844-593-7869 as soon as you become aware of pregnancy.. oYour healthcare provider will give you pregnancy test before you start treatment with YERVOY.. oYou should use an effective method of birth control during treatment and for months after your last dose of YERVOY. Talk to your healthcare provider about birth control methods that you can use during this time.. oTell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with YERVOY. You or your healthcare provider should contact Bristol-Myers Squibb at 1-844-593-7869 as soon as you become aware of pregnancy.. oare breastfeeding or plan to breastfeed. It is not known if YERVOY passes into your breast milk. Do not breastfeed during treatment and for months after your last dose of YERVOY.. oYour healthcare provider will give you YERVOY into your vein through an intravenous (IV) line.. oYERVOY is usually given over 30 minutes. oIf you are receiving YERVOY as treatment for melanoma that has been removed by surgery to help prevent it from coming back, YERVOY will be given over 30 minutes.. oIn combination with nivolumab, YERVOY is usually given every weeks for up to doses. After that, nivolumab alone is usually given every or weeks.. oFor NSCLC that has spread to other parts of your body, YERVOY is given every weeks and nivolumab is given every weeks for up to years. Your healthcare provider will determine if you will also need to receive chemotherapy every weeks for cycles.. oFor malignant pleural mesothelioma that cannot be removed by surgery, YERVOY is given every weeks and nivolumab is given every weeks for up to years.. oWhen YERVOY is used in combination with nivolumab for esophageal squamous cell carcinoma (ESCC), YERVOY is given every weeks and nivolumab is given every or weeks for up to years.. oYour healthcare provider will decide how many treatments you will need.. oYour healthcare provider will do blood tests before starting and during treatment with YERVOY.. 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 YERVOY. oSevere infusion-related reactions. Tell your healthcare provider or nurse right away if you get these symptoms during an infusion of YERVOY:. ochills or shaking. oitching or rash. oflushing. oshortness of breath or wheezing. odizziness. ofeel like passing out. ofever. oback or neck pain. 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 YERVOY. Your healthcare provider will monitor you for these complications.. ofeeling tired. odiarrhea. onausea. oitching. orash. ovomiting. oheadache. oweight loss. ofever. odecreased appetite. odifficulty falling or staying asleep. ofeeling tired. odiarrhea. orash. oitching. onausea. opain in muscles, bones, and joints. ofever. ocough. odecreased appetite. ovomiting. ostomach-area (abdominal) pain. oshortness of breath. oupper respiratory tract infection. oheadache. olow thyroid hormone levels (hypothyroidism). oconstipation. odecreased weight. odizziness. ofeeling tired. opain in muscles, bones, and joints. onausea. odiarrhea. orash. odecreased appetite. oconstipation. oitching.

SPL UNCLASSIFIED SECTION.

1.1 Unresectable or Metastatic Melanoma YERVOY, as single agent or in combination with nivolumab, is indicated for the treatment of unresectable or metastatic melanoma in adult and pediatric patients 12 years and older.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oLactation: Advise not to breastfeed. (8.2). oLactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk Summary. Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], YERVOY can cause fetal harm when administered to pregnant woman. There is insufficient human data for YERVOY exposure in pregnant women. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in dose-related manner (see Data). The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to fetus. Report pregnancies to Bristol-Myers Squibb at 1-844-593-7869.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal Data In combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every weeks from the onset of organogenesis in the first trimester through parturition. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at dose of mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality. In addition, developmental abnormalities were identified in the urogenital system of infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the humans exposure based on area under the curve at dose of mg/kg). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/- heterozygous offspring. Mated CTLA-4+/- heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-). The CTLA-4-/- homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by weeks of age, and all died by to weeks of age with massive lymphoproliferation and multiorgan tissue destruction.. 8.2 Lactation Risk Summary. There are no data on the presence of YERVOY in human milk or its effects on the breastfed child or milk production. In monkeys, ipilimumab was present in milk (see Data). Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with YERVOY and for months following the last dose.. Data. In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at 3 mg/kg dose, ipilimumab was present in milk at concentrations of 0.1 mcg/mL and 0.4 mcg/mL, representing ratio of up to 0.3% of the steady-state serum concentration of the drug.. 8.3 Females and Males of Reproductive Potential Pregnancy Testing. Verify pregnancy status in females of reproductive potential prior to initiating YERVOY [see Use in Specific Populations (8.1)].. Contraception. YERVOY 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 YERVOY and for months following the last dose.. 8.4 Pediatric Use. The safety and effectiveness of YERVOY have been established in pediatric patients aged 12 years and older for the following indications: as single agent and in combination with nivolumab for unresectable or metastatic melanoma, in combination with nivolumab for the treatment of MSI-H or dMMR unresectable and metastatic CRC, and in combination with nivolumab for MSI-H or dMMR mCRC that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Use of YERVOY for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma or MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients. Ipilimumab exposures in pediatric patients 12 years and older are comparable to that of adults, and the courses of melanoma and MSI-H or dMMR mCRC are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.4)].The safety and effectiveness of YERVOY have not been established in pediatric patients younger than 12 years old with unresectable or metastatic melanoma or MSI-H or dMMR mCRC.The safety and effectiveness of YERVOY have not been established in pediatric patients for the adjuvant treatment of melanoma or for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, metastatic non-small cell lung cancer, malignant pleural mesothelioma and esophageal cancer.In dose-finding trial (NCT01445379), 33 patients aged to 21 years (median 13 years) with relapsed or refractory solid tumors were evaluated including unresectable stage IIIc or stage IV melanoma (12), progressive or refractory sarcomas (17), renal or bladder carcinoma (3), and neuroblastoma (1). No responses in the patients with non-melanoma solid tumors and no new safety signals were observed in pediatric patients in this study.. 8.5 Geriatric Use. Single AgentOf the 511 patients treated with YERVOY in Study MDX010-20 (unresectable or metastatic melanoma), 28% were 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients.In Combination with NivolumabOf the 314 patients randomized to YERVOY administered with nivolumab in CHECKMATE-067, 41% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients.Of the 576 patients randomized to YERVOY mg/kg every weeks with nivolumab mg/kg every weeks in CHECKMATE-227 (NSCLC), 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received YERVOY with nivolumab (18%). Of the 396 patients in the primary efficacy population (PD-L1 >=1%) randomized to YERVOY mg/kg every weeks with nivolumab mg/kg every weeks in CHECKMATE-227, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Clinical Studies (14.6)].Of the 303 patients randomized to YERVOY mg/kg every weeks in combination with nivolumab mg/kg every weeks in CHECKMATE-743 (malignant pleural mesothelioma), 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation rate due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received YERVOY with nivolumab (54% and 28%, respectively). For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and discontinuation due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to YERVOY in combination with nivolumab.Of the 550 patients randomized to YERVOY mg/kg with nivolumab in CHECKMATE-214 (renal cell carcinoma), 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was observed between these patients and younger patients. In geriatric patients with intermediate or poor risk, no overall difference in effectiveness was observed.Of the 354 patients with dMMR or MSI-H metastatic CRC (mCRC) who were randomized to YERVOY in combination with nivolumab, 44% were 65 years or older and 14% were 75 years or older. Of the 353 patients randomized to nivolumab, as single agent, 45% were 65 years or older and 13% were 75 years or older. There was higher incidence of any Grade or adverse reactions (55%) in patients aged 65 years or older receiving YERVOY in combination with nivolumab compared to those younger than 65 receiving the combination (42%). There was higher incidence of adverse reactions leading to discontinuation in patients aged 65 years or older receiving YERVOY in combination with nivolumab (23%) compared to those younger than 65 receiving the combination (15%). No overall differences in effectiveness were reported between elderly patients and younger patients receiving YERVOY in combination with nivolumab [see Clinical Studies (14.4)].Of the 335 patients with unresectable hepatocellular carcinoma who were randomized to YERVOY in combination with nivolumab, 52% were 65 years or older and 14% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients.Of the 49 patients who received YERVOY mg/kg with nivolumab in Cohort of CHECKMATE-040 (previously treated hepatocellular carcinoma), 29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical studies of YERVOY in combination with nivolumab did not include sufficient numbers of patients with hepatocellular carcinoma aged 65 and over to determine whether they respond differently from younger patients.Of the 325 patients who received YERVOY mg/kg every weeks in combination with nivolumab mg/kg every weeks in CHECKMATE-648 (ESCC), 43% were 65 years old or older and 7% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was higher discontinuation rate due to adverse reactions in patients aged 75 years or older (38%) relative to all patients who received YERVOY with nivolumab (23%). For patients aged 75 years or older who received chemotherapy, the discontinuation rate due to adverse reactions was 33% relative to 23% for all patients. Study CA184-029 (adjuvant treatment of melanoma) and CHECKMATE-142 (metastatic colorectal cancer) did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.In Combination with Nivolumab and Platinum-Doublet ChemotherapyOf the 361 patients randomized to YERVOY mg/kg every weeks in combination with nivolumab 360 mg every weeks and platinum-doublet chemotherapy every weeks (for cycles) in CHECKMATE-9LA (NSCLC), 51% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was higher discontinuation rate due to adverse reactions in patients aged 75 years or older (43%) relative to all patients who received YERVOY with nivolumab and chemotherapy (24%). For patients aged 75 years or older who received chemotherapy only, the discontinuation rate due to adverse reactions was 16% relative to all patients who had discontinuation rate of 13%. Based on an updated analysis for overall survival, of the 361 patients randomized to YERVOY in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA, the hazard ratio for overall survival was 0.61 (95% CI: 0.47, 0.80) in the 176 patients younger than 65 years compared to 0.73 (95% CI: 0.56, 0.95) in the 185 patients 65 years or older.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oSevere and Fatal Immune-Mediated Adverse Reactions: Immune-mediated adverse reactions (IMAR) can occur in any organ system or tissue, including the following: immune-mediated colitis, immune-mediated hepatitis, immune-mediated dermatologic adverse reactions, immune-mediated endocrinopathies, immune-mediated pneumonitis, and immune-mediated nephritis with renal dysfunction, and can occur at any time during treatment or after discontinuation. Monitor for symptoms and signs that may be clinical manifestations of IMAR. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone level and thyroid function including at baseline and before each dose. In general, withhold YERVOY for severe (grade 3) and permanently discontinue for life-threatening (grade 4) immune-mediated adverse reactions. See Full Prescribing Information for additional dosage modifications. (2.3, 5.1)oInfusion-Related Reactions: Discontinue for severe and life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions. (2.3, 5.2)oComplications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with YERVOY. (5.3)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus and use of effective contraception. (5.4, 8.1, 8.3). oSevere and Fatal Immune-Mediated Adverse Reactions: Immune-mediated adverse reactions (IMAR) can occur in any organ system or tissue, including the following: immune-mediated colitis, immune-mediated hepatitis, immune-mediated dermatologic adverse reactions, immune-mediated endocrinopathies, immune-mediated pneumonitis, and immune-mediated nephritis with renal dysfunction, and can occur at any time during treatment or after discontinuation. Monitor for symptoms and signs that may be clinical manifestations of IMAR. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone level and thyroid function including at baseline and before each dose. In general, withhold YERVOY for severe (grade 3) and permanently discontinue for life-threatening (grade 4) immune-mediated adverse reactions. See Full Prescribing Information for additional dosage modifications. (2.3, 5.1). oInfusion-Related Reactions: Discontinue for severe and life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions. (2.3, 5.2). oComplications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with YERVOY. (5.3). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus and use of effective contraception. (5.4, 8.1, 8.3). 5.1 Severe and Fatal Immune-Mediated Adverse Reactions YERVOY is fully human monoclonal antibody that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, thereby removing inhibition of the immune response with the potential for induction of immune-mediated adverse reactions. Immune-mediated adverse reactions listed herein may not be inclusive of 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 YERVOY. While immune-mediated adverse reactions usually manifest during treatment, immune-mediated adverse reactions can also manifest after discontinuation of YERVOY.Early identification and management are essential to ensure safe use of YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue YERVOY depending on severity [see Dosage and Administration (2.3)]. In general, if YERVOY 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.Immune-Mediated ColitisYERVOY can cause immune-mediated colitis, which may be fatal. 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.YERVOY mg/kg as Single AgentImmune-mediated colitis occurred in 12% (62/511) of patients who received YERVOY mg/kg as single agent, including Grade 3-5 (7%) and Grade (5%). Colitis led to permanent discontinuation of YERVOY in 4.3% and withholding of at least one dose of YERVOY in 0.2% of patients.Systemic corticosteroids were required in 74% (46/62) of patients with immune-mediated colitis. Five patients required coadministration of another immunosuppressant with corticosteroids. Colitis resolved in 76% of the 62 patients. One patient was withheld one or more doses of YERVOY for colitis, and no patient received additional treatment after symptom improvement.YERVOY mg/kg with mg/kg Nivolumab Immune-mediated colitis occurred in 9% (60/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (4.4%), and Grade (3.7%). Colitis led to permanent discontinuation of YERVOY and nivolumab in 3.2% and withholding of YERVOY and nivolumab in 2.7% of patients.In patients who received YERVOY mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated colitis. Systemic corticosteroids were therefore required in 100% (60/60) of patients with immune-mediated colitis. Approximately 23% of patients required coadministration of another immunosuppressant with corticosteroids. Colitis resolved in 95% of the 60 patients. Of the 18 patients in whom YERVOY or nivolumab was withheld for colitis, 16 received additional treatment after symptom improvement; of these, 10 had recurrence of colitis.YERVOY mg/kg with mg/kg Nivolumab Immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or HCC receiving YERVOY mg/kg with nivolumab mg/kg every weeks, including Grade (0.4%), Grade (14%), and Grade (8%) adverse reactions. Colitis led to permanent discontinuation of YERVOY with nivolumab in 14% and withholding of treatment in 4.4% of patients. Systemic corticosteroids were required in 100% (115/115) of patients with colitis. Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 93% of 115 patients. Of the 20 patients in whom YERVOY with nivolumab was withheld for colitis, 16 reinitiated treatment after symptom improvement, and had recurrence of colitis.Immune-Mediated HepatitisYERVOY mg/kg as Single AgentImmune-mediated hepatitis occurred in 4.1% (21/511) of patients who received YERVOY mg/kg as single agent, including Grade 3-5 (1.6%) and Grade (2.5%). Hepatitis led to permanent discontinuation of YERVOY in 0.4% of patients and withholding of at least one dose of YERVOY in none of the patients. Systemic corticosteroids were required in 29% (6/21) of patients with immune-mediated hepatitis. No patients required the coadministration of another immunosuppressant with corticosteroids. Hepatitis resolved in 86% of the 21 patients. YERVOY mg/kg with VemurafenibThe safety and effectiveness of YERVOY in combination with vemurafenib have not been established [see Indications and Usage (1)]. In dose-finding trial, Grade increases in transaminases with or without concomitant increases in total bilirubin occurred in of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg or 720 mg twice daily).YERVOY mg/kg with mg/kg Nivolumab Immune-mediated hepatitis occurred in 7% (48/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (1.2%), Grade (4.9%), and Grade (0.4%). Hepatitis led to permanent discontinuation of YERVOY and nivolumab in 3.6% and withholding of YERVOY and nivolumab in 2.6% of patients.In patients who received YERVOY mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated hepatitis. Systemic corticosteroids were therefore required in 100% (48/48) of patients with immune-mediated hepatitis. Approximately 19% of patients required coadministration of another immunosuppressant with corticosteroids. Hepatitis resolved in 88% of the 48 patients. Of the 17 patients in whom YERVOY or nivolumab was withheld for hepatitis, 14 received additional treatment after symptom improvement; of these, 10 had recurrence of hepatitis.YERVOY mg/kg with mg/kg Nivolumab Immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC receiving YERVOY mg/kg with nivolumab mg/kg every weeks, including Grade (2.4%), Grade (11%), and Grade (1.8%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of YERVOY with nivolumab in 8% and withholding of treatment in 3.5% of patients. Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis. Approximately 9% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 70 patients. Of the 16 patients in whom YERVOY with nivolumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement, and had recurrence of hepatitis.Immune-Mediated Dermatologic Adverse ReactionsYERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, Stevens Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms). Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes. Withhold or permanently discontinue YERVOY depending on severity [see Dosage and Administration (2.3)].YERVOY mg/kg as Single AgentImmune-mediated rash occurred in 15% (76/511) of patients who received YERVOY mg/kg as single agent, including Grade 3-5 (2.5%) and Grade (12%). Rash led to permanent discontinuation of YERVOY in 0.2% and withholding of at least one dose of YERVOY in 1.4% of patients. Systemic corticosteroids were required in 43% (33/76) of patients with immune-mediated rash. Rash resolved in 71% of the 76 patients. Of the patients in whom YERVOY was withheld for rash, received additional treatment after symptom improvement; of these, had recurrence of rash.YERVOY mg/kg with mg/kg NivolumabImmune-mediated rash occurred in 16% (108/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (3.5%) and Grade (4.2%). Rash led to permanent discontinuation of YERVOY and nivolumab in 0.5% of patients and withholding of YERVOY and nivolumab in 2.0% of patients.In patients who received YERVOY mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated rash. Systemic corticosteroids were therefore required in 100% (108/108) of patients. Rash resolved in 75% of 108 patients. Of the 13 patients in whom YERVOY or nivolumab was withheld for rash, 11 received additional treatment after symptom improvement; of these, had recurrence of rash.YERVOY mg/kg with mg/kg NivolumabImmune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving YERVOY mg/kg with nivolumab mg/kg every weeks, including Grade (4.8%) and Grade (10%) adverse reactions. Immune-mediated rash led to permanent discontinuation of YERVOY with nivolumab in 0.4% and withholding of treatment in 3.9% of patients. Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash. Rash resolved in 84% of the 127 of patients. Of the 18 patients in whom YERVOY with nivolumab was withheld for rash, 15 reinitiated treatment after symptom improvement, and had recurrence of rash.Immune-Mediated EndocrinopathiesYERVOY mg/kg as Single AgentGrade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients who received YERVOY mg/kg as single agent. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in patients (1.8%). All of these patients had hypopituitarism with some patients having additional concomitant endocrinopathies, such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushings syndrome. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 required long-term hormone replacement therapy, including adrenal hormones (n=10) and thyroid hormones (n=13).YERVOY mg/kg with mg/kg Nivolumab Hypophysitis: YERVOY can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue YERVOY depending on severity [see Dosage and Administration (2.3)]. Hypophysitis occurred in 4.4% (29/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (0.3%), Grade (2.4%), and Grade (0.9%). Hypophysitis led to permanent discontinuation of YERVOY and nivolumab in 1.2% and withholding of YERVOY with nivolumab in 2.1% of patients. Approximately 72% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 72% (21/29) of patients with immune-mediated hypophysitis. Hypophysitis resolved in 59% of the 29 patients. Of the 14 patients in whom YERVOY or nivolumab was withheld for hypophysitis, 11 received additional treatment after symptom improvement; of these, had recurrence of hypophysitis.Adrenal Insufficiency: Adrenal insufficiency occurred in 7% (48/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (0.3%), Grade (2.5%), and Grade (4.1%). Adrenal insufficiency led to permanent discontinuation of YERVOY with nivolumab in 1.2% and withholding of YERVOY with nivolumab in 2.1% of patients. Approximately 94% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 94% (45/48) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 29% of the 48 patients. Of the 14 patients in whom YERVOY or nivolumab was withheld for adrenal insufficiency, 11 received additional treatment after symptom improvement; of these, had recurrence of adrenal insufficiency.Hyperthyroidism: Hyperthyroidism occurred in 12% (80/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (0.6%) and Grade (4.5%). No patients discontinued YERVOY for hyperthyroidism. Hyperthyroidism led to withholding of YERVOY with nivolumab in 2.3% of patients. Approximately 19% received thyroid synthesis inhibitor. Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism. Hyperthyroidism resolved in 85% of the 80 patients. Of the 15 patients in whom YERVOY or nivolumab was withheld for hyperthyroidism, 11 received additional treatment after symptom improvement; of these, had recurrence of hyperthyroidism.Hypothyroidism: Hypothyroidism occurred in 18% (122/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (0.6%) and Grade (11%). Hypothyroidism led to permanent discontinuation of YERVOY with nivolumab in 0.2% and withholding of YERVOY with nivolumab in 1.4% of patients. Approximately 82% received thyroid hormone replacement. Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism. Hypothyroidism resolved in 27% of the 122 patients. Of the patients in whom YERVOY or nivolumab was withheld for hypothyroidism, received additional treatment after symptom improvement; of these, one patient had recurrence of hypothyroidism. Thyroiditis:Thyroiditis occurred in 2.7% (22/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (4.5%) and Grade (2.2%). Thyroiditis led to permanent discontinuation of YERVOY with nivolumab in 0.2% and withholding of YERVOY with nivolumab in 0.8% of patients. Systemic corticosteroids were required in 18% (4/22) of patients with thyroiditis. Thyroiditis resolved in 64% of the 22 patients. Of the patients in whom YERVOY or nivolumab was withheld for thyroiditis, received additional treatment after symptom improvement; of these, no patients had recurrence of thyroiditis.Type Diabetes Mellitus: Diabetes occurred in 2.7% (15/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (0.6%), Grade (0.3%), and Grade (0.9%). Diabetes led to the permanent discontinuation of YERVOY with nivolumab in 0.5% and withholding of YERVOY with nivolumab in 0.5% of patients. Systemic corticosteroids were required in 7% (1/15) of patients with diabetes. Diabetes resolved in 27% of the 15 patients. Of the patients in whom YERVOY or nivolumab was withheld for diabetes, received additional treatment after symptom improvement; of these, none had recurrence of diabetes. YERVOY mg/kg with mg/kg Nivolumab Hypophysitis:Hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving YERVOY mg/kg with nivolumab mg/kg every weeks, including Grade (2.4%) and Grade (6%) adverse reactions. Hypophysitis led to permanent discontinuation of YERVOY with nivolumab in 0.9% and withholding of treatment in 4.2% of patients. Approximately 86% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis. Hypophysitis resolved in 38% of the 42 patients. Of the 19 patients in whom YERVOY with nivolumab was withheld for hypophysitis, reinitiated treatment after symptom improvement, and had recurrence of hypophysitis.Adrenal Insufficiency:Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving YERVOY mg/kg with nivolumab mg/kg every weeks, including Grade (0.2%), Grade (2.4%), and Grade (4.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of YERVOY with nivolumab in 0.4% of patients and withholding of treatment in 2.0% of patients. Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients. Of the patients in whom YERVOY with nivolumab was withheld for adrenal insufficiency, reinitiated treatment after symptom improvement, and all required hormone replacement therapy for their ongoing adrenal insufficiency.Hypothyroidism:Hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving YERVOY mg/kg with nivolumab mg/kg every weeks, including Grade (0.4%) and Grade (11%) adverse reactions. Hypothyroidism led to permanent discontinuation of YERVOY with nivolumab in 0.9% of patients and withholding of treatment in 0.9% of patients. Approximately 89% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism. Hypothyroidism resolved in 41% of the 91 patients. Of the patients in whom YERVOY with nivolumab was withheld for hypothyroidism, reinitiated treatment after symptom improvement, and none had recurrence of hypothyroidism.Hyperthyroidism:Hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC receiving YERVOY mg/kg with nivolumab mg/kg every weeks, including Grade (0.9%) and Grade (4.2%) adverse reactions. Hyperthyroidism led to permanent discontinuation of YERVOY with nivolumab in no patients and withholding of treatment in 2.4% of patients. Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole. Systemic corticosteroids were required in 17% (7/42) of patients. Hyperthyroidism resolved in 91% of the 42 patients. Of the 11 patients in whom YERVOY with nivolumab was withheld for hyperthyroidism, reinitiated treatment after symptom improvement, and had recurrence of hyperthyroidism.Immune-Mediated PneumonitisYERVOY mg/kg with mg/kg Nivolumab Immune-mediated pneumonitis occurred in 3.9% (26/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (1.4%) and Grade (2.6%). Pneumonitis led to permanent discontinuation of YERVOY and nivolumab in 1.8% and withholding of YERVOY and nivolumab in 1.5% of patients. In patients who received YERVOY mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated pneumonitis. Systemic corticosteroids were therefore required in 100% (26/26) of patients with immune-mediated pneumonitis. Approximately 8% required coadministration of another immunosuppressant with corticosteroids. Pneumonitis resolved in 92% of the 26 patients. Of the 10 patients in whom YERVOY or nivolumab was withheld for pneumonitis, 10 received additional treatment after symptom improvement; of these, had recurrence of pneumonitis.In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving YERVOY mg/kg every weeks with nivolumab mg/kg every weeks, including Grade (0.5%), Grade (3.5%), and Grade (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. The median duration was 1.5 months (range: days to 25+ months). Immune-mediated pneumonitis led to permanent discontinuation of YERVOY with nivolumab in 5% of patients and withholding of YERVOY with nivolumab in 3.6% of patients. Systemic corticosteroids were required in 100% of patients with pneumonitis followed by corticosteroid taper. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after re-initiation of YERVOY with nivolumab.YERVOY mg/kg with mg/kg Nivolumab Immune-mediated pneumonitis occurred in 7% (31/456) of patients who received YERVOY mg/kg with nivolumab for the treatment of HCC or melanoma, including Grade (0.2%), Grade (2.0%), and Grade (4.4%). Immune-mediated pneumonitis led to permanent discontinuation or withholding of treatment in 2.9% and 3.9% of patients, respectively.Systemic corticosteroids were required in 100% of patients with pneumonitis. Pneumonitis resolved in 94% of the patients. Of the 13 patients in whom YERVOY or nivolumab was withheld for pneumonitis, 13 received additional treatment after symptom improvement, and had recurrence of pneumonitis.Immune-Mediated Nephritis with Renal DysfunctionYERVOY mg/kg with mg/kg NivolumabImmune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade (0.6%), Grade (1.1%), and Grade (2.2%). Nephritis with renal dysfunction led to permanent discontinuation of YERVOY and nivolumab in 1.2% and withholding of nivolumab and YERVOY in 1.8% of patients. In patients who received YERVOY mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated nephritis with renal dysfunction. Systemic corticosteroids were therefore required in 100% (27/27) of patients with immune-mediated nephritis with renal dysfunction. Nephritis with renal dysfunction resolved in 67% of the 27 patients. Of the 12 patients in whom YERVOY or nivolumab was withheld for nephritis, 10 received additional treatment after symptom improvement; of these, had recurrence of nephritis.Other Immune-Mediated Adverse ReactionsAcross clinical trials of YERVOY administered as single agent or in combination with nivolumab, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified, as shown below: Nervous System: Autoimmune neuropathy (2%), meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome, nerve paresis, motor dysfunctionCardiovascular: Angiopathy, myocarditis, pericarditis, temporal arteritis, vasculitisOcular: Blepharitis, episcleritis, iritis, orbital myositis, scleritis, uveitis. Some cases can be associated with retinal detachment. If uveitis occurs in combination with other immune-mediated adverse reactions, consider Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving YERVOY and may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.Gastrointestinal: Duodenitis, gastritis, pancreatitis (1.3%)Musculoskeletal and Connective Tissue: Arthritis, myositis, polymyalgia rheumatica, polymyositis, rhabdomyolysisOther (hematologic/immune): Aplastic anemia, conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), hypersensitivity vasculitis, meningitis, neurosensory hypoacusis, psoriasis, sarcoidosis, systemic inflammatory response syndrome, and solid organ transplant rejection.. 5.2 Infusion-Related Reactions. Severe infusion-related reactions can occur with YERVOY. Discontinue YERVOY in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions [see Dosage and Administration (2.3)]. Infusion-related reactions occurred in 0.6% (3/511) of patients who received single-agent YERVOY mg/kg for the unresectable or metastatic treatment of melanoma. Infusion-related reactions occurred in 5% (33/666) of patients who received YERVOY mg/kg with nivolumab for the treatment of RCC or CRC. Infusion-related reactions occurred in 8% (4/49) of patients who received YERVOY mg/kg with nivolumab for the treatment of HCC. Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received YERVOY mg/kg every weeks with nivolumab mg/kg every weeks.. 5.3 Complications of Allogeneic Hematopoietic Stem Cell Transplant after YERVOY. Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive YERVOY either before or after allogeneic hematopoietic stem cell transplantation (HSCT). These complications may occur despite intervening therapy between CTLA-4 receptor blocking antibody and allogeneic HSCT.Follow patients closely for evidence of GVHD and intervene promptly [see Adverse Reactions (6.2) ]. Consider the benefit versus risks of treatment with YERVOY after allogeneic HSCT.. 5.4 Embryo-Fetal Toxicity. Based on its mechanism of action and findings from animal studies, YERVOY can cause fetal harm when administered to pregnant woman. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight) and higher incidences of infant mortality in dose-related manner. The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for months after the last dose [see Use in Specific Populations (8.1 8.3)].. 5.5 Risks Associated When Administered in Combination with Nivolumab. YERVOY is indicated for use in combination with nivolumab for patients with advanced RCC, MSI-H or dMMR mCRC, HCC, and NSCLC. Refer to the nivolumab Full Prescribing Information for additional risk information that applies to the combination use treatment.