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 (>=5%) with YERVOY as single agent are fatigue, diarrhea, pruritus, rash, and colitis. Additional common adverse reactions at the 10 mg/kg dose (>=5%) include nausea, vomiting, headache, weight loss, pyrexia, decreased appetite, and insomnia. (6.1) Most common adverse reactions (>=20%) with YERVOY in combination with nivolumab are fatigue, rash, pruritus, diarrhea, musculoskeletal pain, cough, pyrexia, decreased appetite, nausea, abdominal pain, arthralgia, headache, vomiting, dyspnea, dizziness, hypothyroidism, and decreased weight. (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 10 mg/kg as single agent in 471 patients in Study CA184-029; 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/kgn=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 945 patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma in Study CA184-029 [see Clinical Studies (14.2)]. Study CA184-029 excluded patients with prior systemic therapy for melanoma, autoimmune disease, condition requiring systemic immunosuppression, or positive test for hepatitis B, hepatitis C, or HIV. Patients received YERVOY 10 mg/kg (n=471) or placebo (n=474) administered as an intravenous infusion for doses every weeks followed by 10 mg/kg every 12 weeks beginning at Week 24 up to maximum of years. In this trial, 36% of patients received YERVOY for longer than months and 26% of patients received YERVOY for longer than year. YERVOY-treated patients in the trial received median of doses (range: to 16).The trial population characteristics were: median age 51 years (range: 18 to 84 years), 62% male, 99% White, and baseline ECOG performance status (94%).YERVOY was discontinued for adverse reactions in 52% of patients. Table presents selected adverse reactions from Study CA184-029.Table 7: Adverse Reactions (>=5%) in Patients Receiving YERVOY with Difference Between Arms >5% Compared to Placebo in Study CA184-029Adverse ReactionYERVOY 10 mg/kgn=471Placebo n=474All Grades (%)Grade to (%)All Grades (%)Grade to (%)Dermatologic Rash502.1200 Pruritus452.3150Gastrointestinal Diarrhea4910302.1 Nausea250.2180 Colitis1681.50.4 Vomiting130.460.2General and Administration-Site Conditions Fatigue462.3381.5 Weight Decreased320.290.4 Pyrexia181.14.90.2Nervous System Headache330.8180.2Metabolism and Nutrition Decreased Appetite140.23.40.2Psychiatric Insomnia1004.40Table presents selected laboratory abnormalities from Study CA184-029.Table 8: Laboratory Abnormalities (>5%) Worsening from Baseline in Patients Receiving YERVOY with Difference Between Arms of >5% Compared to Placebo in CA184-029a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Excluding lipase and amylase, YERVOY group (range: 466 to 470 patients) and placebo group (range: 472 to 474 patients). For lipase and amylase, YERVOY group (range: 447 to 448 patients) and placebo group (range: 462 to 464 patients).Laboratory AbnormalityYERVOY 10 mg/kga Placeboa All Grades(%)Grade to 4(%)All Grades(%)Grade to 4(%)Chemistry Increased ALT4610160 Increased AST389140.2 Increased lipase269174.5 Increased amylase172.070.6 Increased alkaline phosphatase170.660.2 Increased bilirubin111.590 Increased creatinine100.260Hematology Decreased hemoglobin250.2140. 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 NivolumabThe 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 9: 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 10 summarizes the laboratory abnormalities in CHECKMATE-214.Table 10: 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: In Combination with NivolumabThe safety of YERVOY with nivolumab was evaluated in 119 patients with previously treated MSI-H or dMMR mCRC in single-arm cohort of CHECKMATE-142 [see Clinical Studies (14.4)]. All patients had received prior fluorouracil-based chemotherapy for metastatic disease; 69% had received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan and 29% had received an anti-EGFR antibody. Patients received YERVOY mg/kg and nivolumab mg/kg on Day of each 21-day cycle for doses, then nivolumab mg/kg every weeks until disease progression or unacceptable toxicity. The median duration of exposure for YERVOY was 2.1 months.Serious adverse reactions occurred in 47% of patients receiving YERVOY and nivolumab. The most frequent serious adverse reactions reported in >=2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common adverse reactions (>=20%) in the YERVOY and nivolumab cohort were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting. Table 11 summarizes adverse reactions in CHECKMATE-142.Table 11: Adverse Reactions Occurring in >=10% of Patients (CHECKMATE-142)Toxicity was graded per NCI CTCAE v4. Includes asthenia. Includes peripheral edema and peripheral swelling. Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort. Includes back pain, pain in extremity, myalgia, neck pain, and bone pain. Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized. Includes nasopharyngitis and rhinitis.Adverse ReactionYERVOY and Nivolumab MSI-H/dMMR Cohort(n=119)All Grades (%)Grades 3-4 (%)General and Administration Site Conditions Fatiguea 496 Pyrexia360 Edemab 70Gastrointestinal Diarrhea453.4 Abdominal painc 305 Nausea260.8 Vomiting201.7 Constipation150Musculoskeletal and Connective Tissue Musculoskeletal paind 363.4 Arthralgia140.8Skin and Subcutaneous Tissue Pruritus281.7 Rashe 254.2 Dry Skin110Infections and Infestations Upper respiratory tract infectionf 90Metabolism and Nutrition Decreased appetite201.7Respiratory, Thoracic, and Mediastinal Cough190.8 Dyspnea131.7Nervous System Headache171.7 Dizziness110Endocrine Hyperglycemia61 Hypothyroidism140.8 Hyperthyroidism120Investigations Weight decreased100Psychiatric Insomnia130.8Other clinically important adverse reactions reported in <10% of patients receiving YERVOY in CHECKMATE-142 were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%).Table 12 summarizes laboratory abnormalities in CHECKMATE-142.Table 12: Laboratory Abnormalities Worsening from Baselinea Occurring in >=10% of Patients (CHECKMATE-142)a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Number of evaluable patients ranges from 87 to 114 for nivolumab with YERVOY and from 62 to 71 for nivolumab.Laboratory AbnormalityYERVOY and Nivolumab MSI-H/dMMR Cohort(n=119)All Grades (%)Grades 3-4 (%)Hematology Anemia429 Thrombocytopenia260.9 Lymphopenia256 Neutropenia180Chemistry Increased AST4012 Increased lipase3912 Increased amylase363.4 Increased ALT3312 Increased alkaline phosphatase285 Hyponatremia265 Increased creatinine253.6 Hyperkalemia230.9 Increased bilirubin215 Hypomagnesemia180 Hypocalcemia160 Hypokalemia151.8Hepatocellular Carcinoma: In Combination with NivolumabThe 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 13 summarizes the adverse reactions and Table 14 summarizes the laboratory abnormalities of YERVOY in combination with nivolumab in CHECKMATE-040.Table 13: 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 14: 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 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.Table 15: 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 16: 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 17 and 18 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.Table 17: 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 blenorrhagica, palmar-plantar erythrodysaesthesia 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 18: 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 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.Table 19: 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 blenorrhagica, 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 20: Laboratory Values Worsening from Baselinea Occurring in >=20% of Patients on YERVOY and Nivolumab CHECKMATE-743Laboratory 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 Anemia432.47515a 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).. 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidences of antibodies to other studies or to other products may be misleading.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.. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval 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 were 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 21 and Figure 1.Table 21: 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 22 and Figure 2.Table 22: 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 .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,d <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,e <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 for the adjuvant treatment of melanoma was evaluated in Study CA184-029 (NCT00636168), randomized (1:1), double-blind, placebo-controlled trial in patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) histologically confirmed cutaneous melanoma. Enrollment required complete resection of melanoma with full lymphadenectomy within 12 weeks prior to randomization. Patients with prior therapy for melanoma, autoimmune disease, and prior or concomitant use of immunosuppressive agents were ineligible. Patients were randomized to receive YERVOY 10 mg/kg or placebo as an intravenous infusion every weeks for doses, followed by YERVOY 10 mg/kg or placebo every 12 weeks from Week 24 to Week 156 (3 years) or until documented disease recurrence or unacceptable toxicity. Randomization was stratified by stage according to American Joint Committee on Cancer (AJCC) 2002 classification (Stage IIIA >1 mm nodal involvement, Stage IIIB, Stage IIIC with to involved lymph nodes, and Stage IIIC with >=4 involved lymph nodes) and by region (North America, Europe, and Australia). The major efficacy outcome measures were independent review committee (IRC)-assessed recurrence-free survival (RFS), defined as the time between the date of randomization and the earliest date of first recurrence (local, regional, or distant metastasis) or death, and overall survival. Tumor assessment was conducted every 12 weeks for the first years then every 24 weeks until distant recurrence.Among 951 patients enrolled, 475 were randomized to receive YERVOY and 476 to placebo. Median age was 51 years (range: 18 to 84), 62% were male, 99% were White, 94% had ECOG performance status of 0. With regard to disease stage, 20% had Stage IIIA with lymph nodes >1 mm, 44% had Stage IIIB, and 36% had Stage IIIC (with no in-transit metastases). Other disease characteristics of the trial population were: clinically palpable lymph nodes (58%), or more positive lymph nodes (54%), and ulcerated primary lesions (42%).The efficacy results are in Table 23 and Figure 3.Table 23: Efficacy Results for Study CA184-029a Stratified by disease stage.YERVOY 10 mg/kgn=475Placebo n=476Recurrence-Free SurvivalNumber of events234 (49%)294 (62%) Recurrence220289 Death145Median in months (95% CI)26 (19, 39)17 (13, 22)Hazard ratio (95% CI)0.75 (0.64, 0.90)p-value (stratified log-ranka)p<0.002Overall SurvivalNumber of deaths162 (34%)214 (45%)Hazard ratio (95% CI)0.72 (0.58, 0.88)p-value (stratified log-ranka)p<0.002Figure 3: Kaplan-Meier Curves for Overall Survival in Study CA184-029. yervoy-os-ca184-029. 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 24 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 24: 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 0.009Efficacy 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 The efficacy of YERVOY with nivolumab was evaluated in CHECKMATE-142 (NCT02060188), multicenter, non-randomized, multiple parallel-cohort, open-label study conducted in patients with locally determined dMMR or MSI-H mCRC who had disease progression during or after prior treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line of treatment for metastatic disease, ECOG PS or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients enrolled in the YERVOY and nivolumab MSI-H or dMMR mCRC cohort received YERVOY mg/kg and nivolumab mg/kg intravenously every weeks for doses, followed by nivolumab mg/kg intravenously as single agent every weeks. Efficacy outcome measures were overall response rate (ORR) as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response (DOR). Tumor assessments were conducted every weeks for the first 24 weeks and every 12 weeks thereafter.A total of 119 patients were enrolled in the YERVOY and nivolumab cohort. The median age was 58 years (range: 21 to 88), with 32% >=65 years of age and 9% >=75 years of age; 59% were male and 92% were white. Baseline ECOG PS was (45%) or (55%), and 29% were reported to have Lynch Syndrome. Across the cohort, 69% received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%, 24%, and 15% received 1, 2, 3, or >=4 prior lines of therapy for metastatic disease, respectively, and 29% had received an anti-EGFR antibody.Efficacy results are shown in Table 25.Table 25: Efficacy Results in MSI-H/dMMR Cohort of CHECKMATE-142a Minimum follow-up 27.5 months for all patients treated with YERVOY and nivolumab (n=119). Estimated using the Clopper-Pearson method.YERVOY and Nivolumaba MSI-H/dMMR CohortAll Patients(n=119)Prior Treatment (Fluoropyrimidine, Oxaliplatin, and Irinotecan)(n=82)Overall Response Rate per BICR; (%)71 (60%)46 (56%) (95% CI)b (50, 69)(45, 67) Complete Response (%)17 (14%)11 (13%) Partial Response (%)54 (45%)35 (43%)Duration of Response Proportion of responders with >=6 months response duration89%87% Proportion of responders with >=12 months response duration77%74%. 14.5 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 26.Table 26: 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 27 and Figure 5.Table 27: 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 5: 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 28.Table 28: 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 6).Figure 6: 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 29 and Figure 7.Table 29: 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 7: 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.

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 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 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 10 mg/kg as Single AgentImmune-mediated colitis occurred in 31% (144/471) of patients who received YERVOY 10 mg/kg as single agent, including fatal (0.2%), Grade (1.5%), Grade (14%), and Grade (14%). Colitis led to permanent discontinuation of YERVOY in 61% of patients and 3.8% of patients missed at least one dose of YERVOY due to colitis.Systemic corticosteroids were required in 85% (123/144) of patients with immune-mediated colitis. Approximately 26% of the 144 patients required coadministration of another immunosuppressant with corticosteroids. Colitis resolved in 90% of the 144 patients. Of the 18 patients who missed one or more doses of YERVOY for colitis, 17 received additional treatment after symptom improvement; of these, 14 had recurrence of colitis.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 10 mg/kg as Single AgentImmune-mediated hepatitis occurred in 15% (73/471) of patients who received YERVOY 10 mg/kg as single agent, including Grade (2.8%), Grade (8%), and Grade (5%). Hepatitis led to permanent discontinuation of YERVOY in 56% of patients and 1.1% of patients missed at least one dose of YERVOY due to hepatitis. Systemic corticosteroids were required in 85% (62/73) of patients with immune-mediated hepatitis. Approximately 15% of the 73 patients required the coadministration of another immunosuppressant with corticosteroids. Hepatitis resolved in 93% of 73 patients. Of the patients who missed one or more doses of YERVOY for hepatitis, received additional treatment after symptom improvement; of these, had recurrence of hepatitis.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 10 mg/kg as Single AgentImmune-mediated rash occurred in 25% (118/471) of patients who received YERVOY 10 mg/kg as single agent, including Grade (4%) and Grade (21%). Rash led to permanent discontinuation in 8% of patients and 1.5% of patients missed at least one dose of YERVOY due to rash.Systemic corticosteroids were required in 70% (83/118) of patients with immune-mediated rash. Rash resolved in 81% of 118 patients. Of the patients who missed one or more doses of YERVOY 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 10 mg/kg as Single AgentImmune-mediated endocrinopathies occurred in 28% of patients (132/471), including Grade (0.6%), Grade (8%) and Grade (20%). Of the 39 patients with Grade to endocrinopathies, 35 patients had hypopituitarism (associated with one or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), patients had hyperthyroidism, and had primary hypothyroidism. Twenty-seven of the 39 patients (69%) were hospitalized for endocrinopathies. Of the 39 patients, 10% were reported to have resolution.Of the 93 patients with Grade endocrinopathy, 74 had primary hypopituitarism associated with one or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism, had primary hypothyroidism, had hyperthyroidism, had thyroiditis with hypo- or hyperthyroidism, had hypogonadism, had both hyperthyroidism and hypopituitarism, and subject developed Graves ophthalmopathy. Of the 93 patients, 20% were reported to have resolution.One hundred twenty-four patients received systemic corticosteroids as immunosuppression and/or adrenal hormone replacement for Grade to endocrinopathy. Of these, 42 (34%) were able to discontinue corticosteroids. Seventy-three patients received thyroid hormones for treatment of Grade to hypothyroidism. Of these, 14 patients (19%) were able to discontinue thyroid replacement therapy.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 2.9% (28/982) of patients who received single-agent YERVOY mg/kg or 10 mg/kg for the 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 (6.3)]. 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 50 mg/10 mL (5 mg/mL) or 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.

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 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: Based on population PK analysis using available pooled data from 565 patients from four adult studies (n=521) and two pediatric studies (n=44), body weight normalized clearance of ipilimumab is comparable between adult and pediatric patients. In pediatric patients with dosing regimen of mg/kg every weeks, the model simulated geometric mean (CV%) steady-state serum peak and trough concentrations of ipilimumab were 65.8 (17.6%) and 20.7 (33.1%) mcg/mL (for to years old), 70.1 (19.6%) and 19.6 (42.9%) mcg/mL (for to <12 years old), and 73.3 (20.6%) and 17.8 (50.8%) mcg/mL (for 12 years and older), which are comparable to those in adult patients.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.

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 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 10 mg/kg every weeks for doses, followed by 10 mg/kg every 12 weeks for up to years. (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)oMicrosatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer: YERVOY mg/kg intravenously over 30 minutes immediately following nivolumab mg/kg intravenously over 30 minutes 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)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 doses. After completion 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 mg/kg 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). oAdminister by intravenous infusion 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 10 mg/kg every weeks for doses, followed by 10 mg/kg every 12 weeks for up to years. (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). oMicrosatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer: YERVOY mg/kg intravenously over 30 minutes immediately following nivolumab mg/kg intravenously over 30 minutes 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). 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 doses. After completion 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 mg/kg 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 mg/kg 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). 2.1 Patient Selection Select patients with metastatic NSCLC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.6)].Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.. 2.2 Recommended Dosage. The recommended dosages of YERVOY as single agent are presented in Table 1.Table 1: Recommended Dosages for YERVOY as Single AgentIndicationRecommended YERVOY DosageDuration of TherapyUnresectable or metastatic melanoma3 mg/kg every weeks(90-minute intravenous infusion)Maximum of dosesAdjuvant treatment of melanoma10 mg/kg every weeksfollowed by 10 mg/kg every 12 weeks(90-minute intravenous infusion)Every weeks up to maximum of dosesEvery 12 weeks for up to yearsThe recommended dosages of YERVOY in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with 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 weeks(90-minute intravenous infusion)with nivolumab mg/kg(30-minute intravenous infusion on the same day)In 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/kg(30-minute intravenous infusion on the same day)In 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 cancer1 mg/kg every weekswith nivolumab mg/kg(30-minute intravenous infusion on the same day)After completing doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity.+ Hepatocellular carcinoma3 mg/kg every weekswith nivolumab mg/kg(30-minute intravenous infusion on the same day)In combination with nivolumabfor doses.After completing 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 mg/kg every weeks(30-minute intravenous infusion)In 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 weeks(30-minute intravenous infusion)and histology-based platinum-doublet chemotherapy 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 weeks(30-minute intravenous infusion)In combination with nivolumab until disease progression, unacceptable toxicity, or up to years in patients without disease progression.+ 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 solution 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. When administered with nivolumab and platinum-doublet chemotherapy, infuse nivolumab first followed by YERVOY and then platinum-doublet chemotherapy on the same day. Use 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 solution 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. When administered with nivolumab and platinum-doublet chemotherapy, infuse nivolumab first followed by YERVOY and then platinum-doublet chemotherapy on the same day. Use separate infusion bags and filters for each infusion.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of 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.Of 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.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.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 49 patients who received YERVOY mg/kg with nivolumab in Cohort of CHECKMATE-040 (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 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 with 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 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.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.

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 vial (5 mg/mL), single-dose vialNDC 0003-2327-11One 200 mg vial (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.

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. (1.1)oTreatment of adult patients with unresectable or metastatic melanoma, in combination with nivolumab. (1.1)oAdjuvant treatment of 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 patients with intermediate or poor risk advanced renal cell carcinoma, as first-line treatment in combination with nivolumab. (1.3)Colorectal CanceroTreatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan, in combination with nivolumab. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.4)Hepatocellular CarcinomaoTreatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib, in combination with nivolumab. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (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). oTreatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older. (1.1). oTreatment of adult patients with unresectable or metastatic melanoma, in combination with nivolumab. (1.1). oAdjuvant treatment of 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 patients with intermediate or poor risk advanced renal cell carcinoma, as first-line treatment in combination with nivolumab. (1.3). oTreatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan, in combination with nivolumab. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.4). oTreatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib, in combination with nivolumab. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (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). Malignant Pleural Mesothelioma. oTreatment of adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with nivolumab. (1.7). 1.1 Unresectable or Metastatic Melanoma YERVOY is indicated for the treatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older.YERVOY, in combination with nivolumab, is indicated for the treatment of unresectable or metastatic melanoma in adult patients.. 1.2 Adjuvant Treatment of Melanoma YERVOY is indicated for the adjuvant treatment of 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 patients with intermediate or poor risk advanced renal cell carcinoma (RCC).. 1.4 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer YERVOY, in combination with nivolumab, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.4)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.. 1.5 Hepatocellular Carcinoma YERVOY, in combination with nivolumab, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.5)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.. 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.

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 mellitusoImmune-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 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 12 years and older for the treatment of unresectable or metastatic melanoma or for the treatment of MSI-H or dMMR mCRC that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Use of YERVOY in this age group is supported by evidence from adequate and well-controlled studies of YERVOY in adults and population pharmacokinetic data demonstrating that the exposure at doses of mg/kg and mg/kg in the pediatric and adult populations are comparable. In addition, the tumor biology and course of advanced melanoma and MSI-H or dMMR mCRC are sufficiently similar in adults and pediatric patients 12 years and older to allow extrapolation of data from adults to pediatric patients.The safety and effectiveness for pediatric patients 12 years and older have not been established for the adjuvant treatment of melanoma or for the treatment of renal cell carcinoma. In addition, the safety and effectiveness have not been established with YERVOY for any indication in pediatric patients less than 12 years of age.YERVOY was evaluated in total of 45 pediatric patients across two clinical trials. In dose-finding trial (NCT01445379), 33 pediatric patients with relapsed or refractory solid tumors were evaluated. The median age was 13 years (range to 21 years) and 20 patients were >=12 years old. YERVOY was also evaluated in an open-label, single-arm trial (NCT01696045) in 12 pediatric patients >=12 years old (range 12 to 16 years) with previously treated or untreated, unresectable Stage or malignant melanoma.Of the 17 patients >=12 years of age with melanoma treated with YERVOY across both studies, patients experienced objective responses including one partial response that was sustained for 16 months. There were no responses in patients with non-melanoma solid tumors. No new safety signals were observed in pediatric patients in these two studies.

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: Based on population PK analysis using available pooled data from 565 patients from four adult studies (n=521) and two pediatric studies (n=44), body weight normalized clearance of ipilimumab is comparable between adult and pediatric patients. In pediatric patients with dosing regimen of mg/kg every weeks, the model simulated geometric mean (CV%) steady-state serum peak and trough concentrations of ipilimumab were 65.8 (17.6%) and 20.7 (33.1%) mcg/mL (for to years old), 70.1 (19.6%) and 19.6 (42.9%) mcg/mL (for to <12 years old), and 73.3 (20.6%) and 17.8 (50.8%) mcg/mL (for 12 years and older), which are comparable to those in adult patients.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.

Boxed Warning, Removed 6/2020Indications and Usage (1) 5/2021Dosage and Administration (2) 5/2021Warnings and Precautions (5) 5/2021.

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 (OPDIVO(R)), 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 eye sightoPersistent 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 in adults and children 12 years of age and older or in combination with nivolumab in adults when melanoma has spread or cannot be removed by surgery.oYERVOY may be used alone to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.oin people 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 in combination with nivolumab may be used when your colon or rectal cancer:has spread to other parts of the body (metastatic),is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), andyou have tried treatment with fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.oin people with liver cancer (hepatocellular carcinoma).oYERVOY may be used in combination with nivolumab if you have previously received 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), 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.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.It is not known if YERVOY is safe and effective in children younger than 12 years of age.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: Your healthcare provider will give you pregnancy test before you start treatment with YERVOY.oYou should use an effective method of birth control during your treatment and for months after the 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.oDo not breastfeed during treatment with YERVOY and for months after the 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 YERVOYoYERVOY alone is given to you into your vein through an intravenous (IV) line over 90 minutes.oWhen YERVOY is used in combination with nivolumab (except for treating unresectable or metastatic melanoma), nivolumab is given to you into your vein through an IV line over 30 minutes. Then YERVOY is also given through an IV over 30 minutes on the same day.oFor unresectable or metastatic melanoma, when YERVOY is used in combination with nivolumab, nivolumab is given to you into your vein through an IV line over 30 minutes. Then YERVOY is also given through an IV over 90 minutes on the same day.oYERVOY in combination with nivolumab is usually given every weeks for 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 either every or 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.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)odecreased 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 healthcare professionals.What are the ingredients of YERVOYActive ingredient: ipilimumabInactive ingredients: diethylene triamine pentaacetic acid (DTPA), mannitol, polysorbate 80, sodium chloride, tris hydrochloride, and Water for InjectionManufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USAFor more information, call 1-800-321-1335U.S. License No. 1713[print code] YERVOY(R) and OPDIVO(R) are trademarks of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: May 2021. 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 eye sight. 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 in adults and children 12 years of age and older or in combination with nivolumab in adults when melanoma has spread or cannot be removed by surgery.oYERVOY may be used alone 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 in adults and children 12 years of age and older or in combination with nivolumab in adults when melanoma has spread or cannot be removed by surgery.. oYERVOY may be used alone to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.. oin people 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 in combination with nivolumab may be used when your colon or rectal cancer:has spread to other parts of the body (metastatic),is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), andyou have tried treatment with fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.. oYERVOY in combination with nivolumab may be used when your colon or rectal cancer:has spread to other parts of the body (metastatic),is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), andyou have tried treatment with fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.. has spread to other parts of the body (metastatic),. is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and. you have tried treatment with fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.. oin people with liver cancer (hepatocellular carcinoma).oYERVOY may be used in combination with nivolumab if you have previously received treatment with sorafenib.. oYERVOY may be used in combination with nivolumab if you have previously received 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), 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.. 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), and your 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.. 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:. Your healthcare provider will give you pregnancy test before you start treatment with YERVOY.oYou should use an effective method of birth control during your treatment and for months after the 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.oDo not breastfeed during treatment with YERVOY and for months after the last dose of YERVOY.. oYou should use an effective method of birth control during your treatment and for months after the 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.. oDo not breastfeed during treatment with YERVOY and for months after the last dose of YERVOY.. oYERVOY alone is given to you into your vein through an intravenous (IV) line over 90 minutes.. oWhen YERVOY is used in combination with nivolumab (except for treating unresectable or metastatic melanoma), nivolumab is given to you into your vein through an IV line over 30 minutes. Then YERVOY is also given through an IV over 30 minutes on the same day.. oFor unresectable or metastatic melanoma, when YERVOY is used in combination with nivolumab, nivolumab is given to you into your vein through an IV line over 30 minutes. Then YERVOY is also given through an IV over 90 minutes on the same day.. oYERVOY in combination with nivolumab is usually given every weeks for 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 either every or 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.. oFor NSCLC that has spread to other parts of your body, YERVOY is given every weeks and nivolumab is given either every or 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.. 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). 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 is indicated for the treatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older.YERVOY, in combination with nivolumab, is indicated for the treatment of unresectable or metastatic melanoma in adult patients.

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 12 years and older for the treatment of unresectable or metastatic melanoma or for the treatment of MSI-H or dMMR mCRC that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Use of YERVOY in this age group is supported by evidence from adequate and well-controlled studies of YERVOY in adults and population pharmacokinetic data demonstrating that the exposure at doses of mg/kg and mg/kg in the pediatric and adult populations are comparable. In addition, the tumor biology and course of advanced melanoma and MSI-H or dMMR mCRC are sufficiently similar in adults and pediatric patients 12 years and older to allow extrapolation of data from adults to pediatric patients.The safety and effectiveness for pediatric patients 12 years and older have not been established for the adjuvant treatment of melanoma or for the treatment of renal cell carcinoma. In addition, the safety and effectiveness have not been established with YERVOY for any indication in pediatric patients less than 12 years of age.YERVOY was evaluated in total of 45 pediatric patients across two clinical trials. In dose-finding trial (NCT01445379), 33 pediatric patients with relapsed or refractory solid tumors were evaluated. The median age was 13 years (range to 21 years) and 20 patients were >=12 years old. YERVOY was also evaluated in an open-label, single-arm trial (NCT01696045) in 12 pediatric patients >=12 years old (range 12 to 16 years) with previously treated or untreated, unresectable Stage or malignant melanoma.Of the 17 patients >=12 years of age with melanoma treated with YERVOY across both studies, patients experienced objective responses including one partial response that was sustained for 16 months. There were no responses in patients with non-melanoma solid tumors. No new safety signals were observed in pediatric patients in these two studies.. 8.5 Geriatric Use. Of 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.Of 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.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.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 49 patients who received YERVOY mg/kg with nivolumab in Cohort of CHECKMATE-040 (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 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 with 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 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.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.