Indication: 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 (1. 4) Hepatocellular Carcinoma (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). YERVOY, in combination with nivolumab, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14. 4) YERVOY, in combination with nivolumab, is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 5) 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).

Indication: Capecitabine is a nucleoside metabolic inhibitor indicated for: Colorectal Cancer 1. 1 Breast Cancer 1. 2 Gastric, Esophageal, or Gastroesophageal Junction Cancer 1. 3 Pancreatic Cancer 1. 4 Capecitabine tablet is indicated for the: Capecitabine tablet is indicated for the: Capecitabine tablet is indicated for the: Capecitabine tablet is indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen.

Indication: Capecitabine is a nucleoside metabolic inhibitor indicated for: Colorectal Cancer adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen. 1 perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy. 1 treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen. 1 Breast Cancer treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline-or taxane-containing chemotherapy is not indicated. 2 treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy. 2 Gastric, Esophageal, or Gastroesophageal Junction Cancer treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen. 3 treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen. 3 Pancreatic Cancer adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen. 4 Capecitabine is indicated for the: adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen. perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy. treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen. Capecitabine is indicated for the: treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated. treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy. Capecitabine is indicated for the: treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen. treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen. Capecitabine is indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen.

Indication: 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.

Indication: OPDIVO QVANTIG is a combination of nivolumab and hyaluronidase indicated for the treatment of multiple cancers, including renal cell carcinoma, melanoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma, used as monotherapy or in combination with chemotherapy or targeted agents in various first-line, adjuvant, neoadjuvant, and previously treated settings, with some indications subject to specific biomarker status, prior therapies, or accelerated approval based on response rates.