YERVOY- ipilimumab_injection

Animal Data
In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 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 a dose of 3 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 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the humans exposure based on area under the curve at a dose of 3 mg/kg). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 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 2 weeks of age, and all died by 3 to 4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.
CLINICAL PHARMACOLOGY
CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a 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 a general increase in T-cell responsiveness, including the anti-tumor immune response. 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 3 weeks for 4 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 3 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 (C min Elimination The mean (percent coefficient of variation) terminal half-life (t 1/2 The CL of ipilimumab was unchanged in presence of anti-ipilimumab antibodies. Specific Populations The 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 m 2 Pediatric Patients The exposures of ipilimumab in pediatric patients 12 years and older are comparable to those in adult patients at the recommended dosage. Drug Interaction Studies Ipilimumab with Nivolumab When YERVOY 1 mg/kg was administered with nivolumab 3 mg/kg every 3 weeks, the CL of ipilimumab was unchanged compared to when YERVOY was administered alone. When YERVOY 3 mg/kg every 3 weeks was administered in combination with nivolumab 1 mg/kg every 3 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 1 mg/kg every 6 weeks was administered in combination with nivolumab 3 mg/kg every 2 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 1 mg/kg every 6 weeks was administered in combination with nivolumab 360 mg every 3 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. The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of YERVOY or of other ipilimumab products. 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. 9%) of 144 patients receiving ipilimumab developed anti-ipilimumab antibodies and 7 (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 1 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. Of 308 patients evaluable for anti-nivolumab antibodies in CHECKMATE-9LA, 34% were positive for anti-nivolumab antibodies and 2. 6% had neutralizing antibodies against nivolumab. Of 271 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-743, 13. 7% were positive for anti-ipilimumab antibodies and 0. 4% were positive for anti-ipilimumab neutralizing antibodies. Of 269 patients evaluable for anti-nivolumab antibodies in CHECKMATE-743, 25. 7% were positive for anti-nivolumab antibodies and 0. 7% had neutralizing antibodies against nivolumab. Anti-drug antibody and neutralizing antibody responses were monitored throughout the treatment period where the benefit to risk ratio was assessed. Incidence of anti-drug antibodies and neutralizing antibodies are presented in Table 24. a Clinical Studies (14) b ADA = treatment-emergent anti-ipilimumab antibodies, NAb = neutralizing antibodies, HCC = hepatocellular carcinoma, RCC = renal cell carcinoma, CRC = colorectal cancer, NSCLC = non-small cell lung cancer. Table 24: YERVOY Anti-Drug Antibody (ADA) and Neutralizing Antibody (NAb) Incidence Treatment Regimen a Indication(s) ADA NAb b YERVOY as a single agent Melanoma 1. 1% (11/1024) 0 (0/11) Adjuvant Melanoma 4. 9 (7/144) 0 (0/7) YERVOY with nivolumab for 4 doses followed by nivolumab as a single agent Melanoma 8. 4% (33/391) 3% (1/33) HCC 5. 3% (13/244) 0 (0/13) RCC and CRC 5. 4% (27/499) 0% (0/27) YERVOY with nivolumab Malignant Pleural Mesothelioma 13. 7% (37/271) 2. 7% (1/37) NSCLC 8. 5% (41/483) 0 (0/41) YERVOY with nivolumab and 2 cycles of platinum-doublet chemotherapy NSCLC 7. 5% (23/305) 21. 7% (5/23) Presence of treatment-emergent anti-ipilimumab antibodies did not affect ipilimumab clearance after administration of ipilimumab as monotherapy or in combination with nivolumab. These anti-drug antibody-associated pharmacokinetic changes were not considered to be clinically significant. There was no identified clinically significant effect of anti-drug antibodies on incidence of infusion-related reactions. In hepatocellular carcinoma, there was no identified clinically significant effect of anti-drug antibodies on efficacy for ipilimumab in combination with nivolumab. For other indications, the effects of anti-drug antibodies on effectiveness have not been fully characterized.

INDICATIONS AND USAGE
YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for: Melanoma (1. 1) (1. 2) Renal Cell Carcinoma (RCC) (1. 3) Colorectal Cancer s patients with unresectable or metastatic (CRC) (1. 4) Hepatocellular Carcinoma unresectable or metastatic (HCC) as first-line treatment in combination with nivolumab. 5 in combination with nivolumab in adult patients with unresectable or metastatic HCC (1. 5) Non-Small Cell Lung Cancer (NSCLC) (1. 6) (1. 6) Malignant Pleural Mesothelioma (1. 7) Esophageal Cancer (1. 8) YERVOY, as a single agent or in combination with nivolumab, is indicated for the treatment of unresectable or metastatic melanoma in adult and pediatric patients 12 years and older. YERVOY is indicated for the adjuvant treatment of adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC). unresectable or metastatic CRC first-line unresectable or metastatic YERVOY, in combination with nivolumab, is indicated for the treatment of adult patients with unresectable or metastatic HCC 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) YERVOY, in combination with nivolumab and 2 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. YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma. YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).
Treatment of MSI -H or dMMR mCRC: In Combination with Nivolumab
The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-8HW, a randomized, open-label, three arm trial in immunotherapy naïve patients with MSI-H or dMMR mCRC [see Clinical Studies (14.4) [see Clinical Studies (14.4) In the YERVOY and nivolumab arm, the median duration of exposure to YERVOY was 2.1 months (range 1 day to 3.7 months); patients received a median of 4 doses (range 1-4). The median duration of treatment in the YERVOY and nivolumab arm was 20.5 months (range: 1 day to 35.9 months); 70% were exposed to treatment for >6 months, and 63% were exposed for >1 year. The median duration of treatment was 16.4 months (range: 1 day to 36 months) in the nivolumab-only arm; 64% were exposed to treatment for >6 months, and 54% were exposed for >1 year. Serious adverse reactions occurred in 46% of patients receiving YERVOY in combination with nivolumab, and 39% of patients receiving nivolumab alone. The most frequent serious adverse reactions reported in >=1% of patients who received YERVOY with nivolumab were adrenal insufficiency (2.8%), hypophysitis (2.8%), diarrhea (2.0%), abdominal pain (2.0%), small intestinal obstruction (2.0%), pneumonia (1.7%), acute kidney injury (1.4%), immune mediated enterocolitis (1.4%), pneumonitis (1.4%), colitis (1.1%), large intestinal obstruction (1.1%), and urinary tract infection (1.1%). The most frequent serious adverse reactions reported in >1% of patients who received OPDIVO, as a single agent, were intestinal obstruction (2.3%), acute kidney injury (1.7%), COVID-19 (1.7%), abdominal pain (1.4%), diarrhea (1.4%), ileus (1.4%), subileus (1.4%), pulmonary embolism (1.4%), adrenal insufficiency (1.1%) and pneumonia (1.1%). Fatal adverse reactions occurred in 2 (0.6%) patients who received YERVOY in combination with nivolumab; these included myocarditis, and pneumonitis (1 each). YERVOY and/or nivolumab were permanently discontinued in 19% of patients receiving the combination. The most frequent adverse reactions (>1%) leading to permanent discontinuation were adrenal insufficiency (1.4%), immune mediated enterocolitis (1.1%), and pneumonitis (1.1%). Nivolumab was permanently discontinued in 13% of patients receiving single agent nivolumab. Adverse reactions leading to the delay of YERVOY and/or nivolumab occurred in 48% of patients receiving the combination; single agent nivolumab was delayed in 37% of patients due to adverse reactions. The most common adverse reactions reported in >=20% of patients treated with YERVOY in combination with nivolumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions reported in >=20% of patients treated with nivolumab as a single agent, were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain. Tables 10 and 11 summarize the adverse reactions and selected laboratory abnormalities, for YERVOY in combination with nivolumab and nivolumab arms respectively, in CHECKMATE-8HW. Table 10: Adverse Reactions in >=10% in Patient and a Difference Between Arms of >5% for All Grades in - CHECKMATE-8HW Toxicity was graded per NCI CTCAE v5. a Adverse Reaction YERVOY and Nivolumab Nivolumab All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Gastrointestinal Diarrhea a 35 4.5 30 3.4 Skin and Subcutaneous Tissue Pruritus 30 0 23 0 Musculoskeletal and Connective Tissue Arthralgia 20 0.6 15 0.6 Endocrine Hypothyroidism 18 0.6 10 0 Hyperthyroidism 12 0 5 0 Table 11: Laboratory Values Worsening from Baseline a a Laboratory Abnormality a YERVOY and Nivolumab Nivolumab All Grades (%) Grades 3-or 4 (%) All Grades (%) Grades 3 or -4 (%) Hematology Lymphocytes decreased 30 5 37 4 Neutrophils decreased 21 1.7 12 0.6 Chemistry Lipase increased 44 10 32 11 Amylase increased 41 4.6 33 5 ALT increased 39 3.5 32 1.4 AST increased 38 3.2 29 1.4 Sodium decreased 36 3.2 30 2.3 Creatinine increased 32 2 25 1.4 Potassium increased 29 1.2 35 0.9 Glucose decreased 17 0 12 0
Unresectable or Metastatic Hepatocellular Carcinoma (HCC)
The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-9DW, a randomized, open-label trial in adult patients with unresectable or metastatic HCC [see Clinical Studies (14. 5) o o In the YERVOY and nivolumab arm, the median duration of exposure to nivolumab was 4. 7 months (range: 6 months and 30% were exposed for >1 year. Serious adverse reactions occurred in 53% of patients treated with YERVOY in combination with nivolumab. The most frequent non liver-related serious adverse reactions reported in >=2% were diarrhea/colitis (4. 5%), gastrointestinal hemorrhage (3%), and rash (2. Liver-related serious adverse reactions occurred in 17% of patients treated with YERVOY in combination with nivolumab, including Grade 3-4 events in 16% of patients. The most frequently reported all grade liver-related serious adverse reactions occurring in >=1% of patients were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2. 4%), ascites (2. 4%), and hepatotoxicity (1. Fatal adverse reactions occurred in 12 (3. 6%) patients who received YERVOY in combination with nivolumab; these included 4 (1. 2%) patients who died due to immune-mediated or autoimmune hepatitis and 4 (1. 2%) patients who died of hepatic failure. Permanent discontinuation due to an adverse reaction occurred in 27% of patients treated with YERVOY in combination with nivolumab. Adverse reactions leading to permanent discontinuation in >1% of patients included immune-mediated hepatitis (1. 8%), diarrhea/colitis (1. 8%), and hepatic failure (1. Dosage interruptions due to an adverse reaction occurred in 62% of patients treated with YERVOY in combination with nivolumab. Adverse reactions which required dosage interruption in >5% of patients included increased AST (13%), increased ALT (11%), and diarrhea/colitis (8%). The most common (>20%) adverse reactions were rash, pruritus, fatigue, and diarrhea. Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9DW. Toxicity was graded per NCI CTCAE v5 a Table 12: Adverse Reactions Occurring in >=10% of YERVOY in combination with Nivolumab-Treated Patients - CHECKMATE-9DW Adverse Reaction YERVOY and Nivolumab Lenvatinib or Sorafenib All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 36 3. 2 Pruritus 34 1. 3 General Fatigue a 33 2. 4 39 4 Pyrexia a 15 0. 5 Edema a 13 1. 5 Gastrointestinal Diarrhea 25 6 39 3. 4 Abdominal pain a 14 1. 5 Nausea 10 0. 9 Musculoskeletal and Connective Tissue Musculoskeletal pain a 17 0. 3 Arthralgia 12 0. 6 Metabolism and Nutrition Decreased appetite 16 1. 8 Endocrine Hypothyroidism a 14 0 27 0 Hyperthyroidism 11 0. 5 0 Respiratory, Thoracic and Mediastinal Cough a 13 0 8 0 Clinically important adverse reactions reported in <10% of patients who received YERVOY with nivolumab were hyperglycemia (8%), adrenal insufficiency (4. 2%), pneumonitis (2. 7%), and pancreatitis (2. a Table 13: Laboratory Values Worsening from Baseline a Laboratory Abnormality YERVOY and Nivolumab (n=332) Lenvatinib or Sorafenib (n=325) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Chemistry Increased AST 62 29 51 14 Increased ALT 61 17 46 9 Increased lipase 58 16 39 5 Decreased albumin 48 0. 6 Hyponatremia 45 6 42 3. 8 Hyperglycemia 44 15 32 2. 1 Increased bilirubin 44 10 44 8 Increased amylase 41 6 26 1 Increased alkaline phosphatase 36 1. 2 38 5 Hypocalcemia 29 0. 9 46 0 Increased creatinine 26 2. 6 Hypokalemia 21 2. 6 Hematology Anemia 44 5 40 3. 8 Lymphopenia 40 6. 1 40 8 Thrombocytopenia 27 4 44 4. 8 Neutropenia 24 4 32 3. 5 The safety of YERVOY 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in a subgroup of 49 patients with HCC and Child-Pugh Class A cirrhosis who progressed on or were intolerant to sorafenib enrolled in Cohort 4 of CHECKMATE-040. YERVOY and nivolumab were administered every 3 weeks for four doses, followed by single-agent nivolumab 240 mg every 2 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: 0 to 4. 5 months) and to nivolumab was 5. 1 months (range: 0 to 35+ months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction. Serious adverse reactions reported in >=4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. Table 14 summarizes the adverse reactions and Table 15 summarizes the laboratory abnormalities of YERVOY in combination with nivolumab in CHECKMATE-040. Table 14: Adverse Reactions Occurring in >=10% of Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040 Adverse Reaction YERVOY and Nivolumab (n=49) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash 53 8 Pruritus 53 4 Musculoskeletal and Connective Tissue Musculoskeletal pain 41 2 Arthralgia 10 0 Gastrointestinal Diarrhea 39 4 Abdominal pain 22 6 Nausea 20 0 Ascites 14 6 Constipation 14 0 Dry mouth 12 0 Dyspepsia 12 2 Vomiting 12 2 Stomatitis 10 0 Respiratory, Thoracic and Mediastinal Cough 37 0 Dyspnea 14 0 Pneumonitis 10 2 Metabolism and Nutrition Decreased appetite 35 2 General Fatigue 27 2 Pyrexia 27 0 Malaise 18 2 Edema 16 2 Influenza-like illness 14 0 Chills 10 0 Nervous System Headache 22 0 Dizziness 20 0 Endocrine Hypothyroidism 20 0 Adrenal insufficiency 18 4 Investigations Weight decreased 20 0 Psychiatric Insomnia 18 0 Blood and Lymphatic System Anemia 10 4 Infections Influenza 10 2 Vascular Hypotension 10 0 Clinically important adverse reactions reported in <10% of patients receiving YERVOY with nivolumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%). Table 15: Select Laboratory Abnormalities (>=10%) Worsening from Baseline in Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040 Laboratory Abnormality YERVOY and Nivolumab (n=47) All Grades (%) Grades 3-4 (%) Hematology Lymphopenia 53 13 Anemia 43 4. 3 Neutropenia 43 9 Leukopenia 40 2. 1 Thrombocytopenia 34 4. 3 Chemistry Increased AST 66 40 Increased ALT 66 21 Increased bilirubin 55 11 Increased lipase 51 26 Hyponatremia 49 32 Hypocalcemia 47 0 Increased alkaline phosphatase 40 4. 3 Increased amylase 38 15 Hypokalemia 26 2. 1 Hyperkalemia 23 4. 3 Increased creatinine 21 0 Hypomagnesemia 11 0 In patients who received YERVOY with nivolumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined as a 1 log increase in HCV RNA from baseline.
Previously Treated Hepatocellular Carcinoma
The safety of YERVOY 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in a subgroup of 49 patients with HCC and Child-Pugh Class A cirrhosis who progressed on or were intolerant to sorafenib enrolled in Cohort 4 of CHECKMATE-040. YERVOY and nivolumab were administered every 3 weeks for four doses, followed by single-agent nivolumab 240 mg every 2 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: 0 to 4.5 months) and to nivolumab was 5.1 months (range: 0 to 35+ months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction. Serious adverse reactions reported in >=4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. Table 14 summarizes the adverse reactions and Table 15 summarizes the laboratory abnormalities of YERVOY in combination with nivolumab in CHECKMATE-040. Table 14: Adverse Reactions Occurring in >=10% of Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040 Adverse Reaction YERVOY and Nivolumab (n=49) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash 53 8 Pruritus 53 4 Musculoskeletal and Connective Tissue Musculoskeletal pain 41 2 Arthralgia 10 0 Gastrointestinal Diarrhea 39 4 Abdominal pain 22 6 Nausea 20 0 Ascites 14 6 Constipation 14 0 Dry mouth 12 0 Dyspepsia 12 2 Vomiting 12 2 Stomatitis 10 0 Respiratory, Thoracic and Mediastinal Cough 37 0 Dyspnea 14 0 Pneumonitis 10 2 Metabolism and Nutrition Decreased appetite 35 2 General Fatigue 27 2 Pyrexia 27 0 Malaise 18 2 Edema 16 2 Influenza-like illness 14 0 Chills 10 0 Nervous System Headache 22 0 Dizziness 20 0 Endocrine Hypothyroidism 20 0 Adrenal insufficiency 18 4 Investigations Weight decreased 20 0 Psychiatric Insomnia 18 0 Blood and Lymphatic System Anemia 10 4 Infections Influenza 10 2 Vascular Hypotension 10 0 Clinically important adverse reactions reported in <10% of patients receiving YERVOY with nivolumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%). Table 15: Select Laboratory Abnormalities (>=10%) Worsening from Baseline in Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040 Laboratory Abnormality YERVOY and Nivolumab (n=47) All Grades (%) Grades 3-4 (%) Hematology Lymphopenia 53 13 Anemia 43 4.3 Neutropenia 43 9 Leukopenia 40 2.1 Thrombocytopenia 34 4.3 Chemistry Increased AST 66 40 Increased ALT 66 21 Increased bilirubin 55 11 Increased lipase 51 26 Hyponatremia 49 32 Hypocalcemia 47 0 Increased alkaline phosphatase 40 4.3 Increased amylase 38 15 Hypokalemia 26 2.1 Hyperkalemia 23 4.3 Increased creatinine 21 0 Hypomagnesemia 11 0 In patients who received YERVOY with nivolumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined as a 1 log increase in HCV RNA from baseline.

(2) Unresectable or Metastatic Melanoma ∘ (2. 2) Adjuvant Treatment of Melanoma (2. 2) Advanced Renal Cell Carcinoma (2. 2) Treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in combination with nivolumab ∘ Adult and pediatric patients weighing 40 kg or greater: 240 mg a maximum of the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab (2. 2) ∘ Pediatric patients weighing less than 40 kg: YERVOY 1 mg/kg immediately following nivolumab 3 mg/kg on the same day every 3 weeks for a maximum of 4 doses. After completing 2. 2 Hepatocellular Carcinoma up to up to (2. 2) Metastatic non-small cell lung cancer ∘ (2. 2) Malignant pleural mesothelioma (2. 2) Esophageal squamous cell carcinoma: (2. 2) Information on FDA-approved tests for patient selection is available at: https://www. gov/CompanionDiagnostics [see Clinical Studies (14. 6) The recommended dosages of YERVOY as a single agent are presented in Table 1. Table 1: Recommended Dosages for YERVOY as a Single Agent * Indication Recommended YERVOY Dosage Duration of Therapy Unresectable or metastatic melanoma 3 mg/kg every 3 weeks* Maximum of 4 doses Adjuvant treatment of melanoma 3 mg/kg every 3 weeks followed by 3 mg/kg every 12 weeks* Every 3 weeks up to a maximum of 4 doses Every 12 weeks for up to 4 additional doses The 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* * dagger double dagger Indication Recommended YERVOY Dosage Duration of Therapy Unresectable or metastatic melanoma 3 mg/kg every 3 weeks double dagger with nivolumab 1 mg/kg double dagger In combination with nivolumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier. After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity. dagger Advanced renal cell carcinoma 1 mg/kg every 3 weeks double dagger with nivolumab 3 mg/kg double dagger In combination with nivolumab After completing 4 doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity. dagger Microsatellite instability-high (MSI‑H) or mismatch repair deficient (dMMR) metastatic colorectal cancer Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more: 1 mg/kg every 3 weeks double dagger with nivolumab 240 mg double dagger In combination with nivolumab dagger After completing 4 doses of combination therapy, administer nivolumab as single agent until disease progression, unacceptable toxicity , or up to 2 years dagger Pediatric patients age 12 years and older and weighing less than 40 kg: 1 mg/kg every 3 weeks double dagger double dagger Hepatocellular carcinoma 3 mg/kg every 3 weeks double dagger with nivolumab 1 mg/kg double dagger In combination with nivolumab a maximum of 4 After completing a maximum of dagger Metastatic non-small cell lung cancer expressing PD‑L1 1 mg/kg every 6 weeks with nivolumab 360 mg double dagger In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. dagger Metastatic or recurrent non-small cell lung cancer 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks double dagger and histology-based platinum‑doublet chemotherapy every 3 weeks In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. dagger 2 cycles of histology-based platinum-doublet chemotherapy Malignant pleural mesothelioma 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks double dagger In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. dagger Esophageal squamous cell carcinoma 1 mg/kg every 6 weeks double dagger double dagger In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years. 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 Reactions ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit of normal * a b c d Adverse Reaction Severity* Dosage Modifications Immune-Mediated Adverse Reactions [See Warnings and Precautions (5. 1) Colitis Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Hepatitis with no tumor involvement of the liver or Hepatitis with tumor involvement of the liver/non-HCC AST or ALT increases to more than 3 times and up to 5 times the ULN or Total bilirubin increases to more than 1. 5 times and up to 3 times the ULN Withhold a AST or ALT more than 5 times the ULN or Total bilirubin more than 3 times the ULN Permanently discontinue Hepatitis with tumor involvement of the liver b c Baseline AST/ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST/ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN. Withhold a AST/ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN. Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Endocrinopathies d Grades 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Pneumonitis Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold a Grade 4 increased blood creatinine Permanently discontinue Neurological Toxicities Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Myocarditis Grade 2, 3 or 4 Permanently discontinue Ophthalmologic Grade 2, 3, or 4 that does not improve to Grade 1 within 2 weeks while receiving topical therapy or that requires systemic treatment Permanently discontinue Other Adverse Reactions Infusion-Related Reactions [see Warnings and Precautions (5. 2) Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue final concentration ranging from 1 mg/mL to 2 mg/mL lowprotein .

The following clinically significant adverse reactions are described elsewhere in the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) Most common adverse reactions (>=20%) with YERVOY as a single agent are fatigue, diarrhea, pruritus, rash, nausea, and headache. 1) Most common adverse reactions (>=20%) with YERVOY in combination with nivolumab are fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness. 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. 1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 3 mg/kg as a single agent (or in combination with an investigational gp100 peptide vaccine) in 511 patients in Study MDX010-20; YERVOY 1 mg/kg administered with nivolumab 3 mg/kg in 1,362 patients in CHECKMATE-214, CHECKMATE-142, CHECKMATE-227, and CHECKMATE-743; YERVOY 3 mg/kg administered with nivolumab 1 mg/kg in 456 patients enrolled in CHECKMATE-067, CHECKMATE-040, and another randomized trial; and to YERVOY 1 mg/kg, administered in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA. 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) The trial population characteristics were: median age 57 years (range: 19 to 90), 59% male, 94% White, and baseline ECOG performance status 0 (56%). YERVOY was discontinued for adverse reactions in 10% of patients. Table 4 presents adverse reactions from Study MDX010-20. Table 4: Selected Adverse Reactions (>=5%) in Patients Receiving YERVOY with a Difference Between Arms of >5% for All Grades and >1% for Grades 3 to 5 Compared to gp100 Peptide Vaccine in Study MDX010-20 Adverse Reactions YERVOY 3 mg/kg YERVOY 3 mg/kg and gp100 n=380 n=132 All Grades (%) Grade All Grades (%) Grade All Grades (%) Grade General and Administration-Site Conditions Fatigue 41 7 34 5 31 3 Gastrointestinal Diarrhea 32 5 37 4 20 1 Colitis 8 5 5 3 2 0 Dermatologic Pruritus 31 0 21 <1 11 0 Rash 29 2 25 2 8 0 The safety of YERVOY, administered with nivolumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14. 1) Patients were randomized to receive: The median duration of exposure to nivolumab was 2. 8 months (range: 1 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 3 or 4 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. 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 5 and 6 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 a Higher Incidence than in the YERVOY Arm (Between Arm Difference of >=5% All Grades or >=2% Grades 3-4) - CHECKMATE-067 Toxicity was graded per NCI CTCAE v4. a b c d e Adverse Reaction YERVOY and (n=313) (n=311) All Grades (%) Grades All Grades (%) Grades All Grades (%) Grades General Fatigue a 62 7 59 1. 2 Pyrexia 40 1. 6 16 0 18 0. 6 Gastrointestinal Diarrhea 54 11 36 5 47 7 Nausea 44 3. 9 Vomiting 31 3. 6 Skin and Subcutaneous Tissue Rash b 53 6 40 1. 5 Vitiligo 9 0 10 0. 3 5 0 Musculoskeletal and Connective Tissue Musculoskeletal pain c 32 2. 9 Arthralgia 21 0. 3 Metabolism and Nutrition Decreased appetite 29 1. 9 22 0 24 1. 3 Respiratory, Thoracic and Mediastinal Cough/productive cough 27 0. 6 22 0 Dyspnea/exertional dyspnea 24 2. 6 Infections Upper respiratory tract infection d 23 0 22 0. 3 17 0 Endocrine Hypothyroidism 19 0. 6 11 0 5 0 Hyperthyroidism 11 1. 3 6 0 1 0 Investigations Decreased weight 12 0 7 0 7 0. 3 Vascular Hypertension e 7 2. 3 Clinically important adverse reactions in <10% of patients who received YERVOY with nivolumab: Gastrointestinal Disorders: Skin and Subcutaneous Tissue Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Table 6: Laboratory Abnormalities Worsening from Baseline a a Laboratory Abnormality YERVOY and All Grades (%) Grade All Grades (%) Grade All Grades (%) Grade Chemistry Increased ALT 55 16 25 3. 7 Hyperglycemia 53 5 46 7 26 0 Increased AST 52 13 29 3. 7 Hyponatremia 45 10 22 3. 3 26 7 Increased lipase 43 22 32 12 24 7 Increased alkaline phosphatase 41 6 27 2. 0 Hypocalcemia 31 1. 7 Increased amylase 27 10 19 2. 6 Increased creatinine 26 2. 3 Hematology Anemia 52 2. 6 41 6 Lymphopenia 39 5 41 4. 0 The safety of YERVOY was evaluated in Study E1609, an open-label, multicenter, randomized trial for the adjuvant treatment of patients with completely resected node positive cutaneous melanoma [see Clinical Studies (14. 2) Fatal adverse reactions occurred in 1. 4% of patients who received YERVOY, including gastric perforation (0. 2%), and cardiac arrest (0. Permanent discontinuation of YERVOY due to an adverse reaction occurred in 35% of patients. The most common adverse reactions (>=20%) in the YERVOY arm were fatigue, diarrhea, rash, pruritus, nausea, and headache. Table 7 summarizes adverse reactions in E1609. Table 7: Adverse Reactions (>10%) in Patients Receiving YERVOY 3 mg/kg in E1609 Adverse Reaction YERVOY 3 mg/kg HDI All Grades (%) Grade 3 to 4 (%) All Grades (%) Grade 3 to 4 (%) General disorders and administration site conditions Fatigue 56 3 87 22 Decreased appetite 14 0. 1 Pyrexia 10 0 31 0. 8 Gastrointestinal Diarrhea 49 10 34 0. 8 Nausea 29 1. 2 Abdominal Pain 19 1 9 0. 4 Vomiting 11 0. 3 Colitis 10 8 1 0. 4 Dermatologic Rash 46 4 18 1 Pruritus 41 2 15 0 Nervous System Disorders Headache 25 2 45 3 Endocrine Endocrine disorders, other 19 4. 1 2 0 Hypothyroidism 11 0. 2 Adrenal insufficiency 10 2 0. 6 0 Across clinical studies in which patients received YERVOY as a 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. The safety of YERVOY in combination with nivolumab was evaluated in 1082 patients with previously untreated advanced RCC in CHECKMATE-214 [see Clinical Studies (14. 3) 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 8 summarizes adverse reactions in CHECKMATE-214. Table 8: Adverse Reactions (>15%) in Patients Receiving YERVOY and Nivolumab in CHECKMATE-214 Toxicity was graded per NCI CTCAE v4. a b c d Adverse Reaction YERVOY 1 mg/kg and Nivolumab Sunitinib Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) General and Administration Site Conditions Fatigue a 58 8 69 13 Pyrexia 25 0. 6 Edema b 16 0. 6 Skin and Subcutaneous Tissue Rash c 39 3. 1 Pruritus/generalized pruritus 33 0. 5 11 0 Gastrointestinal Diarrhea 38 4. 6 58 6 Nausea 30 2. 5 Vomiting 20 0. 1 Abdominal pain 19 1. 9 Constipation 17 0. 4 18 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 37 4. 6 Arthralgia 23 1. 3 16 0 Respiratory, Thoracic, and Mediastinal Cough/productive cough 28 0. 4 Dyspnea/exertional dyspnea 20 2. 1 Metabolism and Nutrition Decreased appetite 21 1. 9 Nervous System Headache 19 0. 9 Endocrine Hypothyroidism 18 0. 2 Table 9 summarizes the laboratory abnormalities in CHECKMATE-214. Table 9: Laboratory Abnormalities (>15%) Worsening from Baseline in Patients Receiving YERVOY and Nivolumab in CHECKMATE-214 a Laboratory Abnormality YERVOY 1 mg/kg and Nivolumab a Sunitinib a Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Chemistry Increased lipase 48 20 51 20 Increased creatinine 42 2. 7 Increased ALT 41 7 44 2. 7 Increased AST 40 4. 1 Increased amylase 39 12 33 7 Hyponatremia 39 10 36 7 Increased alkaline phosphatase 29 2. 0 Hyperkalemia 29 2. 9 Hypocalcemia 21 0. 6 Hypomagnesemia 16 0. 6 Hematology Anemia 43 3. 0 64 9 Lymphopenia 36 5 63 14 In addition, among patients with TSH <= ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the YERVOY with nivolumab group compared to the sunitinib group (31% and 61%, respectively). The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-8HW, a randomized, open-label, three arm trial in immunotherapy naïve patients with MSI-H or dMMR mCRC [see Clinical Studies (14. 4) [see Clinical Studies (14. 4) In the YERVOY and nivolumab arm, the median duration of exposure to YERVOY was 2. 1 months (range 1 day to 3. 7 months); patients received a median of 4 doses (range 1-4). The median duration of treatment in the YERVOY and nivolumab arm was 20. 5 months (range: 1 day to 35. 9 months); 70% were exposed to treatment for >6 months, and 63% were exposed for >1 year. The median duration of treatment was 16. 4 months (range: 1 day to 36 months) in the nivolumab-only arm; 64% were exposed to treatment for >6 months, and 54% were exposed for >1 year. Serious adverse reactions occurred in 46% of patients receiving YERVOY in combination with nivolumab, and 39% of patients receiving nivolumab alone. The most frequent serious adverse reactions reported in >=1% of patients who received YERVOY with nivolumab were adrenal insufficiency (2. 8%), hypophysitis (2. 8%), diarrhea (2. 0%), abdominal pain (2. 0%), small intestinal obstruction (2. 0%), pneumonia (1. 7%), acute kidney injury (1. 4%), immune mediated enterocolitis (1. 4%), pneumonitis (1. 4%), colitis (1. 1%), large intestinal obstruction (1. 1%), and urinary tract infection (1. The most frequent serious adverse reactions reported in >1% of patients who received OPDIVO, as a single agent, were intestinal obstruction (2. 3%), acute kidney injury (1. 7%), COVID-19 (1. 7%), abdominal pain (1. 4%), diarrhea (1. 4%), ileus (1. 4%), subileus (1. 4%), pulmonary embolism (1. 4%), adrenal insufficiency (1. 1%) and pneumonia (1. Fatal adverse reactions occurred in 2 (0. 6%) patients who received YERVOY in combination with nivolumab; these included myocarditis, and pneumonitis (1 each). YERVOY and/or nivolumab were permanently discontinued in 19% of patients receiving the combination. The most frequent adverse reactions (>1%) leading to permanent discontinuation were adrenal insufficiency (1. 1%), and pneumonitis (1. Nivolumab was permanently discontinued in 13% of patients receiving single agent nivolumab. Adverse reactions leading to the delay of YERVOY and/or nivolumab occurred in 48% of patients receiving the combination; single agent nivolumab was delayed in 37% of patients due to adverse reactions. The most common adverse reactions reported in >=20% of patients treated with YERVOY in combination with nivolumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions reported in >=20% of patients treated with nivolumab as a single agent, were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain. Tables 10 and 11 summarize the adverse reactions and selected laboratory abnormalities, for YERVOY in combination with nivolumab and nivolumab arms respectively, in CHECKMATE-8HW. Table 10: Adverse Reactions in >=10% in Patient and a Difference Between Arms of >5% for All Grades in - CHECKMATE-8HW Toxicity was graded per NCI CTCAE v5. a Adverse Reaction YERVOY and Nivolumab Nivolumab All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Gastrointestinal Diarrhea a 35 4. 4 Skin and Subcutaneous Tissue Pruritus 30 0 23 0 Musculoskeletal and Connective Tissue Arthralgia 20 0. 6 Endocrine Hypothyroidism 18 0. 6 10 0 Hyperthyroidism 12 0 5 0 Table 11: Laboratory Values Worsening from Baseline a a Laboratory Abnormality a YERVOY and Nivolumab Nivolumab All Grades (%) Grades 3-or 4 (%) All Grades (%) Grades 3 or -4 (%) Hematology Lymphocytes decreased 30 5 37 4 Neutrophils decreased 21 1. 6 Chemistry Lipase increased 44 10 32 11 Amylase increased 41 4. 6 33 5 ALT increased 39 3. 4 AST increased 38 3. 4 Sodium decreased 36 3. 3 Creatinine increased 32 2 25 1. 4 Potassium increased 29 1. 9 Glucose decreased 17 0 12 0 The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-9DW, a randomized, open-label trial in adult patients with unresectable or metastatic HCC [see Clinical Studies (14. 5) o o In the YERVOY and nivolumab arm, the median duration of exposure to nivolumab was 4. 7 months (range: 6 months and 30% were exposed for >1 year. Serious adverse reactions occurred in 53% of patients treated with YERVOY in combination with nivolumab. The most frequent non liver-related serious adverse reactions reported in >=2% were diarrhea/colitis (4. 5%), gastrointestinal hemorrhage (3%), and rash (2. Liver-related serious adverse reactions occurred in 17% of patients treated with YERVOY in combination with nivolumab, including Grade 3-4 events in 16% of patients. The most frequently reported all grade liver-related serious adverse reactions occurring in >=1% of patients were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2. 4%), ascites (2. 4%), and hepatotoxicity (1. Fatal adverse reactions occurred in 12 (3. 6%) patients who received YERVOY in combination with nivolumab; these included 4 (1. 2%) patients who died due to immune-mediated or autoimmune hepatitis and 4 (1. 2%) patients who died of hepatic failure. Permanent discontinuation due to an adverse reaction occurred in 27% of patients treated with YERVOY in combination with nivolumab. Adverse reactions leading to permanent discontinuation in >1% of patients included immune-mediated hepatitis (1. 8%), diarrhea/colitis (1. 8%), and hepatic failure (1. Dosage interruptions due to an adverse reaction occurred in 62% of patients treated with YERVOY in combination with nivolumab. Adverse reactions which required dosage interruption in >5% of patients included increased AST (13%), increased ALT (11%), and diarrhea/colitis (8%). The most common (>20%) adverse reactions were rash, pruritus, fatigue, and diarrhea. Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9DW. Toxicity was graded per NCI CTCAE v5 a Table 12: Adverse Reactions Occurring in >=10% of YERVOY in combination with Nivolumab-Treated Patients - CHECKMATE-9DW Adverse Reaction YERVOY and Nivolumab Lenvatinib or Sorafenib All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 36 3. 2 Pruritus 34 1. 3 General Fatigue a 33 2. 4 39 4 Pyrexia a 15 0. 5 Edema a 13 1. 5 Gastrointestinal Diarrhea 25 6 39 3. 4 Abdominal pain a 14 1. 5 Nausea 10 0. 9 Musculoskeletal and Connective Tissue Musculoskeletal pain a 17 0. 3 Arthralgia 12 0. 6 Metabolism and Nutrition Decreased appetite 16 1. 8 Endocrine Hypothyroidism a 14 0 27 0 Hyperthyroidism 11 0. 5 0 Respiratory, Thoracic and Mediastinal Cough a 13 0 8 0 Clinically important adverse reactions reported in <10% of patients who received YERVOY with nivolumab were hyperglycemia (8%), adrenal insufficiency (4. 2%), pneumonitis (2. 7%), and pancreatitis (2. a Table 13: Laboratory Values Worsening from Baseline a Laboratory Abnormality YERVOY and Nivolumab (n=332) Lenvatinib or Sorafenib (n=325) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Chemistry Increased AST 62 29 51 14 Increased ALT 61 17 46 9 Increased lipase 58 16 39 5 Decreased albumin 48 0. 6 Hyponatremia 45 6 42 3. 8 Hyperglycemia 44 15 32 2. 1 Increased bilirubin 44 10 44 8 Increased amylase 41 6 26 1 Increased alkaline phosphatase 36 1. 2 38 5 Hypocalcemia 29 0. 9 46 0 Increased creatinine 26 2. 6 Hypokalemia 21 2. 6 Hematology Anemia 44 5 40 3. 8 Lymphopenia 40 6. 1 40 8 Thrombocytopenia 27 4 44 4. 8 Neutropenia 24 4 32 3. 5 The safety of YERVOY 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in a subgroup of 49 patients with HCC and Child-Pugh Class A cirrhosis who progressed on or were intolerant to sorafenib enrolled in Cohort 4 of CHECKMATE-040. YERVOY and nivolumab were administered every 3 weeks for four doses, followed by single-agent nivolumab 240 mg every 2 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: 0 to 4. 5 months) and to nivolumab was 5. 1 months (range: 0 to 35+ months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction. Serious adverse reactions reported in >=4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. Table 14 summarizes the adverse reactions and Table 15 summarizes the laboratory abnormalities of YERVOY in combination with nivolumab in CHECKMATE-040. Table 14: Adverse Reactions Occurring in >=10% of Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040 Adverse Reaction YERVOY and Nivolumab (n=49) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash 53 8 Pruritus 53 4 Musculoskeletal and Connective Tissue Musculoskeletal pain 41 2 Arthralgia 10 0 Gastrointestinal Diarrhea 39 4 Abdominal pain 22 6 Nausea 20 0 Ascites 14 6 Constipation 14 0 Dry mouth 12 0 Dyspepsia 12 2 Vomiting 12 2 Stomatitis 10 0 Respiratory, Thoracic and Mediastinal Cough 37 0 Dyspnea 14 0 Pneumonitis 10 2 Metabolism and Nutrition Decreased appetite 35 2 General Fatigue 27 2 Pyrexia 27 0 Malaise 18 2 Edema 16 2 Influenza-like illness 14 0 Chills 10 0 Nervous System Headache 22 0 Dizziness 20 0 Endocrine Hypothyroidism 20 0 Adrenal insufficiency 18 4 Investigations Weight decreased 20 0 Psychiatric Insomnia 18 0 Blood and Lymphatic System Anemia 10 4 Infections Influenza 10 2 Vascular Hypotension 10 0 Clinically important adverse reactions reported in <10% of patients receiving YERVOY with nivolumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%). Table 15: Select Laboratory Abnormalities (>=10%) Worsening from Baseline in Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040 Laboratory Abnormality YERVOY and Nivolumab (n=47) All Grades (%) Grades 3-4 (%) Hematology Lymphopenia 53 13 Anemia 43 4. 3 Neutropenia 43 9 Leukopenia 40 2. 1 Thrombocytopenia 34 4. 3 Chemistry Increased AST 66 40 Increased ALT 66 21 Increased bilirubin 55 11 Increased lipase 51 26 Hyponatremia 49 32 Hypocalcemia 47 0 Increased alkaline phosphatase 40 4. 3 Increased amylase 38 15 Hypokalemia 26 2. 1 Hyperkalemia 23 4. 3 Increased creatinine 21 0 Hypomagnesemia 11 0 In patients who received YERVOY with nivolumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined as a 1 log increase in HCV RNA from baseline. The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-227, a 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) Serious adverse reactions occurred in 58% of patients. YERVOY and nivolumab were discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction. The most frequent (>=2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1. 7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. The most common (>=20%) adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus. Tables 16 and 17 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227. Table 16: Adverse Reactions in >=10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-227 a b c d e f g h i j k l m Adverse Reaction YERVOY and Nivolumab Platinum-Doublet Chemotherapy All Grades Grades 3-4 All Grades Grades 3-4 General Fatigue a 44 6 42 4. 4 Pyrexia 18 0. 4 Edema b 14 0. 5 Skin and Subcutaneous Tissue Rash c 34 4. 4 Pruritus d 21 0. 3 0 Metabolism and Nutrition Decreased appetite 31 2. 4 Musculoskeletal and Connective Tissue Musculoskeletal pain e 27 1. 7 Arthralgia 13 0. 2 Gastrointestinal Diarrhea/colitis f 26 3. 9 Nausea 21 1. 5 Constipation 18 0. 5 Vomiting 13 1. 3 Abdominal pain g 10 0. 7 Respiratory, Thoracic, and Mediastinal Dyspnea h 26 4. 1 Cough i 23 0. 2 13 0 Hepatobiliary Hepatitis j 21 9 10 1. 2 Endocrine Hypothyroidism k 16 0. 2 0 Hyperthyroidism l 10 0 0. 5 0 Infections and Infestations Pneumonia m 13 7 8 4. 0 Nervous System Headache 11 0. 5 6 0 Other clinically important adverse reactions in CHECKMATE-227 were: Skin and Subcutaneous Tissue: Gastrointestinal: Musculoskeletal and Connective Tissue: Nervous System: Blood and Lymphatic System: Eye Disorders: Cardiac: Table 17: Laboratory Values Worsening from Baseline a a Laboratory Abnormality YERVOY and Nivolumab Platinum-doublet Chemotherapy Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Hematology Anemia 46 3. 6 78 14 Lymphopenia 46 5 60 15 Chemistry Hyponatremia 41 12 26 4. 9 Increased AST 39 5 26 0. 4 Increased ALT 36 7 27 0. 7 Increased lipase 35 14 14 3. 4 Increased alkaline phosphatase 34 3. 2 Increased amylase 28 9 18 1. 9 Hypocalcemia 28 1. 3 Hyperkalemia 27 3. 4 Increased creatinine 22 0. 2 The safety of YERVOY in combination with nivolumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Clinical Studies (14. 6) 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 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. Study therapy with YERVOY in combination with nivolumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction. The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. Tables 18 and 19 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA. Table 18: Adverse Reactions in >10% of Patients Receiving YERVOY and Nivolumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA Toxicity was graded per NCI CTCAE v4. a b c d e f g h i j Adverse Reaction YERVOY and Nivolumab and Platinum-Doublet Chemotherapy Platinum-Doublet Chemotherapy All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 49 5 40 4. 9 Pyrexia 14 0. 6 Musculoskeletal and Connective Tissue Musculoskeletal pain b 39 4. 0 Gastrointestinal Nausea 32 1. 9 Diarrhea c 31 6 18 1. 7 Constipation 21 0. 6 Vomiting 18 2. 4 Abdominal pain d 12 0. 9 Skin and Subcutaneous Tissue Rash e 30 4. 3 Pruritus f 21 0. 9 0 Alopecia 11 0. 6 Metabolism and Nutrition Decreased appetite 28 2. 7 Respiratory, Thoracic and Mediastinal Cough g 19 0. 9 Dyspnea h 18 4. 2 Endocrine Hypothyroidism i 19 0. 4 0 Nervous System Headache 11 0. 6 7 0 Dizziness j 11 0. 6 6 0 Table 19: Laboratory Values Worsening from Baseline a a Laboratory Abnormality YERVOY and Nivolumab and Platinum-Doublet Chemotherapy Platinum-Doublet Chemotherapy Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Anemia 70 9 74 16 Lymphopenia 41 6 40 11 Neutropenia 40 15 42 15 Leukopenia 36 10 40 9 Thrombocytopenia 23 4. 3 24 5 Chemistry Hyperglycemia 45 7 42 2. 6 Hyponatremia 37 10 27 7 Increased ALT 34 4. 2 Increased lipase 31 12 10 2. 2 Increased alkaline phosphatase 31 1. 3 Increased amylase 30 7 19 1. 3 Increased AST 30 3. 3 Hypomagnesemia 29 1. 6 Hypocalcemia 26 1. 8 Increased creatinine 26 1. 6 Hyperkalemia 22 1. 1 The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see Clinical Studies (14. 7) 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 4 (1. 3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. Both YERVOY and nivolumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction. An additional 4. 7% of patients permanently discontinued YERVOY alone due to adverse reactions. The most common (>=20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus. Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743. Table 20: Adverse Reactions in >=10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-743 a b c d e f g h i j k l m Adverse Reaction YERVOY and Nivolumab Chemotherapy All Grades Grades 3-4 All Grades Grades 3-4 General Fatigue a 43 4. 3 45 6 Pyrexia b 18 1. 7 Edema c 17 0 8 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 38 3. 1 Arthralgia 13 1. 1 0 Skin and Subcutaneous Tissue Rash e 34 2. 4 Pruritus f 21 1. 4 0 Gastrointestinal Diarrhea g 32 6 12 1. 1 Nausea 24 0. 5 Constipation 19 0. 7 Abdominal pain h 15 1 10 0. 7 Vomiting 14 0 18 2. 1 Respiratory, Thoracic, and Mediastinal Dyspnea i 27 2. 2 Cough j 23 0. 7 9 0 Metabolism and Nutrition Decreased appetite 24 1. 4 Endocrine Hypothyroidism k 15 0 1. 4 0 Infections and Infestations Upper respiratory tract infection l 12 0. 3 7 0 Pneumonia m 10 4. 1 Table 21: Laboratory Values Worsening from Baseline a a Laboratory Abnormality YERVOY and Nivolumab Chemotherapy Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Chemistry Hyperglycemia 53 3. 1 Increased AST 38 7 17 0 Increased ALT 37 7 15 0. 4 Increased lipase 34 13 9 0. 8 Hyponatremia 32 8 21 2. 9 Increased alkaline phosphatase 31 3. 1 12 0 Hyperkalemia 30 4. 7 Hypocalcemia 28 0 16 0 Increased amylase 26 5 13 0. 9 Increased creatinine 20 0. 4 Hematology Lymphopenia 43 8 57 14 Anemia 43 2. 4 75 15 The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-648, a randomized, active-controlled, multicenter, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC [see Clinical Studies (14. 8) 2 2 Among patients who received YERVOY and nivolumab, the median duration of exposure was 2. 8 months (range: 0 to 24 months). Serious adverse reactions occurred in 69% of patients receiving YERVOY in combination with nivolumab. The most frequent serious adverse reactions reported in >=2% of patients who received YERVOY with nivolumab were pneumonia (10%), pyrexia (4. 3%), pneumonitis (4. 0%), aspiration pneumonia (3. 7%), dysphagia (3. 7%), hepatic function abnormal (2. 8%), decreased appetite (2. 8%), adrenal insufficiency (2. 5%), and dehydration (2. Fatal adverse reactions occurred in 5 (1. 6%) patients who received YERVOY in combination with nivolumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome. YERVOY and/or nivolumab were discontinued in 23% of patients and delayed in 46% of patients for an adverse reaction. The most common adverse reactions reported in >=20% of patients treated with YERVOY in combination with nivolumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation. Tables 22 and 23 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648. Table 22: Adverse Reactions in >=10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-648 Adverse Reaction YERVOY and Nivolumab (n=322) Cisplatin and 5-FU All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Toxicity was graded per NCI CTCAE v4. a b c d e f g h Skin and Subcutaneous Tissue Rash a 31 3. 1 7 0 Pruritis 17 0. 6 0 General Fatigue c 28 2. 9 Pyrexia b 23 0. 3 Gastrointestinal Nausea 22 0. 6 Diarrhea 22 1. 0 Constipation 20 0. 0 Vomiting 15 1. 0 Dysphagia 12 5 12 4. 9 Stomatitis d 11 0. 0 Abdominal pain e 10 0. 7 Metabolism and Nutrition Decreased appetite 17 4. 0 50 6 Musculoskeletal and Connective Tissue Musculoskeletal pain f 14 0. 3 Infections and Infestations Pneumonia g 14 8 10 2. 6 Endocrine Hypothyroidism 14 0 0. 3 0 Respiratory, Thoracic and Mediastinal Cough h 13 0. 3 Investigations Weight decreased 12 1. 0 Table 23: Laboratory Values Worsening from Baseline a Laboratory Abnormality YERVOY and Nivolumab Cisplatin and 5-FU Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) a Hematology Anemia 52 7 66 14 Lymphopenia 50 13 44 8 Neutropenia 13 1. 3 48 13 Thrombocytopenia 12 1. 8 Chemistry Hyponatremia 45 11 40 8 Hyperglycemia 43 4. 8 Increased AST 39 6 11 1. 4 Increased ALT 33 6 8 0. 7 Hypocalcemia 32 0 23 0. 7 Increased alkaline phosphatase 31 3. 3 15 0 Hyperkalemia 23 1. 7 Hypokalemia 19 5 17 6 Hypercalcemia 15 2. 0 8 0 Hypoglycemia 15 1. 2 7 0 Increased creatinine 15 0. 7 Hypomagnesemia 15 0 25 1. 8 The following adverse reactions have been identified during post-approval use of YERVOY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Immune System: Skin and Subcutaneous Tissue:.

Lactation 8. 2 Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12. 1) (see Data In the U. 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. In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 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. 2 times the human exposure at a dose of 3 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 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7. 2 times the humans exposure based on area under the curve at a dose of 3 mg/kg). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 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 2 weeks of age, and all died by 3 to 4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction. 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 In monkeys treated at dose levels resulting in exposures 2. 2 times higher than those in humans at a 3 mg/kg dose, ipilimumab was present in milk at concentrations of 0. 1 mcg/mL and 0. 4 mcg/mL, representing a ratio of up to 0. 3% of the steady-state serum concentration of the drug. Verify pregnancy status in females of reproductive potential prior to initiating YERVOY [see Use in Specific Populations (8. 1) YERVOY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8. 1) The safety and effectiveness of YERVOY have been established in pediatric patients aged 12 years and older for the following indications: as a single agent and in combination with nivolumab for unresectable or metastatic melanoma, in combination with nivolumab for the treatment of MSI-H or dMMR unresectable and metastatic CRC, and in combination with nivolumab for MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of YERVOY for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma or MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients. Ipilimumab exposures in pediatric patients 12 years and older are comparable to that of adults, and the courses of melanoma and MSI-H or dMMR mCRC are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy [see Adverse Reactions (6. 1) Clinical Pharmacology (12. 3) Clinical Studies (14. 4) The safety and effectiveness of YERVOY have not been established in pediatric patients younger than 12 years old with unresectable or metastatic melanoma or MSI-H or dMMR mCRC. The safety and effectiveness of YERVOY have not been established in pediatric patients for the adjuvant treatment of melanoma or for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, metastatic non-small cell lung cancer, malignant pleural mesothelioma and esophageal cancer. In a dose-finding trial (NCT01445379), 33 patients aged 2 to 21 years (median 13 years) with relapsed or refractory solid tumors were evaluated including unresectable stage IIIc or stage IV melanoma (12), progressive or refractory sarcomas (17), renal or bladder carcinoma (3), and neuroblastoma (1). No responses in the patients with non-melanoma solid tumors and no new safety signals were observed in pediatric patients in this study. Single Agent 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. In Combination with Nivolumab 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. Of the 576 patients randomized to YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 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 a 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 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-227, the hazard ratio for overall survival was 0. 70 (95% CI: 0. 89) in the 199 patients younger than 65 years compared to 0. 91 (95% CI: 0. 15) in the 197 patients 65 years or older [see Clinical Studies (14. 6) Of the 303 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 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. 11) in the 71 patients younger than 65 years compared to 0. 74 (95% CI: 0. 93) in the 232 patients 65 years or older randomized to YERVOY in combination with nivolumab. Of the 550 patients randomized to YERVOY 1 mg/kg with nivolumab in CHECKMATE-214 (renal cell carcinoma), 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was observed between these patients and younger patients. In geriatric patients with intermediate or poor risk, no overall difference in effectiveness was observed. Of the 354 patients with dMMR or MSI-H metastatic CRC (mCRC) who were randomized to YERVOY in combination with nivolumab, 44% were 65 years or older and 14% were 75 years or older. Of the 353 patients randomized to nivolumab, as a single agent, 45% were 65 years or older and 13% were 75 years or older. There was a higher incidence of any Grade 3 or 4 adverse reactions (55%) in patients aged 65 years or older receiving YERVOY in combination with nivolumab compared to those younger than 65 receiving the combination (42%). There was a higher incidence of adverse reactions leading to discontinuation in patients aged 65 years or older receiving YERVOY in combination with nivolumab (23%) compared to those younger than 65 receiving the combination (15%). No overall differences in effectiveness were reported between elderly patients and younger patients receiving YERVOY in combination with nivolumab [see Clinical Studies (14. 4) Of the 335 patients with unresectable hepatocellular carcinoma who were randomized to YERVOY in combination with nivolumab, 52% were 65 years or older and 14% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients. Of the 49 patients who received YERVOY 3 mg/kg with nivolumab in Cohort 4 of CHECKMATE-040 (previously treated hepatocellular carcinoma), 29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical studies of YERVOY in combination with nivolumab did not include sufficient numbers of patients with hepatocellular carcinoma aged 65 and over to determine whether they respond differently from younger patients. Of the 325 patients who received YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-648 (ESCC), 43% were 65 years old or older and 7% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (38%) relative to all patients who received YERVOY with nivolumab (23%). For patients aged 75 years or older who received chemotherapy, the discontinuation rate due to adverse reactions was 33% relative to 23% for all patients. Study CA184-029 (adjuvant treatment of melanoma) and CHECKMATE-142 (metastatic colorectal cancer) did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In Combination with Nivolumab and Platinum-Doublet Chemotherapy Of the 361 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and platinum-doublet chemotherapy every 3 weeks (for 2 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 a 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 a 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. 80) in the 176 patients younger than 65 years compared to 0. 73 (95% CI: 0. 95) in the 185 patients 65 years or older.

NONCLINICAL TOXICOLOGY
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 STUDIES
The efficacy of YERVOY was investigated in a Study MDX010-20, a 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-A2*0201 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 a dose of 3 mg/kg as an intravenous infusion every 3 weeks for 4 doses with an investigational peptide vaccine with incomplete Freund’s adjuvant - gp100 administered at a dose of 2 mg peptide by deep subcutaneous injection every 3 weeks for 4 doses; gp100 administered at a dose of 2 mg by deep subcutaneous injection every 3 weeks for 4 doses as a single agent with a placebo; or YERVOY administered at a dose of 3 mg/kg by intravenous infusion every 3 weeks for 4 doses with a 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 3 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 a history of previously treated brain metastasis, 98% had ECOG performance status of 0 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 4 planned doses. The median duration of follow-up was 8. The efficacy results are shown in Table 25 and Figure 1. Table 25: Efficacy Results for Study MDX010-20 a b YERVOY 3 mg/kg n=137 YERVOY 3 mg/kg and gp100 gp100 n=136 Overall Survival Median in months (95% CI) 10 (8. 7) Hazard ratio (vs. gp100) (95% CI) 0. 85) p-value p=0. 0004 Hazard ratio (vs. YERVOY) (95% CI) 1. 30) Best Overall Response Rate (BORR) (95% CI) 10. 2%) Median duration of response in months NR b 11. 5 NR b Figure 1: Kaplan-Meier Curves for Overall Survival in Study MDX010-20 CHECKMATE-067 (NCT01844505) was a 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 6 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: Randomization was stratified by PD-L1 expression (>=5% vs. <5% tumor cell membrane expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M stage per the AJCC staging system (M0, M1a, M1b vs. Tumor assessments were conducted 12 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. The major efficacy outcome measures were investigator-assessed PFS per RECIST v1. 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 0 (73%) or 1 (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 a single agent. Efficacy results are shown in Table 26 and Figure 2. Table 26: Efficacy Results - CHECKMATE-067 a b c d e f YERVOY and Nivolumab YERVOY Overall Survival a Deaths (%) 128 (41) 142 (45) 197 (63) Hazard ratio b (95% CI) 0. 78) p-value c, d <0. 0001 Progression-free Survival a Disease progression or death 151 (48%) 174 (55%) 234 (74%) Median (months) (95% CI) 11. 9 Hazard ratio b (95% CI) 0. 69) p-value c, e <0. 0001 Confirmed Overall Response Rate a 50% 40% 14% (95% CI) (44, 55) (34, 46) (10, 18) p-value f <0. 0001 Complete response 8. 9% Partial response 41% 31% 12% Duration of Response Proportion >=6 months in duration 76% 74% 63% Range (months) 1. 8+ Figure 2: Overall Survival - CHECKMATE-067 Based on a 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. 6) in the YERVOY arm. Based on a minimum follow-up of 28 months, the median PFS was 11. 7 months (95% CI: 8. 9) in the YERVOY and nivolumab arm, 6. 9 months (95% CI: 4. 5) in the nivolumab arm, and 2. 9 months (95% CI: 2. 2) in the YERVOY arm. Based on a 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. yervoy-os-checkmate-067 yervoy-os-mdx010-20 The efficacy of YERVOY was evaluated in Study E1609 (NCT01274338), an open-label, multicenter, randomized trial for the adjuvant treatment of cutaneous melanoma in patients with completely resected node positive disease (either clinically detectable or any size with ulceration or mitosis >=1/mm 2 2 2 Randomization was stratified by AJCC 7th edition stage (IIIB, IIIC, M1a, or M1b). Tumor assessments were conducted every 3 months in patients 5 years from study entry for up to 20 years. Treatment continued for a maximum of 60 weeks with ipilimumab or 52 weeks with HDI, or until unacceptable toxic effects, disease progression, or withdrawal of consent. The major efficacy outcome measures were investigator-assessed recurrence-free survival (RFS) by imaging (for CNS lesions) or imaging and positive cytology or histology (for non-CNS lesions) and overall survival (OS). Only the efficacy results for the recommended starting dose of 3 mg/kg YERVOY are described below. A total of 1051 patients were randomized to YERVOY 3 mg/kg (n=523) and HDI (n=528). The median age was 54 years (range: 18 to 83), 62% were male, 97% were white, 0. 3% were Asian, and 0. 4% were Black. Regarding disease stage, 53% had Stage IIIB, 40% had Stage IIIC (with no in-transit metastases), and 7% had Stage IV disease. The efficacy results are in Table 27 and Figure 3. Table 27: Efficacy Results for E1609 a YERVOY 3 mg/kg HDI Overall Survival Number of deaths (%) 130 (25) 134 (25) Hazard ratio (95% CI) 0. 99) p-value (stratified log-rank a 0. 044 5-year OS Rates (95% CI) 72 67 Recurrence-Free Survival Number of events (%) 246 (47) 232 (44) Median in years (95% CI) 4. 5 Hazard ratio (95% CI) 0. 02) Figure 3: Kaplan-Meier Curves for Overall Survival with Ipilimumab 3 mg/kg vs. HDI in Study E1609 kmc-os-ipili-e1609 The efficacy of YERVOY with nivolumab was evaluated in CHECKMATE-214 (NCT02231749), a 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 3 mg/kg and YERVOY 1 mg/kg administered intravenously every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every two weeks or to sunitinib administered orally 50 mg daily for the first 4 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 1 or more of 6 prognostic risk factors as per the IMDC criteria: less than one year from time of initial RCC diagnosis to randomization, Karnofsky performance status (KPS) 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 a baseline KPS of 70% to 80% and 90% to 100%, respectively. Efficacy results from CHECKMATE-214 are presented in Table 28 and Figure 4. In intermediate/poor risk patients, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to YERVOY and nivolumab arm as compared with sunitinib arm. OS benefit was observed regardless of PD-L1 expression level. The trial did not demonstrate a statistically significant improvement in PFS. Table 28: Efficacy Results for CHECKMATE-214 a b c d e f Efficacy Parameter Intermediate/Poor-Risk YERVOY 1 mg/kg and Nivolumab Sunitinib Overall Survival Number of deaths 140 (32. 9%) 188 (44. 5%) Median in months NE 25. 9 Hazard ratio (99. 89) p-value b,c <0. 0001 Confirmed Objective Response Rate (95% CI) 41. 0%) Complete Response 40 (9. 2%) Partial Response 137 (32. 2%) 107 (25. 4%) Median duration of response in months (95% CI) NE (21. 8, NE) p-value d,e <0. 0001 Progression-free Survival Number of events (progression or death) 228 (53. 6%) 228 (54. 0%) Median in months 11. 4 Hazard ratio (99. 05) p-value b NS f Figure 4: Kaplan-Meier Curves for Overall Survival (Intermediate/Poor Risk Population) in CHECKMATE-214 CHECKMATE-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 a hazard ratio of 1. 45 (95% CI: 0. The efficacy of nivolumab and YERVOY in previously untreated renal cell carcinoma with favorable risk disease has not been established. yervoy-os-checkmate-214 CHECKMATE-8HW (NCT03143153) was a randomized, 3-arm, open-label trial in immunotherapy-naive patients across all lines of therapy with unresectable or metastatic CRC with known tumor MSI-H or dMMR (MSI-H/dMMR) status as determined in accordance with local standard of practice using PCR, NGS or IHC, assays. Central assessment of MSI-H status using PCR (Idylla MSI) test and dMMR status using IHC (Omnis MMR) test was conducted retrospectively on patient tumor specimens used for local MSI-H/dMMR status determination. Patients with confirmed MSI-H/dMMR status by either central test comprised the primary study population. The trial excluded patients with brain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroids or immunosuppressants, or had been treated with checkpoint inhibitors. Patients were randomized to receive one of the following treatments: o 2 2 2 2 2 o 2 2 2 2 2 Randomization was stratified by tumor location (right vs left) and by prior lines of therapy (0, 1, 2L+). Patients randomized to the chemotherapy arm could receive YERVOY plus nivolumab combination upon progression assessed by BICR. Study treatment was administered until disease progression, unacceptable toxicity, or for up to 2 years for patients who received YERVOY plus nivolumab or nivolumab monotherapy. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue nivolumab as a single agent. Nivolumab with or without YERVOY could be administered beyond RECIST 1. 1-assessed progressive disease if there was a clinical benefit as determined by investigator and therapy was tolerated. Tumor assessments per RECIST v1. 1 were conducted every 6 weeks for the first 24 weeks, then every 8 weeks thereafter up until week 96, then every 16 weeks thereafter up until week 144, and then every 24 weeks. The evaluation of efficacy relied on the comparison of patients with centrally confirmed MSI-H/dMMR mCRC randomized to YERVOY in combination with nivolumab versus chemotherapy in the first-line (1L) setting and the comparison of patients with centrally confirmed MSI-H/dMMR mCRC randomized to YERVOY in combination with nivolumab vs nivolumab in all lines setting. The major efficacy outcome measure was BICR-assessed PFS per RECIST 1. Additional efficacy measures included ORR and duration of response assessed by BICR and OS. The baseline characteristics of the total of 839 patients randomized were: the median age was 63 years (range: 20 to 87), with 46% >=65 years of age and 14% >=75 years of age; 50% were male and 87% were White, 9. 3% were Asian, 1. 5% Black or African American, and 2. 3% other race; 9. 2% were Hispanic or Latino, 50% Not Hispanic or Latino, 41% ethnicity unknown. Baseline ECOG performance status was 0 (52%) and (48%); number of prior lines of therapy was 0 (56%) and 1 (24%), and >=2 (19%); tumor location was right-sided or left-sided for 69% and 31% of patients. The baseline characteristics in patients with centrally confirmed MSI-H/dMMR is consistent with all randomized patients. Among 303 patients in the first-line setting were randomly assigned to YERVOY in combination with nivolumab (202) and to chemotherapy (101), 171 and 84 patients had centrally confirmed MSI-H/dMMR status in YERVOY in combination with nivolumab arm and chemotherapy arm, respectively. In the 1L setting, 200 of 202 patients assigned to receive YERVOY in combination with nivolumab and 88 of 101 patients assigned to received chemotherapy received at least 1 dose of study treatment. Among the 88 patients who received chemotherapy, 58% and 42% of patients received oxaliplatin-containing regimens and irinotecan-containing regimens, respectively, and 66 (75%) patients received a targeted agent, either bevacizumab (64%) or cetuximab (11%). The BICR-assessed PFS efficacy results for patients with centrally confirmed MSI-H/dMMR randomized to the YERVOY and nivolumab arm compared with chemotherapy in the 1L setting are presented in Table 29 and Figure 5. The comparative results of ORR and OS between arms were not available at the time of the PFS analysis due to statistical testing strategy. Table 29: Efficacy Results - CHECKMATE-8HW NR: Not Reached; NE: Not Estimable. Minimum follow-up was 6. 1 months at data cutoff date 12Oct2023. a b c YERVOY and Nivolumab Chemotherapy Progression-free Survival Disease progression or death (%) 48 (28) 52 (62) Median in months b NR (38. 8) Hazard ratio c 0. 32) p-value a <0. 0001 Figure 5: Progression-free Survival, (First line YERVOY + nivolumab vs Chemotherapy)- CHECKMATE-8HW All Lines YERVOY in combination with nivolumab Among 707 patients across all treatment lines who were randomly assigned to YERVOY in combination with nivolumab (354) and to nivolumab (353) single agent, 296 and 286 patients had centrally confirmed MSI-H/dMMR status in the YERVOY in combination with nivolumab arm and in the nivolumab arm, respectively. Patients receiving at least 1 dose of study treatment included 352 of 354 patients randomized to OPDIVO in combination with ipilimumab, and 351 of 353 patients randomized to single agent OPDIVO. The BICR-assessed PFS and ORR efficacy results for patients with centrally confirmed MSI-H/dMMR randomized to the YERVOY in combination with nivolumab compared with nivolumab single agent across all treatment lines setting are presented in Table 30 and Figure 6. At the time of PFS analysis OS between arms were not available due to statistical testing strategy. Table 30: Efficacy Results All Lines - CHECKMATE-8HW NR: Not Reached; NE: Not Estimable. Minimum follow-up was 16. 7 months at data cutoff date 28Aug2024. a b c d YERVOY and Nivolumab Nivolumab Progression-free Survival Disease progression or death n (%) 101 (34) 136 (48) Median (months) b (95% CI) NR (53. 1, NE) Hazard ratio c 0. 81) p-value a 0. 0003 Objective Response Rate (ORR) Response Rate, n (%) (95% CI) 209 (71%) (65, 76) 165 (58%) (52, 63) Complete Response Rate, n (%) 90 (30%) 80 (28%) Partial Response, n (%) 119 (40%) 65 (30%) p-value d 0. 0011 Figure 6: Progression-free Survival (All lines (YERVOY + Nivolumab vs Nivolumab)- CHECKMATE-8HW pfs-first-line-checkmate-8hw pfs-all-lines-checkmate-8hw CHECKMATE-9DW (NCT04039607) was a randomized (1:1), open-label trial in adults (18 years of age or older) with unresectable or metastatic HCC. Patients had histologically confirmed HCC, Child Pugh Class A, ECOG performance status 0 or 1, and no prior systemic therapy for advanced disease. Esophagogastroduodenoscopy was not mandated prior to enrollment. The trial excluded patients with active autoimmune disease, brain or leptomeningeal metastases, a history of hepatic encephalopathy (within 12 months of randomization), a platelet count <60,000, clinically significant ascites, medical conditions requiring systemic immunosuppression, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV). Patients were randomized to receive either: o o Randomization was stratified by etiology (HBV vs. non-viral), macrovascular invasion and/or extrahepatic spread (present or absent), and alpha-fetoprotein levels (>=400 or <400 ng/mL). Study treatment for YERVOY in combination with nivolumab continued until disease progression, unacceptable toxicity, or up to 2 years. Treatment beyond RECIST 1. 1 defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at week 9 and week 16, then every 8 weeks up to 48 weeks, and then every 12 weeks thereafter until disease progression, treatment discontinuation, or initiation of subsequent therapy. The primary efficacy outcome measure was OS in all randomized patients. Additional efficacy measures included BICR-assessed ORR and DOR based on RECIST 1. A total of 668 patients were randomized to receive YERVOY in combination with nivolumab (n=335) or investigator’s choice (n=333) of lenvatinib or sorafenib. In the investigator arm, 85% and 15% of treated patients received lenvatinib or sorafenib, respectively. The trial population characteristics were: median age was 66 years (range: 20 to 89), with 53% >=65 years old; 82% male; 53% White, 44% Asian, 2. 2% Black; 12% Hispanic or Latino, 48% Not Hispanic or Latino, 40% not reported. Baseline ECOG performance status was 0 (71%) or 1 (29%). Thirty-four percent (34%) of patients had HBV infection, 28% had HCV infection, and 36% had no evidence of HBV or HCV infection. Nineteen percent (19%) of patients had alcoholic liver disease and 11% had non-alcoholic fatty liver disease. The majority of patients had BCLC stage C (73%) disease at baseline, 19% had stage B, and 6% had stage A. Patients with Child-Pugh scores of 5, 6, and 7 were 77%, 20%, and 3%, respectively; 1 patient with Child Pugh 8 was enrolled. A total of 54% of patients had extrahepatic spread; 25% had macrovascular invasion; and 33% had AFP levels >=400 µg/L. CHECKMATE-9DW demonstrated a statistically significant improvement in OS and ORR. The minimum follow-up was 26. Efficacy results are shown in Table 31 and Figure 7. a b c d e + Censored observation Table : Efficacy Results - CHECKMATE-9DW YERVOY and Nivolumab Lenvatinib or Sorafenib Overall Survival Deaths (%) 194 (58%) 228 (68%) Median (months) (95% CI) 23. 5) Hazard ratio (95% CI) a 0. 96) p-value b 0. 0180 Overall Response Rate, n (%) c 121 (36. 2) (95% CI) (31. 3) p-value d <0. 0001 Complete response (%) 23 (6. 8) Partial response (%) 98 (29. 4) Duration of Response (months) c Median (95% CI) 30. 5+ Figure 7: Overall Survival - CHECKMATE-9DW yervoy-os-checkmate-9dw CHECKMATE-040 (NCT01658878) was a 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 A cirrhosis. The trial excluded patients with active autoimmune disease, brain metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible. The efficacy of YERVOY 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in Cohort 4 of CHECKMATE-040. A total of 49 patients received the combination regimen, which was administered every 3 weeks for four doses, followed by single-agent nivolumab at 240 mg every 2 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 0 (61%) or 1 (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 µg/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 2 or more prior systemic therapies. Efficacy results are shown in Table 32. Table 32: Efficacy Results - Cohort 4 of CHECKMATE-040 a b YERVOY and Nivolumab Overall Response Rate per BICR, a 16 (33%) (95% CI) b (20, 48) Complete response 4 (8%) Partial response 12 (24%) Duration of Response per BICR, a n=16 Range (months) 4. 5+ Percent with duration >=6 months 88% Percent with duration >=12 months 56% Percent with duration >=24 months 31% Overall Response Rate per BICR, a 17 (35%) (95% CI) b (22, 50) Complete response 6 (12%) Partial response 11 (22%) CHECKMATE-227 (NCT02477826) was a 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 0 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 2 weeks prior to enrolment, and either off corticosteroids, or on a 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 a central laboratory. Randomization was stratified by tumor histology (non-squamous versus squamous). The evaluation of efficacy relied on the comparison between: Chemotherapy regimens consisted of pemetrexed (500 mg/m 2 2 2 2 2 2 Study treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Treatment continued beyond disease progression if a 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 a single agent. Tumor assessments were performed every 6 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, a 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 0 (34%) or 1 (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 a statistically significant improvement in OS for PD-L1 >=1% patients randomized to the YERVOY and nivolumab arm compared to platinum-doublet chemotherapy arm. The OS results are presented in Table 33 and Figure 8. Table 33: Efficacy Results (PD-L1 >=1%) - CHECKMATE-227 Part 1a a b YERVOY and Nivolumab Platinum-Doublet Chemotherapy Overall Survival Events (%) 258 (65%) 298 (75%) Median (months) a (95% CI) 17. 7) Hazard ratio (95% CI) b 0. 94) Stratified log-rank p-value 0. 0066 Figure 8: Overall Survival (PD-L1 >=1%) - CHECKMATE-227 BICR-assessed PFS showed a HR of 0. 82 (95% CI: 0. 97), with a median PFS of 5. 1 months (95% CI: 4. 3) in the YERVOY and nivolumab arm and 5. 6 months (95% CI: 4. 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. yervoy-os-checkmate-227 CHECKMATE-9LA (NCT03215706) was a 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 0 or 1, and no prior anticancer therapy (including EGFR and ALK inhibitors) for metastatic disease. Patients with stable brain metastases were eligible for enrollment. Patients were randomized 1:1 to receive either: Platinum-doublet chemotherapy consisted of either carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m 2 2 2 2 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 0 (31%) or 1 (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 a statistically significant benefit in OS, PFS, and ORR. Efficacy results from the prespecified interim analysis when 351 events were observed (87% of the planned number of events for final analysis) are presented in Table 34. Table 34: Efficacy Results - CHECKMATE-9LA a b c d e f YERVOY and Nivolumab and Platinum-Doublet Chemotherapy Platinum-Doublet Chemotherapy Overall Survival Events (%) 156 (43. 5) Median (months) 14. 7 Hazard ratio (96. 71% CI) a 0. 87) Stratified log-rank p-value b 0. 0006 Progression-free Survival per BICR Events (%) 232 (64. 6) Hazard ratio (97. 48% CI) a 0. 86) Stratified log-rank p-value c 0. 0001 Median (months) d 6. 0 Overall Response Rate per BICR (%) 38 25 (95% CI) e (33, 43) (21, 30) Stratified CMH test p-value f 0. 0003 Duration of Response per BICR Median (months) d 10. 1 With an additional 4. 6 months of follow-up the hazard ratio for overall survival was 0. 66 (95% CI: 0. 80) and median survival was 15. 6 months (95% CI: 13. 9 months (95% CI: 9. 5) for patients receiving YERVOY and nivolumab and platinum-doublet chemotherapy or platinum-doublet chemotherapy, respectively (Figure 9). Figure 9: Overall Survival - CHECKMATE-9LA yervoy-os-checkmate-9la CHECKMATE-743 (NCT02899299) was a 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: 2 2 2 Stratification factors for randomization were tumor histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and sex (male vs. Study treatment continued for up to 2 years, or until disease progression or unacceptable toxicity. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. 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 0 (40%) or 1 (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 a statistically significant improvement in OS for patients randomized to YERVOY in combination with nivolumab compared to chemotherapy. Efficacy results from the prespecified interim analysis are presented in Table 35 and Figure 10. Table 35: Efficacy Results - CHECKMATE-743 a b c d e YERVOY and Nivolumab Chemotherapy Overall Survival a Events (%) 200 (66) 219 (73) Median (months) b (95% CI) 18. 1 Hazard ratio (95% CI) c 0. 89) Stratified log-rank p-value d 0. 002 Progression-free Survival Events (%) 218 (72) 209 (69) Hazard ratio (95% CI) c 1. 21) Median (months) b (95% CI) 6. 2 Overall Response Rate e 40% 43% (95% CI) (34, 45) (37, 49) Duration of Response Median (months) a 11. 7 Figure 10: Overall Survival - CHECKMATE-743 In a 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. 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. 70), with median OS of 16. 9 months in the YERVOY and nivolumab arm and 8. 8 months in the chemotherapy arm. yervoy-os-checkmate-743 CHECKMATE-648 (NCT03143153) was a randomized, active-controlled, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC (squamous or adenosquamous histology). The trial enrolled patients whose tumor was evaluable for tumor cell (TC) PD-L1 expression [also called PD-L1 tumor proportion score (TPS)], which was evaluated using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. Patients were not amenable to chemoradiation or surgery with curative intent. A retrospective scoring of a patient’s tumor PD-L1 status using Combined Positive Score (CPS) was also conducted using the PD-L1-stained tumor specimens used for randomization. Prior treatment with curative intent was allowed if completed more than six months prior to trial enrollment. The trial excluded patients with brain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to apparent invasion of tumor to organs adjacent to the esophageal tumor. Patients were randomized to receive one of the following treatments: 2 2 Patients were treated until disease progression, unacceptable toxicity, or up to 2 years. Randomization was stratified by TC PD-L1 expression (>=1% vs. <1% or indeterminate), region (East Asia vs. Rest of Asia vs. Rest of World), ECOG performance status (0 vs. 1), and number of organs with metastases (<=1 vs. The major efficacy outcome measures were OS and BICR-assessed PFS in patients with TC PD-L1 expression >=1%. Additional efficacy measures included OS in all randomized patients, BICR-assessed PFS in all randomized patients, and ORR assessed by BICR in TC PD-L1 expression >=1% and in all randomized patients. The tumor assessments per RECIST v1. 1 were conducted every 6 weeks up to and including week 48, then every 12 weeks thereafter. A total of 649 patients were randomized in Arms A and C of CHECKMATE-648 study among whom 644 and 601 patients had quantifiable TC PD-L1 expression and CPS at baseline, respectively. The trial population characteristics were: median age 64 years (range: 26 to 81), 46% were >=65 years of age, 84% were male, 71% were Asian, 25% were White, and 1. 5% were Black. Patients had histological confirmation of squamous cell carcinoma (99%) or adenosquamous cell carcinoma (1. 4%) in the esophagus. Baseline ECOG performance status was 0 (46%) or 1 (54%). Efficacy results are shown in Table 36 and Figures 11 and 12. Table 36: Efficacy Results - Arms A and C of CHECKMATE-648 a b c S1, S2 YERVOY and Nivolumab Cisplatin and Fluorouracil YERVOY and Nivolumab Cisplatin and Fluorouracil All Patients TC PD-L1 expression >=1% Overall Survival Deaths (%) 216 (66) 232 (72) 106 (67) 121 (77) Median (months) (95% CI) 12. 7, 10) Hazard ratio (95% CI) b 0. 84) - p-value c 0. 0110 S1 - 0. 0010 S2 - Progression-free Survival a Disease progression or death (%) 258 (79) 210 (65) 123 (78) 100 (64) Median (months) (95% CI) 2. 8) Hazard ratio (95% CI) b 1. 34) - p-value c NT - NS - Overall Response Rate, n (%) a, NT 90 (27. 7) (95% CI) (22. 8) Complete response (%) 36 (11. 1) Partial response (%) 54 (16. 6) Duration of Response Median (95% CI) 11. 8+ Figure 11: Overall Survival (All Randomized) - CHECKMATE-648 (A) OS in All Randomized Patients (B) OS in TC PD-L1 >=1% Figure 12: Progression-free Survival en dash CHECKMATE-648 (A) PFS in All Randomized Patients (B) PFS in TC PD-L1 >=1% An exploratory subgroup analysis of patients with TC PD-L1 expression <1% (n=329) was conducted. The unstratified OS HR for YERVOY with nivolumab (n=164) vs. chemotherapy (n=165) was 0. 97 (95% CI: 0. 26) with median OS of 12 months (95% CI: 10. 0) on the YERVOY with nivolumab arm and 12. 2 months (95% CI: 10. 7, 14) on the chemotherapy arm. Exploratory subgroup analyses were also conducted by PD-L1 status per CPS (>=1 and <1) for YERVOY with nivolumab arm compared to chemotherapy. Among the 601 patients with quantifiable PD-L1 CPS at baseline, 280 in the chemotherapy arm, and 266 in the YERVOY with nivolumab arm had PD-L1 CPS >=1. A total of 24 patients in the chemotherapy arm and 31 patients in the YERVOY with nivolumab arm had PD-L1 CPS <1. The unstratified OS HR was 0. 76 (95% CI: 0. 93) for PD-L1 CPS >=1 subgroup and 1. 0 (95% CI: 0. 94) for PD-L1 CPS <1 subgroup. yervoy-os-checkmate-648-a yervoy-os-checkmate-648-b yervoy-pfs-checkmate-648-A yervoy-pfs-checkmate-648-B.

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