OPDIVO QVANTIG

OPDIVO QVANTIG is a fixed-combination drug product containing nivolumab and hyaluronidase (human recombinant). Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. It is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line. Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. Hyaluronidase (human recombinant) is a glycosylated single-chain protein produced by CHO cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). Hyaluronidase (human recombinant) has a molecular weight of approximately 61 kDa. OPDIVO QVANTIG (nivolumab and hyaluronidase-nvhy) injection is a sterile, preservative-free, clear to opalescent, colorless to yellow solution that may contain a few translucent-to-white particles, supplied in a single-dose vial for subcutaneous use. Each 2.5 mL single-dose vial contains 300 mg of nivolumab and 5,000 units of hyaluronidase (human recombinant), and the inactive ingredients: histidine (3.88 mg), histidine hydrochloride monohydrate (5.25 mg), methionine (1.87 mg), pentetic acid (0.049 mg), polysorbate 80 (1.25 mg), sucrose (214 mg), and Water for Injection, USP. The pH is 5.5 to 6.5. Each 5 mL single-dose vial contains 600 mg of nivolumab and 10,000 units of hyaluronidase (human recombinant), and the inactive ingredients: histidine (7.75 mg), histidine hydrochloride monohydrate (10.5 mg), methionine (3.73 mg), pentetic acid (0.0985 mg), polysorbate 80 (2.5 mg), sucrose (428 mg), and Water for Injection, USP. The pH is 5.5 to 6.5.

OPDIVO QVANTIG is a combination of nivolumab, a programmed death receptor-1 (PD-1)-blocking antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of: Renal Cell Carcinoma (RCC) • adult patients with intermediate or poor risk advanced RCC, as a first-line treatment following combination treatment with intravenous nivolumab and ipilimumab. (1.1) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma. • adult patients with advanced RCC, as a first-line treatment in combination with cabozantinib. (1.1) • adult patients with advanced RCC who have received prior anti-angiogenic therapy. ( 1.1 ) Melanoma • adult and pediatric (12 years and older who weigh 30 kg or greater) patients with unresectable or metastatic melanoma. (1.2) • adult and pediatric (12 years and older who weigh 30 kg or greater) patients with unresectable or metastatic melanoma following combination treatment with intravenous nivolumab and ipilimumab. (1.2) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic melanoma. • for the adjuvant treatment of adult and pediatric (12 years and older who weigh 30 kg or greater) patients with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. (1.3) Non-Small Cell Lung Cancer (NSCLC) • adult patients with resectable (tumors ≥4 cm or node positive) NSCLC in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. (1.4) • adult patients with resectable (tumors ≥4 cm or node positive) NSCLC and no known EGFR mutations or ALK rearrangements, for neoadjuvant treatment, in combination with platinum-doublet chemotherapy, followed by OPDIVO QVANTIG monotherapy as adjuvant treatment after surgery. (1.5) • adult patients with metastatic NSCLC and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO QVANTIG. (1.6) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC. Squamous Cell Carcinoma of the Head and Neck (SCCHN) • adult patients with recurrent or metastatic SCCHN with disease progression on or after a platinum-based therapy. (1.7) Urothelial Carcinoma (UC) • adjuvant treatment of adult patients with UC who are at high risk of recurrence after undergoing radical resection of UC. (1.8) • adult patients with unresectable or metastatic urothelial carcinoma, as first-line treatment in combination with cisplatin and gemcitabine. (1.8) • adult patients with locally advanced or metastatic UC who: • have disease progression during or following platinum-containing chemotherapy. • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.8) Colorectal Cancer (CRC) • adult and pediatric (12 years and older who weigh 30 kg or greater) patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC), following combination treatment with intravenous nivolumab and ipilimumab. (1.9) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic MSI-H or dMMR CRC. • adult and pediatric (12 years and older who weigh 30 kg or greater) patients with MSI-H or dMMR metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. (1.9) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic MSI-H or dMMR CRC. Hepatocellular Carcinoma (HCC) • adult patients with unresectable or metastatic HCC, as a first-line treatment following combination treatment with intravenous nivolumab and ipilimumab. (1.10) • adult patients with unresectable or metastatic HCC, who have been previously treated with sorafenib, following combination treatment with intravenous nivolumab and ipilimumab. (1.10) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic HCC. Esophageal Cancer • adult patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, who have received neoadjuvant chemoradiotherapy (CRT). (1.11) • adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) as first-line treatment in combination with fluoropyrimidine- and platinum-containing chemotherapy whose tumors express PD-L1 (≥1). (1.11) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC. • adult patients with unresectable advanced, recurrent or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy. (1.11) Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma • adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (≥1) in combination with fluoropyrimidine- and platinum-containing chemotherapy. (1.12) 1.1 Advanced Renal Cell Carcinoma OPDIVO QVANTIG™, as monotherapy, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC) following treatment with intravenous nivolumab and ipilimumab combination therapy. Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma. OPDIVO QVANTIG, in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced RCC. OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with advanced RCC who have received prior anti-angiogenic therapy. 1.2 Unresectable or Metastatic Melanoma OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult and pediatric patients 12 years and older who weigh 30 kg or greater with unresectable or metastatic melanoma. OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult and pediatric patients 12 years and older who weigh 30 kg or greater with unresectable or metastatic melanoma following treatment with intravenous nivolumab and ipilimumab combination therapy. Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic melanoma. 1.3 Adjuvant Treatment of Melanoma OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older who weigh 30 kg or greater with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. 1.4 Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC). 1.5 Neoadjuvant and Adjuvant Treatment of Resectable Non-Small Cell Lung Cancer OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated for the neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by OPDIVO QVANTIG as monotherapy in the adjuvant setting after surgical resection. 1.6 Metastatic Non-Small Cell Lung Cancer OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO QVANTIG. Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC. 1.7 Squamous Cell Carcinoma of the Head and Neck OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy. 1.8 Urothelial Carcinoma OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC. OPDIVO QVANTIG, in combination with cisplatin and gemcitabine, is indicated for the first-line treatment of adult patients with unresectable or metastatic UC. OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with locally advanced or metastatic UC who: • have disease progression during or following platinum-containing chemotherapy. • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 1.9 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult and pediatric patients 12 years and older who weigh 30 kg or greater with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) following treatment with intravenous nivolumab and ipilimumab combination therapy. OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult and pediatric patients 12 years and older who weigh 30 kg or greater, with MSI-H or dMMR metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic MSI-H or dMMR CRC. 1.10 Hepatocellular Carcinoma • OPDIVO QVANTIG, as monotherapy, is indicated for the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) following treatment with intravenous nivolumab and ipilimumab combination therapy. • OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have been previously treated with sorafenib following treatment with intravenous nivolumab and ipilimumab combination therapy . Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable or metastatic HCC. 1.11 Esophageal Cancer OPDIVO QVANTIG as monotherapy, is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT). OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1) [see Dosage and Administration (2.2) ] . Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC. OPDIVO QVANTIG as monotherapy, is indicated for the treatment of adult patients with unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy. 1.12 Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (≥1) [see Dosage and Administration (2.2) ] .

• OPDIVO QVANTIG has different dosage and administration instructions than intravenous nivolumab products. • OPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. • OPDIVO QVANTIG is to be administered by a healthcare professional only. (2.1) OPDIVO QVANTIG is for subcutaneous use only. • Administer by subcutaneous injection over 3 to 5 minutes. (2.3) • Renal cell carcinoma • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks administered in combination with cabozantinib 40 mg once daily without food. (2.3) • Melanoma • Adult and pediatric patients (12 years and older) who weigh 40 kg or greater: 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • Pediatric patients (12 years and older) who weigh 30 kg or greater but less than 40 kg: 300 mg/5,000 units every 2 weeks or 600 mg/10,000 units every 4 weeks. (2.3) • Neoadjuvant treatment of resectable (tumors ≥4 cm or node positive) non-small cell lung cancer • 900 mg/15,000 units with platinum-doublet chemotherapy on the same day every 3 weeks for 3 cycles. (2.3) • Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer • 900 mg/15,000 units with platinum-doublet chemotherapy on the same day every 3 weeks for up to 4 cycles, then continued as single-agent OPDIVO QVANTIG 1,200 mg/20,000 units every 4 weeks after surgery for up to 13 cycles (~1 year). (2.3) • Metastatic non-small cell lung cancer • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • Squamous cell carcinoma of the head and neck • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • Urothelial carcinoma • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • First-line unresectable or metastatic urothelial carcinoma • 900 mg/15,000 units every 3 weeks with cisplatin and gemcitabine on the same day for up to 6 cycles, then 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • MSI-H or dMMR metastatic Colorectal cancer • Adult and pediatric patients weighing 40 kg or greater: 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • Pediatric patients weighing 30 kg or greater but less than 40 kg: 300 mg/5,000 units every 2 weeks or 600 mg/10,000 units every 4 weeks. (2.3) • Hepatocellular carcinoma • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • Esophageal cancer • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks administered in combination with fluoropyrimidine- and platinum-containing chemotherapy. (2.3) • Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma • 600 mg/10,000 units every 2 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks. (2.3) • 900 mg/15,000 units every 3 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks. (2.3) • See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. 2.1 Important Dosage and Administration Information OPDIVO QVANTIG has different dosage and administration instructions than intravenously administered nivolumab products [see Dosage and Administration (2.5) ]. OPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. Do not administer intravenously. OPDIVO QVANTIG is to be administered by a healthcare professional only. Adult patients currently receiving intravenous nivolumab as a single agent, or in combination with chemotherapy or cabozantinib, may switch to subcutaneous OPDIVO QVANTIG at their next scheduled dose. 2.2 Patient Selection Esophageal Cancer Select patients with unresectable advanced or metastatic ESCC for treatment with OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapy based on PD-L1 expression [see Clinical Studies (14.11) ] . • An FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic ESCC is not available. Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma Select patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma for treatment with OPDIVO QVANTIG in combination with fluoropyrimidine-and platinum-containing chemotherapy based on PD-L1 expression [see Clinical Studies (14.12) ] . • An FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma is not available. 2.3 Recommended Dosage The recommended dosages of OPDIVO QVANTIG as monotherapy are presented in Table 1. Administer OPDIVO QVANTIG as a subcutaneous injection over 3 to 5 minutes [see Dosage and Administration (2.5) ] . Table 1: Recommended Dosages for OPDIVO QVANTIG as Monotherapy † Dosing recommendations for monotherapy or monotherapy following intravenous nivolumab and ipilimumab combination therapy. Indication Recommended OPDIVO QVANTIG Dosage Duration of Therapy Advanced renal cell carcinoma† 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease progression or unacceptable toxicity Metastatic non-small cell lung cancer Squamous cell carcinoma of the head and neck Locally advanced or metastatic urothelial carcinoma Hepatocellular carcinoma previously treated with sorafenib † Esophageal squamous cell carcinoma Unresectable or metastatic melanoma† Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater: 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease progression or unacceptable toxicity Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg: 300 mg nivolumab and 5,000 units hyaluronidase every 2 weeks or 600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks Adjuvant treatment of melanoma Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater: 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease recurrence or unacceptable toxicity for up to 1 year Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg: 300 mg nivolumab and 5,000 units hyaluronidase every 2 weeks or 600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks Unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer† Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater: 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease progression or unacceptable toxicity, or up to 2 years Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg: 300 mg nivolumab and 5,000 units hyaluronidase every 2 weeks or 600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following prior treatment for metastatic disease† Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater: 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease progression or unacceptable toxicity Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg: 300 mg nivolumab and 5,000 units hyaluronidase every 2 weeks or 600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks First-line unresectable or metastatic hepatocellular carcinoma† 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease progression or unacceptable toxicity, or up to 2 years Adjuvant treatment of urothelial carcinoma 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease recurrence or unacceptable toxicity for up to 1 year Adjuvant treatment of resected esophageal or gastroesophageal junction cancer The recommended dosages of OPDIVO QVANTIG in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with OPDIVO QVANTIG for the recommended dosage information, as appropriate. Table 2: Recommended Dosages for OPDIVO QVANTIG in Combination with Other Therapeutic Agents Indication Recommended OPDIVO QVANTIG Dosage Duration of Therapy Advanced renal cell carcinoma 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Administer OPDIVO QVANTIG in combination with cabozantinib 40 mg orally once daily without food OPDIVO QVANTIG: Until disease progression, unacceptable toxicity, or up to 2 years Cabozantinib: Until disease progression or unacceptable toxicity Neoadjuvant treatment of resectable non-small cell lung cancer 900 mg nivolumab and 15,000 units hyaluronidase with platinum-doublet chemotherapy on the same day every 3 weeks In combination with platinum-doublet chemotherapy for 3 cycles Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer Neoadjuvant: 900 mg nivolumab and 15,000 units hyaluronidase with platinum-doublet chemotherapy on the same day every 3 weeks Neoadjuvant: in combination with platinum-doublet chemotherapy until disease progression or unacceptable toxicity, for up to 4 cycles Adjuvant: 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Adjuvant: following neoadjuvant therapy and surgery, administer as a single agent until disease progression, recurrence, or unacceptable toxicity, for up to 13 cycles (up to 1 year) First-line unresectable or metastatic urothelial carcinoma 900 mg nivolumab and 15,000 units hyaluronidase every 3 weeks Administer OPDIVO QVANTIG in combination with cisplatin and gemcitabine on the same day every 3 weeks In combination with cisplatin and gemcitabine for up to 6 cycles 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks After completing up to 6 cycles of combination therapy, administer as single agent until disease progression, unacceptable toxicity, or up to 2 years from first dose Esophageal squamous cell carcinoma 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Administer OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapy Until disease progression, unacceptable toxicity, or up to 2 years Chemotherapy: Until disease progression or unacceptable toxicity Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma 600 mg nivolumab and 10,000 units hyaluronidase with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks or 900 mg nivolumab and 15,000 units hyaluronidase with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks OPDIVO QVANTIG: Until disease progression, unacceptable toxicity, or up to 2 years Chemotherapy: Until disease progression or unacceptable toxicity 2.4 Dosage Modifications No dose reduction for OPDIVO QVANTIG is recommended. In general, withhold OPDIVO QVANTIG for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue OPDIVO QVANTIG for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for OPDIVO QVANTIG or OPDIVO QVANTIG in combination with other anti-cancer agents for adverse reactions that require management different from these general guidelines are summarized in Table 3 and Table 4. Table 3: Recommended Dosage Modifications for Adverse Reactions a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO QVANTIG based on recommendations for hepatitis with no liver involvement. c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens-Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit of normal Adverse Reaction Severity Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Pneumonitis Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Colitis For colitis in patients treated with combination therapy with ipilimumab, see Table 4. Grade 2 or 3 Withhold a Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy with cabozantinib, see Table 4. AST/ALT increases to >3 and ≤8 times ULN or Total bilirubin increases to >1.5 and ≤3 times ULN. Withhold a AST or ALT increases to >8 times ULN or Total bilirubin increases to >3 times ULN. Permanently discontinue Hepatitis with tumor involvement of the liver b Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN or Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. Withhold a AST/ALT increases to >10 times ULN or Total bilirubin increases to >3 times ULN. Permanently discontinue Endocrinopathies c Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold a Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grades 2, 3, or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with Combination Therapy a Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO QVANTIG is withheld or discontinued when administered in combination with cabozantinib. b After recovery, rechallenge with one or both of OPDIVO QVANTIG and cabozantinib may be considered. If rechallenging with cabozantinib with or without OPDIVO QVANTIG, refer to cabozantinib Prescribing Information. Treatment Adverse Reaction Severity Dosage Modification OPDIVO QVANTIG in combination with cabozantinib Liver enzyme elevations ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN Withhold a both OPDIVO QVANTIG and cabozantinib until adverse reactions recover b to Grades 0-1 ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN Permanently discontinue a both OPDIVO QVANTIG and cabozantinib 2.5 Preparation and Administration To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is OPDIVO QVANTIG for subcutaneous use and NOT intravenous nivolumab. Do NOT administer OPDIVO QVANTIG intravenously. OPDIVO QVANTIG should be administered by a healthcare professional. Each OPDIVO QVANTIG vial is for one-time use only. It is a ready-to-use solution for injection. It should not be diluted. Visually inspect for particulate matter and discoloration prior to administration. OPDIVO QVANTIG is a clear to opalescent, colorless to yellow solution. Discard if the solution is discolored or contains extraneous particulate matter other than a few translucent-to-white particles. Do not shake. Preparation No incompatibilities were observed between OPDIVO QVANTIG and polypropylene and polycarbonate syringes, or between OPDIVO QVANTIG and polyethylene, polyurethane, polyvinyl chloride, and fluorinated ethylene propylene subcutaneous administration sets. A syringe and a transfer needle are needed to withdraw OPDIVO QVANTIG solution from the vial. OPDIVO QVANTIG may be injected subcutaneously using a 23G to 25G (3/8 to 5/8 inch) hypodermic injection needle or subcutaneous administration set (eg., winged/butterfly). Calculate the appropriate number of vials of OPDIVO QVANTIG (300 mg/5,000 units and/or 600 mg/10,000 units) needed based on the prescribed dose. Allow vial(s) to reach room temperature 20°C to 25°C (68°F to 77°F) before withdrawing dose. • 300 mg nivolumab and 5,000 units hyaluronidase ∘ Withdraw 2.5 mL from the 300 mg/5,000 units vial of OPDIVO QVANTIG into the syringe. • 600 mg nivolumab and 10,000 units hyaluronidase ∘ Withdraw 5 mL from the 600 mg/10,000 units vial of OPDIVO QVANTIG into the syringe. • 900 mg nivolumab and 15,000 units hyaluronidase ∘ Withdraw 5 mL from the 600 mg/10,000 units vial and 2.5 mL from the 300 mg/5,000 units vial of OPDIVO QVANTIG into a single syringe for a total volume of 7.5 mL . • 1,200 mg nivolumab and 20,000 units hyaluronidase ∘ Withdraw 5 mL from each vial of 600 mg/10,000 units OPDIVO QVANTIG into a single syringe for a total volume of 10 mL . Select the appropriate syringe label provided in the carton that matches the prescribed dose and apply to the prepared syringe. Discard partially used or empty vials of OPDIVO QVANTIG. If the dose is not to be used immediately, attach a tip cap to the syringe prior to storage. To avoid clogging of the hypodermic injection needle, attach a 23G to 25G (3/8 to 5/8 inch) hypodermic injection needle to the syringe immediately prior to administration. Storage in Syringe Once withdrawn into the syringe, OPDIVO QVANTIG should be used immediately. If not used immediately, store the syringe: • In the refrigerator at 2°C to 8°C (36°F to 46°F), protected from light for up to 72 hours ; do not freeze, or • At room temperature 20°C to 25°C (68°F to 77°F) for up to 8 hours. Storage at room temperature for this duration does not require protection from light. • Discard if storage time exceeds these limits. • If stored in the refrigerator, allow the solution to come to room temperature before administration. Administration • Administer the full contents of the syringe into the subcutaneous tissue of 1 of the 4 quadrants of the abdomen, or thigh over a period of 3 to 5 minutes. • Alternate injection sites across the 4 quadrants of the abdomen or thighs for successive injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If the administration of OPDIVO QVANTIG is interrupted, continue administering at the same site, or at an alternate site. • During treatment with OPDIVO QVANTIG, do not administer other subcutaneous medications at the same site used for OPDIVO QVANTIG.

None. • None. (4)

The following clinically significant adverse reactions are described elsewhere in the labeling. • Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] • Complications of Allogeneic HSCT [see Warnings and Precautions (5.2) ] • Most common adverse reactions (≥10%) with OPDIVO QVANTIG as monotherapy in patients with Renal Cell Carcinoma were: musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain. (6.1) • Safety of OPDIVO QVANTIG for the following indications is based on safety of intravenous nivolumab in these populations. The most common adverse reactions with intravenous nivolumab for these indications are presented below. • As monotherapy for the treatment of advanced renal cell carcinoma; adjuvant treatment of completely resected Stage IIB, IIC, III, or IV melanoma; unresectable or metastatic melanoma; adjuvant treatment of NSCLC, metastatic NSCLC; squamous cell carcinoma of the head and neck; urothelial carcinoma; MSI-H or dMMR mCRC; hepatocellular carcinoma; esophageal cancer: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection. (6.1) • In combination with cabozantinib for the first-line treatment of advanced renal cell carcinoma: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1) • In combination with platinum-doublet chemotherapy for the neoadjuvant treatment of NSCLC: nausea, constipation, fatigue, decreased appetite, and rash. (6.1) • In combination with cisplatin and gemcitabine for the treatment of urothelial cancer: nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. (6.1) • In combination with fluoropyrimidine- and platinum- containing chemotherapy for the treatment of esophageal cancer and gastric cancer: nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO QVANTIG as a single agent in 247 patients enrolled in CHECKMATE-67T, with additional data from intravenous nivolumab single-agent (1994 patients), and from intravenous nivolumab in combination with cabozantinib (320 patients) for select adverse reactions. Advanced Renal Cell Carcinoma CHECKMATE-67T was a multicenter, randomized, open-label study in adult patients with advanced or metastatic RCC. Patients received OPDIVO QVANTIG dose of 1,200 mg of nivolumab and 20,000 units of hyaluronidase subcutaneously every 4 weeks (n=247) or 3 mg/kg of nivolumab intravenously every 2 weeks (n=245). Among patients who received OPDIVO QVANTIG, 52% were exposed for 6 months or longer and 20% were exposed for greater than 1 year. Serious adverse reactions occurred in 28% of patients who received OPDIVO QVANTIG. Serious adverse reactions in >1% of patients included pleural effusion (1.6%), pneumonitis (1.6%), hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). Fatal adverse reactions occurred in 3 patients (1.2%) who received OPDIVO QVANTIG and included myocarditis, myositis, and colitis complications. Permanent discontinuation of OPDIVO QVANTIG due to an adverse reaction occurred in 10% of patients. The most common adverse reaction which resulted in permanent discontinuation was pneumonitis (2%). Dosage interruptions of OPDIVO QVANTIG due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in >2% of patients included COVID-19 (4.5%), increased blood creatinine (2.8%), anemia, diarrhea, and fatigue (2.4% each). The most common adverse reactions (≥10%) were musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain. Tables 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-67T. Table 5: Adverse Reactions* in ≥5% of Adult Patients with RCC Receiving OPDIVO QVANTIG in CHECKMATE-67T * Toxicity was graded per NCI CTCAE v5. a Includes multiple related terms Adverse Reaction OPDIVO QVANTIG (n=247) Intravenous Nivolumab (n=245) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 20 2.4 25 3.3 Injection site reaction a 8 0 0 0 Edema 5 0.4 11 0.8 Musculoskeletal and Connective Tissue Musculoskeletal pain a 31 1.6 39 3.3 Skin and Subcutaneous Tissue Pruritus 16 0.4 21 0 Rash a 15 1.2 13 1.2 Gastrointestinal Diarrhea a 11 0.4 14 0.4 Abdominal pain a 10 0 10 0.4 Nausea 8 0 9 0 Constipation 8 0 6 0 Vomiting 6 0.4 4.9 0 Respiratory, Thoracic, and Mediastinal Cough 11 0 11 0 Endocrine Hypothyroidism a 12 0 17 0 Metabolism and Nutrition Hyperglycemia 9 2.4 13 2.0 Decreased appetite 9 0 11 0.8 Clinically important adverse reactions in <5% of patients who received OPDIVO QVANTIG include: Cardiac: myocarditis Respiratory, thoracic, and mediastinal: pneumonitis, dyspnea Endocrine: adrenal insufficiency, hyperthyroidism, thyroiditis Gastrointestinal: colitis, pancreatitis Hepatobiliary: hepatitis Nervous system: peripheral neuropathy Skin and subcutaneous tissue: psoriasis, erythema Musculoskeletal and connective tissue: arthritis Blood and lymphatic system: eosinophilia Eye disorders: uveitis Immune system: hypersensitivity Table 6: Laboratory Values Worsening from Baseline a (≥20%) in Patients with RCC Receiving OPDIVO QVANTIG in CHECKMATE-67T a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO QVANTIG group (range: 232 to 235 patients) and intravenous nivolumab group (range: 240 to 244 patients). Laboratory Abnormality OPDIVO QVANTIG Intravenous Nivolumab All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Hemoglobin decreased 46 7 48 9 Lymphocytes decreased 36 6 45 9 Chemistry Creatinine increased 38 1.3 43 0.4 Sodium decreased 34 2.6 40 2.5 Potassium increased 34 3.0 45 2.9 Alkaline phosphatase increased 32 2.1 33 2.0 Calcium increased 29 2.1 31 4.1 Albumin decreased 25 1.7 35 0.4 ALT increased 21 1.3 26 4.1 Adverse Reactions in Patients Treated with Intravenous Nivolumab The safety of OPDIVO QVANTIG for its approved indications [see Indications and Usage (1) ] has been established in adequate and well-controlled clinical studies of intravenous nivolumab. Below is a description of adverse reactions in these adequate and well-controlled clinical studies. First-line Renal Cell Carcinoma CHECKMATE-214 The safety of intravenous nivolumab with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC; patients received intravenous nivolumab 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=535) [see Clinical Studies (14.1) ] . The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in intravenous nivolumab and ipilimumab-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the intravenous nivolumab and ipilimumab arm were exposed to treatment for >6 months and 38% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients receiving intravenous nivolumab and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of intravenous nivolumab and ipilimumab patients. Fifty-four percent (54%) of patients receiving intravenous nivolumab and ipilimumab had a dose interruption for an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous nivolumab and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in ≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of intravenous nivolumab and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia. Tables 7 and 8 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of intravenous nivolumab and ipilimumab‑treated patients in CHECKMATE-214. Table 7: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab and Ipilimumab - CHECKMATE-214 Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes peripheral edema, peripheral swelling. c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption. d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. Adverse Reaction Intravenous Nivolumab and Ipilimumab (n=547) Sunitinib (n=535) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Adverse Reaction 99 65 99 76 General Fatigue a 58 8 69 13 Pyrexia 25 0.7 17 0.6 Edema b 16 0.5 17 0.6 Skin and Subcutaneous Tissue Rash c 39 3.7 25 1.1 Pruritus/generalized pruritus 33 0.5 11 0 Gastrointestinal Diarrhea 38 4.6 58 6 Nausea 30 2 43 1.5 Vomiting 20 0.9 28 2.1 Abdominal pain 19 1.6 24 1.9 Constipation 17 0.4 18 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 37 4 40 2.6 Arthralgia 23 1.3 16 0 Respiratory, Thoracic and Mediastinal Cough/productive cough 28 0.2 25 0.4 Dyspnea/exertional dyspnea 20 2.4 21 2.1 Metabolism and Nutrition Decreased appetite 21 1.8 29 0.9 Nervous System Headache 19 0.9 23 0.9 Endocrine Hypothyroidism 18 0.4 27 0.2 Table 8: Laboratory Values Worsening from Baseline a Occurring in >15% of Patients on Intravenous Nivolumab and Ipilimumab - CHECKMATE-214 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and ipilimumab group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients). Laboratory Abnormality Intravenous Nivolumab and Ipilimumab Sunitinib Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased lipase 48 20 51 20 Increased creatinine 42 2.1 46 1.7 Increased ALT 41 7 44 2.7 Increased AST 40 4.8 60 2.1 Increased amylase 39 12 33 7 Hyponatremia 39 10 36 7 Increased alkaline phosphatase 29 2 32 1 Hyperkalemia 29 2.4 28 2.9 Hypocalcemia 21 0.4 35 0.6 Hypomagnesemia 16 0.4 26 1.6 Hematology Anemia 43 3 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 intravenous nivolumab and ipilimumab group compared to the sunitinib group (31% and 61%, respectively). CHECKMATE-9ER The safety of intravenous nivolumab with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received intravenous nivolumab 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320) [see Clinical Studies (14.1) ] . Cabozantinib could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in intravenous nivolumab and cabozantinib-treated patients. In this trial, 82% of patients in the intravenous nivolumab and cabozantinib arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab and cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. Adverse reactions leading to discontinuation of either intravenous nivolumab or cabozantinib occurred in 20% of patients: 7% intravenous nivolumab only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either intravenous nivolumab or cabozantinib occurred in 83% of patients: 3% intravenous nivolumab only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially. The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. Tables 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER. Table 9: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab and Cabozantinib - CHECKMATE-9ER Toxicity was graded per NCI CTCAE v4. a Includes abdominal discomfort, abdominal pain lower, abdominal pain upper. b Includes gastroesophageal reflux disease. c Includes asthenia. d Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure. e Includes mucosal inflammation, aphthous ulcer, mouth ulceration. f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic. g Includes blood pressure increased, blood pressure systolic increased. h Includes primary hypothyroidism. i Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. j Includes productive cough. k Includes nasopharyngitis, pharyngitis, rhinitis. Adverse Reaction Intravenous Nivolumab and Cabozantinib (n=320) Sunitinib (n=320) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Diarrhea 64 7 47 4.4 Nausea 27 0.6 31 0.3 Abdominal pain a 22 1.9 15 0.3 Vomiting 17 1.9 21 0.3 Dyspepsia b 15 0 22 0.3 General Fatigue c 51 8 50 8 Hepatobiliary Hepatotoxicity d 44 11 26 5 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 40 8 41 8 Stomatitis e 37 3.4 46 4.4 Rash f 36 3.1 14 0 Pruritus 19 0.3 4.4 0 Vascular Hypertension g 36 13 39 14 Endocrine Hypothyroidism h 34 0.3 30 0.3 Musculoskeletal and Connective Tissue Musculoskeletal pain i 33 3.8 29 3.1 Arthralgia 18 0.3 9 0.3 Metabolism and Nutrition Decreased appetite 28 1.9 20 1.3 Nervous System Dysgeusia 24 0 22 0 Headache 16 0 12 0.6 Respiratory, Thoracic and Mediastinal Cough j 20 0.3 17 0 Dysphonia 17 0.3 3.4 0 Infections and Infestations Upper respiratory tract infection k 20 0.3 8 0.3 Table 10: Laboratory Values Worsening from Baseline a Occurring in >20% of Patients on Intravenous Nivolumab and Cabozantinib - CHECKMATE-9ER a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and cabozantinib group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients). Laboratory Abnormality Intravenous Nivolumab and Cabozantinib Sunitinib Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased ALT 79 9.8 39 3.5 Increased AST 77 7.9 57 2.6 Hypophosphatemia 69 28 48 10 Hypocalcemia 54 1.9 24 0.6 Hypomagnesemia 47 1.3 25 0.3 Hyperglycemia 44 3.5 44 1.7 Hyponatremia 43 11 36 12 Increased lipase 41 14 38 13 Increased amylase 41 10 28 6 Increased alkaline phosphatase 41 2.8 37 1.6 Increased creatinine 39 1.3 42 0.6 Hyperkalemia 35 4.7 27 1 Hypoglycemia 26 0.8 14 0.4 Hematology Lymphopenia 42 6.6 45 10 Thrombocytopenia 41 0.3 70 9.7 Anemia 37 2.5 61 4.8 Leukopenia 37 0.3 66 5.1 Neutropenia 35 3.2 67 12 Previously Treated Renal Cell Carcinoma CHECKMATE-025 The safety of intravenous nivolumab was evaluated in CHECKMATE-025, a randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received intravenous nivolumab 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.1) ] . The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in intravenous nivolumab-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients. Rate of death on treatment or within 30 days of the last dose was 4.7% on the intravenous nivolumab arm. Serious adverse reactions occurred in 47% of patients receiving intravenous nivolumab. Study therapy was discontinued for adverse reactions in 16% of intravenous nivolumab patients. Forty-four percent (44%) of patients receiving intravenous nivolumab had a dose interruption for an adverse reaction. The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the intravenous nivolumab group compared to the everolimus group (26% and 14%, respectively). Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025. Table 11: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab - CHECKMATE-025 Toxicity was graded per NCI CTCAE v4. a Includes asthenia, decreased activity, fatigue, and malaise. b Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI). c Includes colitis, enterocolitis, and gastroenteritis. d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema. Adverse Reaction Intravenous Nivolumab (n=406) Everolimus (n=397) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Adverse Reaction 98 56 96 62 General Fatigue a 56 6 57 7 Pyrexia 17 0.7 20 0.8 Respiratory, Thoracic and Mediastinal Cough/productive cough 34 0 38 0.5 Dyspnea/exertional dyspnea 27 3 31 2 Upper respiratory infection b 18 0 11 0 Gastrointestinal Nausea 28 0.5 29 1 Diarrhea c 25 2.2 32 1.8 Constipation 23 0.5 18 0.5 Vomiting 16 0.5 16 0.5 Skin and Subcutaneous Tissue Rash d 28 1.5 36 1 Pruritus/generalized pruritus 19 0 14 0 Metabolism and Nutrition Decreased appetite 23 1.2 30 1.5 Musculoskeletal and Connective Tissue Arthralgia 20 1 14 0.5 Back pain 21 3.4 16 2.8 Other clinically important adverse reactions in CHECKMATE-025 were: General Disorders and Administration Site Conditions: peripheral edema/edema Gastrointestinal Disorders: abdominal pain/discomfort Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain Nervous System Disorders: headache/migraine, peripheral neuropathy Investigations: weight decreased Skin Disorders: palmar-plantar erythrodysesthesia Table 12: Laboratory Values Worsening from Baseline a Occurring in >15% of Patients on Intravenous Nivolumab - CHECKMATE-025 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients). Laboratory Abnormality Intravenous Nivolumab Everolimus Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Lymphopenia 42 6 53 11 Anemia 39 8 69 16 Chemistry Increased creatinine 42 2 45 1.6 Increased AST 33 2.8 39 1.6 Increased alkaline phosphatase 32 2.3 32 0.8 Hyponatremia 32 7 26 6 Hyperkalemia 30 4 20 2.1 Hypocalcemia 23 0.9 26 1.3 Increased ALT 22 3.2 31 0.8 Hypercalcemia 19 3.2 6 0.3 Lipids Increased triglycerides 32 1.5 67 11 Increased cholesterol 21 0.3 55 1.4 Unresectable or Metastatic Melanoma Previously Treated Metastatic Melanoma CHECKMATE-037 The safety of intravenous nivolumab was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.2) ] . Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m 2 intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m 2 intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in intravenous nivolumab‑treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received intravenous nivolumab for >6 months and 3% of patients received intravenous nivolumab for >1 year. The population characteristics in the intravenous nivolumab group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the intravenous nivolumab group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%). Serious adverse reactions occurred in 41% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving intravenous nivolumab had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving intravenous nivolumab. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving intravenous nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of patients) was rash. Tables 13 and 14 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037. Table 13: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037 Toxicity was graded per NCI CTCAE v4. a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis. b Includes rhinitis, pharyngitis, and nasopharyngitis. Adverse Reaction Intravenous Nivolumab (n=268) Chemotherapy (n=102) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 21 0.4 7 0 Pruritus 19 0 3.9 0 Respiratory, Thoracic and Mediastinal Cough 17 0 6 0 Infections Upper respiratory tract infection b 11 0 2 0 General Peripheral edema 10 0 5 0 Clinically important adverse reactions in <10% of patients who received intravenous nivolumab were: Cardiac Disorders: ventricular arrhythmia Eye Disorders: iridocyclitis General Disorders and Administration Site Conditions: infusion-related reactions Investigations: increased amylase, increased lipase Nervous System Disorders: dizziness, peripheral and sensory neuropathy Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis Table 14: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients). Laboratory Abnormality Intravenous Nivolumab Chemotherapy All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Increased AST 28 2.4 12 1 Hyponatremia 25 5 18 1.1 Increased alkaline phosphatase 22 2.4 13 1.1 Increased ALT 16 1.6 5 0 Hyperkalemia 15 2 6 0 Previously Untreated Metastatic Melanoma CHECKMATE-066 The safety of intravenous nivolumab was also evaluated in CHECKMATE-066, a randomized, double-blind, active‑controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.2) ] . The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206) or dacarbazine 1000 mg/m 2 intravenously every 3 weeks (n=205). The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in intravenous nivolumab-treated patients. In this trial, 47% of patients received intravenous nivolumab for >6 months and 12% of patients received intravenous nivolumab for >1 year. The trial population characteristics in the intravenous nivolumab group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the intravenous nivolumab group with ECOG performance status 0 (71% vs. 59%). Serious adverse reactions occurred in 36% of patients receiving intravenous nivolumab. Adverse reactions led to permanent discontinuation of intravenous nivolumab in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of intravenous nivolumab discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving intravenous nivolumab. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus. Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066. Table 15: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066 Toxicity was graded per NCI CTCAE v4. a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema. b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain. c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and skin reaction. d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis. Adverse Reaction Intravenous Nivolumab (n=206) Dacarbazine (n=205) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue 49 1.9 39 3.4 Edema a 12 1.5 4.9 0 Musculoskeletal and Connective Tissue Musculoskeletal pain b 32 2.9 25 2.4 Skin and Subcutaneous Tissue Rash c 28 1.5 12 0 Pruritus 23 0.5 12 0 Vitiligo 11 0 0.5 0 Erythema 10 0 2.9 0 Infections Upper respiratory tract infection d 17 0 6 0 Clinically important adverse reactions in <10% of patients who received intravenous nivolumab were: Nervous System Disorders: peripheral neuropathy Table 16: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients). Laboratory Abnormality Intravenous Nivolumab Dacarbazine All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Increased ALT 25 3 19 0.5 Increased AST 24 3.6 19 0.5 Increased alkaline phosphatase 21 2.6 14 1.6 Increased bilirubin 13 3.1 6 0 CHECKMATE-067 The safety of intravenous nivolumab, administered with ipilimumab 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 (14.2) ] . The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV. Patients were randomized to receive: • Intravenous nivolumab 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (nivolumab and ipilimumab arm; n=313), or • Intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (nivolumab arm; n=313), or • Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab arm; n=311). The median duration of exposure to intravenous nivolumab was 2.8 months (range: 1 day to 36.4 months) for the intravenous nivolumab and ipilimumab arm and 6.6 months (range: 1 day to 36.0 months) for the intravenous nivolumab arm. In the intravenous nivolumab and ipilimumab arm, 39% were exposed to intravenous nivolumab for ≥6 months and 30% exposed for >1 year. In the intravenous nivolumab arm, 53% were exposed for ≥6 months and 40% for >1 year. The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC) Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy. Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the intravenous nivolumab and ipilimumab arm relative to the intravenous nivolumab arm. The most frequent (≥10%) serious adverse reactions in the intravenous nivolumab and ipilimumab arm and the intravenous nivolumab arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1%). The most frequent adverse reactions leading to discontinuation of both drugs in the intravenous nivolumab and ipilimumab arm and of intravenous nivolumab in the intravenous nivolumab arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%). The most common (≥20%) adverse reactions in the intravenous nivolumab and ipilimumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. The most common (≥20%) adverse reactions in the intravenous nivolumab arm were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract infection, decreased appetite, headache, constipation, arthralgia, and vomiting. Tables 17 and 18 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067. Table 17: Adverse Reactions Occurring in ≥10% of Patients on the Intravenous Nivolumab and Ipilimumab Arm or the Intravenous Nivolumab Arm and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067 Toxicity was graded per NCI CTCAE v4. a Includes asthenia and fatigue. b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash. c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. e Includes hypertension and blood pressure increased. Adverse Reaction Intravenous Nivolumab and Ipilimumab (n=313) Intravenous Nivolumab (n=313) Ipilimumab (n=311) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 62 7 59 1.6 51 4.2 Pyrexia 40 1.6 16 0 18 0.6 Gastrointestinal Diarrhea 54 11 36 5 47 7 Nausea 44 3.8 30 0.6 31 1.9 Vomiting 31 3.8 20 1 17 1.6 Skin and Subcutaneous Tissue Rash b 53 6 40 1.9 42 3.5 Vitiligo 9 0 10 0.3 5 0 Musculoskeletal and Connective Tissue Musculoskeletal pain c 32 2.6 42 3.8 36 1.9 Arthralgia 21 0.3 21 1 16 0.3 Metabolism and Nutrition Decreased appetite 29 1.9 22 0 24 1.3 Respiratory, Thoracic and Mediastinal Cough/productive cough 27 0.3 28 0.6 22 0 Dyspnea/exertional dyspnea 24 2.9 18 1.3 17 0.6 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 2.2 11 5 9 2.3 Clinically important adverse reactions in <10% of patients who received intravenous nivolumab with ipilimumab or intravenous nivolumab as a single agent were: Gastrointestinal Disorders: stomatitis, intestinal perforation Skin and Subcutaneous Tissue Disorders: vitiligo Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis) Nervous System Disorders: neuritis, peroneal nerve palsy Table 18: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥20% of Patients Treated with Intravenous Nivolumab with Ipilimumab or Single-Agent Intravenous Nivolumab and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and ipilimumab (range: 75 to 297); intravenous nivolumab (range: 81 to 306); ipilimumab (range: 61 to 301). Laboratory Abnormality Intravenous Nivolumab and Ipilimumab Intravenous Nivolumab Ipilimumab All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Increased ALT 55 16 25 3 29 2.7 Hyperglycemia 53 5.3 46 7 26 0 Increased AST 52 13 29 3.7 29 1.7 Hyponatremia 45 10 22 3.3 26 7 Increased lipase 43 22 32 12 24 7 Increased alkaline phosphatase 41 6 27 2 23 2 Hypocalcemia 31 1.1 15 0.7 20 0.7 Increased amylase 27 10 19 2.7 15 1.6 Increased creatinine 26 2.7 19 0.7 17 1.3 Hematology Anemia 52 2.7 41 2.6 41 6 Lymphopenia 39 5 41 4.9 29 4 Adjuvant Treatment of Melanoma CHECKMATE-76K The safety of intravenous nivolumab as a single agent was evaluated in CHECKMATE-76K, a randomized (2:1), double-blind trial in 788 patients with completely resected Stage IIB/C melanoma who received intravenous nivolumab 480 mg by intravenous infusion over 30 minutes every 4 weeks (n=524) or placebo by intravenous infusion over 30 minutes every 4 weeks (n=264) for up to 1 year [see Clinical Studies (14.3) ] . The median duration of exposure was 11 months in patients treated with intravenous nivolumab and 11 months in patients treated with placebo. Serious adverse reactions occurred in 18% of patients treated with intravenous nivolumab. A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). Permanent discontinuation of intravenous nivolumab due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of intravenous nivolumab in >1% of patients included diarrhea (1.1%), arthralgia (1.7%), and rash (1.7%). Dosage interruptions of intravenous nivolumab due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dosage interruption in >1% of patients included COVID-19 infection, infusion related reaction, diarrhea, arthralgia, and increased ALT. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, rash, diarrhea, and pruritus. Tables 19 and 20 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-76K. Table 19: Adverse Reactions Occurring in ≥10% of Patients Treated with Intravenous Nivolumab - CHECKMATE-76K Toxicity was graded per NCI CTCAE v5. a Includes asthenia. b Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, spinal pain, pain in extremity. c Includes dermatitis, dermatitis acneiform, dyshidrotic eczema, eczema, eczema asteatotic, eyelid rash, genital rash, pemphigoid, penile rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, toxic skin eruption. d Includes autoimmune colitis, colitis, diarrhea, enteritis, enterocolitis e Includes autoimmune hypothyroidism, blood thyroid stimulating hormone increased. f Includes cluster headache, migraine. Adverse Reaction Intravenous Nivolumab (n=524) Placebo (n=264) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 36 0.4 34 0.4 Musculoskeletal and connective tissue Musculoskeletal pain b 30 0.4 26 0.4 Skin and Subcutaneous Tissue Rash c 28 1.1 15 0.4 Pruritus 20 0.2 11 0 Gastrointestinal Diarrhea d 23 1.3 16 0 Nausea 14 0 11 0 Endocrine Hypothyroidism e 14 0 2.3 0 Nervous system Headache f 12 0.2 14 0.8 Table 20: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients - CHECKMATE-76K a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 262 to 513 patients) and placebo group (range: 138 to 261 patients). Laboratory Abnormality Intravenous Nivolumab (n=524) Placebo (n=264) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Anemia 19 0 14 0 Lymphopenia 17 1.1 17 1.7 Neutropenia 10 0 10 0.4 Chemistry AST increased 25 2.2 16 0.4 Lipase increased 22 2.9 21 2.3 ALT increased 20 2.1 15 0.4 Amylase increased 17 0.4 9 0 Creatinine increased 15 0.4 13 0 Sodium decreased 13 0.6 11 0.4 Potassium increased 13 1 15 1.1 CHECKMATE-238 The safety of intravenous nivolumab as a single agent was evaluated in CHECKMATE-238, a randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year (n=453) [see Clinical Studies (14.3) ] . The median duration of exposure was 11.5 months in intravenous nivolumab‑treated patients and was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received intravenous nivolumab for >6 months. Serious adverse reactions occurred in 18% of intravenous nivolumab-treated patients. Study therapy was discontinued for adverse reactions in 9% of intravenous nivolumab-treated patients and 42% of ipilimumab-treated patients. Twenty-eight percent of intravenous nivolumab-treated patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions occurred in 25% of intravenous nivolumab-treated patients. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of intravenous nivolumab-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). Tables 21 and 22 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238. Table 21: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-Treated Patients - CHECKMATE-238 Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness. c Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized, erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption. d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity. e Includes postural dizziness and vertigo. f Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis. g Includes secondary hypothyroidism and autoimmune hypothyroidism. Adverse Reaction Intravenous Nivolumab (n=452) Ipilimumab 10 mg/kg (n=453) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 57 0.9 55 2.4 Gastrointestinal Diarrhea 37 2.4 55 11 Nausea 23 0.2 28 0 Abdominal pain b 21 0.2 23 0.9 Constipation 10 0 9 0 Skin and Subcutaneous Tissue Rash c 35 1.1 47 5.3 Pruritus 28 0 37 1.1 Musculoskeletal and Connective Tissue Musculoskeletal pain d 32 0.4 27 0.4 Arthralgia 19 0.4 13 0.4 Nervous System Headache 23 0.4 31 2.0 Dizziness e 11 0 8 0 Infections Upper respiratory tract infection f 22 0 15 0.2 Respiratory, Thoracic and Mediastinal Cough/productive cough 19 0 19 0 Dyspnea/exertional dyspnea 10 0.4 10 0.2 Endocrine Hypothyroidism g 12 0.2 7.5 0.4 Table 22: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients - CHECKMATE-238 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 400 to 447 patients) and ipilimumab 10 mg/kg group (range: 392 to 443 patients). Laboratory Abnormality Intravenous Nivolumab Ipilimumab 10 mg/kg All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Lymphopenia 27 0.4 12 0.9 Anemia 26 0 34 0.5 Leukopenia 14 0 2.7 0.2 Neutropenia 13 0 6 0.5 Chemistry Increased Lipase 25 7 23 9 Increased ALT 25 1.8 40 12 Increased AST 24 1.3 33 9 Increased Amylase 17 3.3 13 3.1 Hyponatremia 16 1.1 22 3.2 Hyperkalemia 12 0.2 9 0.5 Increased Creatinine 12 0 13 0 Hypocalcemia 10 0.7 16 0.5 Non-Small Cell Lung Cancer Neoadjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell Lung Cancer CHECKMATE-816 The safety of intravenous nivolumab in combination with platinum-doublet chemotherapy was evaluated in CHECKMATE-816, a randomized, open-label, multicenter trial in patients with resectable NSCLC [see Clinical Studies (14.4) ] . Patients received either intravenous nivolumab 360 mg administered in combination with platinum-doublet chemotherapy administered every 3 weeks for 3 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 3 cycles. The median age of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 – 84); 72% male; 47% White, 50% Asian, and 2% Black/African American. Serious adverse reactions occurred in 30% of patients who were treated with intravenous nivolumab in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy. Study therapy with intravenous nivolumab in combination with platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one treatment withheld for an adverse reaction. The most common adverse reactions (≥1%) resulting in permanent discontinuation of intravenous nivolumab in combination with platinum-doublet chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and fatigue (1.1%). The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased appetite, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were neutropenia, hyperglycemia, leukopenia, lymphopenia, increased amylase, anemia, thrombocytopenia, and hyponatremia. Tables 23 and 24 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-816. Table 23: Adverse Reactions in >10% of Patients with Early-Stage NSCLC Receiving Neoadjuvant Intravenous Nivolumab and Platinum-Doublet Chemotherapy in CHECKMATE-816 Toxicity was graded per NCI CTCAE v4. a Includes fatigue and asthenia. b Includes rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, drug eruption, maculopapular rash, and pruritic rash. c Includes peripheral neuropathy, dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensory neuropathy. Adverse Reaction Intravenous Nivolumab and Platinum-Doublet Chemotherapy (n=176) Platinum-Doublet Chemotherapy (n=176) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Gastrointestinal Nausea 38 0.6 45 1.1 Constipation 34 0 32 1.1 Vomiting 11 1.1 13 0.6 General Fatigue a 26 2.3 23 1.1 Malaise 15 0.6 14 0.6 Metabolism and Nutrition Decreased appetite 20 1.1 23 2.3 Skin and Subcutaneous Tissue Rash b 20 2.3 7 0 Alopecia 11 0 15 0 Nervous System Peripheral neuropathy c 13 0 6 0 Table 24: Select Laboratory Values Worsening from Baseline a Occurring in >20% of Patients with Early-Stage NSCLC Receiving Neoadjuvant Intravenous Nivolumab and Platinum-Doublet Chemotherapy in CHECKMATE-816 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and platinum-doublet chemotherapy group (range: 73 to 171 patients) and platinum-doublet chemotherapy group (range: 68 to 171 patients). Laboratory Abnormality Intravenous Nivolumab and Platinum-Doublet Chemotherapy a Platinum-Doublet Chemotherapy a All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Hematology Anemia 63 3.5 70 6 Neutropenia 58 22 58 27 Leukopenia 53 5 51 11 Lymphopenia 38 4.7 31 1.8 Thrombocytopenia 24 2.9 22 3 Chemistry Hyperglycemia 37 6 35 2.9 Hypomagnesemia 25 1.2 29 1.2 Hyponatremia 25 2.4 28 1.8 Increased amylase 23 3.6 13 1.8 Increased ALT 23 0 20 1.2 Neoadjuvant and Adjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell Lung Cancer CHECKMATE-77T The safety of intravenous nivolumab in combination with neoadjuvant platinum-doublet chemotherapy followed by surgery and continued adjuvant treatment with intravenous nivolumab as a single agent after surgery was evaluated in CHECKMATE-77T, a randomized, double-blind, multicenter trial in patients with previously untreated resectable Stage IIA (>4 cm) to IIIB (T3N2 or T4N2) NSCLC (per the AJCC Cancer Staging Manual 8th Edition) [see Clinical Studies (14.5) ] . Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. The median duration of exposure to intravenous nivolumab was 10.3 months (range: 1 day to 22.3 months). The study population characteristics were: median age 66 years (range: 35 - 86); 71% male; 72% White, 25% Asian, 1.7% Black/African American, and 1.5% other race; and 6% Hispanic or Latino. Adverse reactions occurring in patients with resectable NSCLC receiving intravenous nivolumab in combination with platinum-doublet chemotherapy, given as neoadjuvant treatment and followed as a single agent adjuvant treatment after surgery, were generally similar to those occurring in patients in other clinical trials across tumor types receiving intravenous nivolumab in combination with chemotherapy. Neoadjuvant Phase of CHECKMATE-77T A total of 228 patients received at least 1 dose of intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment and 230 patients received at least 1 dose of placebo in combination with platinum-doublet chemotherapy as neoadjuvant treatment. Serious adverse reactions occurred in 21% of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent (≥2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis (0.4% each). Permanent discontinuation of any study drug due to an adverse reaction occurred in 13% of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent (≥1%) adverse reaction that led to permanent discontinuation of any study drug was peripheral sensory neuropathy (2.2%). Of the 228 intravenous nivolumab-treated patients and 230 placebo-treated patients who received neoadjuvant treatment, 5.3% (n=12) and 3.5% (n=8), respectively, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in intravenous nivolumab-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2 patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19, and myositis (1 patient each). Of the 178 intravenous nivolumab-treated patients who received surgery, 4.5% (n=8) experienced delay of surgery (surgery more than 6 weeks from last neoadjuvant treatment) due to adverse reactions. Of the 178 placebo-treated patients who received surgery, 3.9% (n=7) experienced delay of surgery due to adverse reactions. Of the 178 intravenous nivolumab-treated patients who received surgery, 7% (n=13) did not receive adjuvant treatment due to adverse reactions. Of the 178 placebo-treated patients who received surgery, 2.8% (n=5) did not receive adjuvant treatment due to adverse reactions. Adjuvant Phase of CHECKMATE-77T A total of 142 patients in the intravenous nivolumab arm and 152 patients in the placebo arm received at least 1 dose of adjuvant treatment. Of the patients who received single agent intravenous nivolumab as adjuvant treatment, 22% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. Permanent discontinuation of adjuvant intravenous nivolumab due to an adverse reaction occurred in 14% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant intravenous nivolumab were pneumonitis (4.2%) and diarrhea (1.4%). Second-line Treatment of Metastatic NSCLC CHECKMATE-017 and CHECKMATE-057 The safety of intravenous nivolumab was evaluated in CHECKMATE-017, a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies (14.6) ] . These trials excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received intravenous nivolumab 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks or docetaxel 75 mg/m 2 intravenously every 3 weeks. The median duration of therapy in intravenous nivolumab-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to 21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In CHECKMATE-017, 36% of patients received intravenous nivolumab for at least 6 months and 18% of patients received intravenous nivolumab for at least 1 year and in CHECKMATE-057, 30% of patients received intravenous nivolumab for >6 months and 20% of patients received intravenous nivolumab for >1 year. Across both trials, the median age of intravenous nivolumab-treated patients was 61 years (range: 37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were White. Ten percent of patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%). In CHECKMATE-057, in the intravenous nivolumab arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued in 11% of patients and was delayed in 28% of patients for an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions (≥20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. Tables 25 and 26 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057. Table 25: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-017 and CHECKMATE-057 Toxicity was graded per NCI CTCAE v4. Adverse Reaction Intravenous Nivolumab (n=418) Docetaxel (n=397) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Respiratory, Thoracic and Mediastinal Cough 31 0.7 24 0 Metabolism and Nutrition Decreased appetite 28 1.4 23 1.5 Skin and Subcutaneous Tissue Pruritus 10 0.2 2 0 Other clinically important adverse reactions observed in intravenous nivolumab-treated patients and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades). Table 26: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients for all NCI CTCAE Grades and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-017 and CHECKMATE-057 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients), except for TSH: intravenous nivolumab group n=314 and docetaxel group n=297. b Not graded per NCI CTCAE v4. Laboratory Abnormality Intravenous Nivolumab Docetaxel All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Hyponatremia 35 7 34 4.9 Increased AST 27 1.9 13 0.8 Increased alkaline phosphatase 26 0.7 18 0.8 Increased ALT 22 1.7 17 0.5 Increased creatinine 18 0 12 0.5 Increased TSH b 14 N/A 6 N/A Squamous Cell Carcinoma of the Head and Neck CHECKMATE-141 The safety of intravenous nivolumab was evaluated in CHECKMATE-141, a randomized, active-controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with progression during or within 6 months of receiving prior platinum-based therapy [see Clinical Studies (14.7) ] . The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma). Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either cetuximab (400 mg/m 2 initial dose intravenously followed by 250 mg/m 2 weekly), or methotrexate (40 to 60 mg/m 2 intravenously weekly), or docetaxel (30 to 40 mg/m 2 intravenously weekly). The median duration of exposure to nivolumab was 1.9 months (range: 1 day to 16.1+ months) in intravenous nivolumab-treated patients. In this trial, 18% of patients received intravenous nivolumab for >6 months and 2.5% of patients received intravenous nivolumab for >1 year. The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the intravenous nivolumab group were ≥65 years of age and 37% in the comparator group were ≥65 years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and 90% had prior radiation therapy. Serious adverse reactions occurred in 49% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC. The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in ≥10% of intravenous nivolumab-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea. The most common laboratory abnormalities occurring in ≥10% of intravenous nivolumab-treated patients and at a higher incidence than investigator’s choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH. Urothelial Carcinoma Adjuvant Treatment of Urothelial Carcinoma (UC) CHECKMATE-274 The safety of intravenous nivolumab was evaluated in CHECKMATE-274, a randomized, double‑blind, multicenter trial of adjuvant intravenous nivolumab versus placebo in adult patients who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal pelvis or ureter) and were at high risk of recurrence [see Clinical Studies (14.8) ] . Patients received intravenous nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=351) or placebo (n=348) until recurrence or unacceptable toxicity for a maximum of 1 year. The median duration of intravenous nivolumab treatment was 8.8 months (range: 0 to 12.5). Serious adverse reactions occurred in 30% of intravenous nivolumab patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). Intravenous nivolumab was discontinued for adverse reactions in 18% of patients. Intravenous nivolumab was delayed for adverse reaction in 33% of patients. The most common adverse reactions (reported in ≥20% of patients) were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection. Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-274. Table 27: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-274 Toxicity was graded per NCI CTCAE v4. a Includes acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis contact, eczema, eczema asteatotic, eczema nummular, erythema, erythema multiforme, lichen sclerosus, lichenoid keratosis, pemphigoid, photosensitivity reaction, pigmentation disorder, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rosacea, skin exfoliation, skin lesion, skin reaction, toxic skin eruption, and urticaria. b Includes colitis, colitis microscopic, diarrhea, duodenitis, enteritis, immune-mediated enterocolitis. c Includes abdominal pain, abdominal discomfort, abdominal tenderness, lower and upper abdominal pain. d Includes musculoskeletal pain, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain. e Includes cystitis, escherichia urinary tract infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, urethritis, urinary tract infection, urinary tract infection bacterial, urinary tract infection staphylococcal, and urosepsis. f Includes upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis. g Includes acute kidney injury, autoimmune nephritis, blood creatinine increased, glomerular filtration rate decreased, immune-mediated nephritis, nephritis, renal failure, and renal impairment. h Includes cough, productive cough, and upper-airway cough syndrome. i Includes dyspnea and exertional dyspnea. j Includes dizziness, postural dizziness and vertigo. k Includes aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, cholangitis, drug-induced liver injury, hepatic failure, hepatic function abnormal, hepatitis, hepatocellular injury, hyperbilirubinemia, gamma-glutamyl transferase increased, liver injury, and transaminases increased. Adverse Reaction Intravenous Nivolumab (n=351) Placebo (n=348) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 36 1.7 19 0.3 Pruritus 30 0 16 0 General Fatigue/Asthenia 36 1.1 32 0.3 Pyrexia 10 0.3 10 0.3 Gastrointestinal Diarrhea b 30 2.8 27 1.7 Nausea 16 0.6 13 0 Abdominal pain c 15 0.9 15 0.6 Constipation 13 0.3 15 0.3 Musculoskeletal and Connective Tissue Musculoskeletal pain d 28 0.6 24 0.9 Arthralgia 11 0.3 13 0 Infections Urinary tract infection e 22 6 23 9 Upper respiratory tract infection f 16 0.3 16 0.6 Endocrine Hyperthyroidism 11 0 1.1 0 Hypothyroidism 11 0 2.3 0 Renal and Urinary Disorders Renal dysfunction g 17 1.7 16 0.9 Respiratory, Thoracic and Mediastinal Cough h 14 0 11 0 Dyspnea i 11 0.3 6 0.3 Metabolism and Nutrition Decreased appetite 13 0.9 7 0.3 Nervous System Disorders Dizziness j 11 0.3 9 0 Hepatobiliary Hepatitis k 11 4 8 0.6 Table 28: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-274 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 322 to 348 patients) and placebo group (range: 312 to 341 patients). Laboratory Abnormality Intravenous Nivolumab (n=351) Placebo (n=348) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Increased creatinine 36 1.7 36 2.6 Increased amylase 34 8 23 3.2 Increased lipase 33 12 31 10 Hyperkalemia 32 5 30 6 Increased alkaline phosphatase 24 2.3 15 0.6 Increased AST 24 3.5 16 0.9 Increased ALT 23 2.9 15 0.6 Hyponatremia 22 4.1 17 1.8 Hypocalcemia 17 1.2 11 0.9 Hypomagnesemia 16 0 9 0 Hypercalcemia 12 0.3 8 0.3 Hematology Lymphopenia 33 2.9 27 1.5 Anemia 30 1.4 28 0.9 Neutropenia 11 0.6 10 0.3 First-line Treatment of Unresectable or Metastatic UC CHECKMATE-901 The safety of intravenous nivolumab was evaluated in CHECKMATE-901, a randomized, open-label trial in cisplatin-eligible patients with unresectable or metastatic UC [see Clinical Studies (14.8) ] . Patients received either intravenous nivolumab 360 mg with cisplatin and gemcitabine every 3 weeks for up to 6 cycles followed by single-agent intravenous nivolumab 480 mg every 4 weeks up to 2 years (n=304), or cisplatin and gemcitabine chemotherapy every 3 weeks for up to 6 cycles (n=288). Patients discontinuing cisplatin alone were permitted to switch to carboplatin. Among patients who received intravenous nivolumab with chemotherapy, the median duration of intravenous nivolumab exposure was 7.4 months (range: 0.03 to 47.9 months). Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab in combination with chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). The most common adverse reactions (reported in ≥20% of patients) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. Fatal adverse reactions occurred in 3.6% of patients who received intravenous nivolumab in combination with chemotherapy; these included sepsis (1%). Intravenous nivolumab and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction. Tables 29 and 30 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-901. Table 29: Adverse Reactions Occurring in ≥10% of Treated Patients - CHECKMATE-901 Toxicity was graded per NCI CTCAE v4. a Includes colitis, immune-mediated enterocolitis. b Includes upper abdominal pain, lower abdominal pain, abdominal discomfort, epigastric discomfort, gastrointestinal pain, and hepatic pain. c Includes asthenia. d Includes peripheral edema, swelling, peripheral swelling, localized edema, swelling, face edema, testicular edema, gravitational edema, and edema genital. e Includes hyperthermia, body temperature increased and hyperpyrexia. f Includes back pain, arthralgia, bone pain, arthritis, musculoskeletal chest pain, non-cardiac chest pain, myalgia, neck pain, pain in extremity, and spinal pain. g Includes maculopapular rash, erythematous rash, macular rash, papular rash, pustular rash, acneiform dermatitis, dermatitis, allergic dermatitis, atopic dermatitis, exfoliative rash, eczema asteatotic, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, eczema, dermatitis exfoliative generalized, and skin exfoliation. h Includes paresthesia, peripheral sensory neuropathy, hypoesthesia, dysesthesia, neuralgia, hyperesthesia, peripheral motor neuropathy, polyneuropathy. i Includes occipital neuralgia. j Includes urosepsis, cystitis, pyelonephritis, pyelonephritis acute, urinary tract infection enterococcal, escherichia urinary tract infection. k Includes blood stimulating hormone increased. l Includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, anuria, azotemia. Adverse Reaction Intravenous Nivolumab and Platinum-Doublet Chemotherapy (n=304) Platinum-Doublet Chemotherapy (n=288) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal disorders Nausea 52 0.3 53 1 Constipation 30 0 28 0.7 Vomiting 23 1.3 19 2.1 Diarrhea a 19 2 14 0 Abdominal pain b 14 0.3 9 0.3 General Fatigue c 48 3.9 43 4.2 Edema d 18 0 9 0.3 Pyrexia e 14 1 14 0 Musculoskeletal and Connective Tissue Musculoskeletal pain f 33 3 21 0.3 Metabolism and Nutrition Decreased appetite 30 1.6 19 1 Skin and Subcutaneous Tissue Rash g 25 2.3 7 0.3 Pruritus 17 0.7 3.5 0 Nervous System Disorders Peripheral neuropathy h 20 0.7 14 0 Headache i 11 0 5 0 Infections Urinary tract infection j 19 8 18 8 Endocrine disorders Hypothyroidism k 17 0 0.3 0 Renal and Urinary Disorders Renal dysfunction l 14 6 11 1.7 Hematuria 11 1 7 1.4 Investigations Weight decreased 11 0.3 6 0 Table 30: Selected Laboratory Abnormalities Worsening from Baseline a Occurring in ≥20% of Patients - CHECKMATE-901 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 289-301 patients) and chemotherapy group (range: 265-281 patients). Laboratory Abnormality Intravenous Nivolumab and Platinum-Doublet Chemotherapy (n=304) Platinum-Doublet Chemotherapy (n=288) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Anemia 88 21 80 21 Neutropenia 82 35 76 28 Lymphopenia 71 17 56 13 Thrombocytopenia 60 13 51 8 Chemistry Increased creatinine 53 2.4 42 1.1 Hypomagnesemia 48 3.8 39 1.5 Hyponatremia 43 13 39 8 Hyperglycemia 41 3.9 37 3.2 Hypocalcemia 36 2.1 24 1.1 Hyperkalemia 33 3.0 32 1.1 Increased amylase 32 4.2 23 3.6 Increased AST 31 2.4 17 0.7 Increased ALT 29 2.4 19 0.7 Previously Treated Advanced or Metastatic UC CHECKMATE-275 The safety of intravenous nivolumab was evaluated in CHECKMATE-275, a single arm trial in which 270 patients with locally advanced or metastatic UC had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies (14.8) ] . Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a dose interruption for an adverse reaction. Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with intravenous nivolumab. Serious adverse reactions occurred in 54% of patients. Intravenous nivolumab was discontinued for adverse reactions in 17% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite. Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275. Table 31: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-275 Toxicity was graded per NCI CTCAE v4. a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain. b Includes abdominal discomfort, lower and upper abdominal pain. c Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular, maculopapular, or pruritic. d Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism, hypothyroidism, thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased, tri-iodothyronine increased. Adverse Reaction Intravenous Nivolumab (n=270) All Grades (%) Grades 3-4 (%) Adverse Reaction 99 51 General Asthenia/fatigue/malaise 46 7 Pyrexia/tumor associated fever 17 0.4 Edema/peripheral edema/peripheral swelling 13 0.4 Musculoskeletal and Connective Tissue Musculoskeletal pain a 30 2.6 Arthralgia 10 0.7 Metabolism and Nutrition Decreased appetite 22 2.2 Gastrointestinal Nausea 22 0.7 Diarrhea 17 2.6 Constipation 16 0.4 Abdominal pain b 13 1.5 Vomiting 12 1.9 Respiratory, Thoracic and Mediastinal Cough/productive cough 18 0 Dyspnea/exertional dyspnea 14 3.3 Infections Urinary tract infection/escherichia/fungal urinary tract infection 17 7 Skin and Subcutaneous Tissue Rash c 16 1.5 Pruritus 12 0 Endocrine Thyroid disorders d 15 0 Table 32: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients - CHECKMATE-275 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: range: 84 to 256 patients. Laboratory Abnormality Intravenous Nivolumab a All Grades (%) Grades 3-4 (%) Chemistry Hyperglycemia 42 2.4 Hyponatremia 41 11 Increased creatinine 39 2 Increased alkaline phosphatase 33 5.5 Hypocalcemia 26 0.8 Increased AST 24 3.5 Increased lipase 20 7 Hyperkalemia 19 1.2 Increased ALT 18 1.2 Increased amylase 18 4.4 Hypomagnesemia 16 0 Hematology Lymphopenia 42 9 Anemia 40 7 Thrombocytopenia 15 2.4 Leukopenia 11 0 MSI-H or dMMR Metastatic Colorectal Cancer First-line Treatment of MSI-H or dMMR Metastatic Colorectal Cancer (mCRC) CHECKMATE-8HW The safety of intravenous nivolumab in combination with ipilimumab, or as a single agent, 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 (14.11) ] . Patients received one of the following: • Intravenous nivolumab 240 mg every 3 weeks and ipilimumab 1 mg/kg every 3 weeks for a maximum of 4 doses, then intravenous nivolumab 480 mg every 4 weeks • Intravenous nivolumab 240 mg every 2 weeks for 6 doses, then intravenous nivolumab 480 mg every 4 weeks • Investigator’s choice chemotherapy: mFOLFOX or FOLFIRI [see Clinical Studies (14.11) ] In the intravenous nivolumab and ipilimumab arm, the median duration of exposure to intravenous nivolumab was 20.5 months (range: 0 to 35.9 months), 70% patients were exposed for >6 months and 63% were exposed for >1 year. In the intravenous nivolumab arm, the median duration of exposure to intravenous nivolumab was 16.4 months (range: 0 to 36 months), 64% patients were exposed for >6 months and 54% were exposed for >1 year. Serious adverse reactions occurred in 46% of patients receiving intravenous nivolumab in combination with ipilimumab, and 39% of patients receiving intravenous nivolumab alone. The most frequent serious adverse reactions reported in ≥1% of patients who received intravenous nivolumab with ipilimumab 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 intravenous nivolumab, 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 intravenous nivolumab in combination with ipilimumab; these included myocarditis, and pneumonitis (1 each). Fatal adverse reactions occurring in 3 (0.9%) patients who received intravenous nivolumab as a single agent; these included pneumonitis (n=2) and myasthenia gravis. Intravenous nivolumab and/or ipilimumab 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%). Intravenous nivolumab was permanently discontinued in 13% of patients receiving single agent intravenous nivolumab. Adverse reactions leading to the delay of intravenous nivolumab and/or ipilimumab occurred in 48% of patients receiving the combination; single agent intravenous nivolumab was delayed in 37% of patients due to adverse reactions. The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with ipilimumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab as a single agent, were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain. Tables 33 and 34 summarize selected adverse reactions and selected laboratory abnormalities for intravenous nivolumab in combination with ipilimumab and the single agent intravenous nivolumab arms respectively, in CHECKMATE-8HW. Table 33: Adverse Reactions a in ≥10% in Patients with a Difference Between Arms of >5% for All Grades in CHECKMATE-8HW Toxicity was graded per NCI CTCAE v5. a Includes colitis, diarrhea, enterocolitis, immune mediated enterocolitis Adverse Reaction Intravenous Nivolumab and Ipilimumab (n=352) Intravenous Nivolumab (n=351) 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 34: Laboratory Values Worsening from Baseline a in ≥10% of Patients and a Difference Between Arms of >5% for All Grades - CHECKMATE-8HW a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 108 to 343 patients) or nivolumab group (range: 102 to 348 patients). Laboratory Abnormality a Intravenous Nivolumab and Ipilimumab (n=352) Intravenous Nivolumab (n=351) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) 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 Hematology Lymphocytes decreased 30 5 37 4 Neutrophils decreased 21 1.7 12 0.6 MSI-H or dMMR mCRC After Progression Following Treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan CHECKMATE-142 The safety of intravenous nivolumab administered as a single agent or in combination with ipilimumab was evaluated in CHECKMATE‑142, a multicenter, non-randomized, multiple parallel-cohort, open-label trial [see Clinical Studies (14.9) ] . In CHECKMATE-142, 74 patients with mCRC received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or until intolerable toxicity and 119 patients with mCRC received intravenous nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses, then intravenous nivolumab 3 mg/kg every 2 weeks until disease progression or until unacceptable toxicity. In the intravenous nivolumab with ipilimumab cohort, serious adverse reactions occurred in 47% of patients. Treatment was discontinued in 13% of patients and delayed in 45% of patients for an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting. Tables 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-142. Based on the design of CHECKMATE-142, the data below cannot be used to identify statistically significant differences between the two cohorts summarized below for any adverse reaction. Table 35: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-142 Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes peripheral edema and peripheral swelling. c Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort. d Includes back pain, pain in extremity, myalgia, neck pain, and bone pain. e Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized. f Includes nasopharyngitis and rhinitis. Adverse Reaction Intravenous Nivolumab (n=74) Intravenous Nivolumab and Ipilimumab (n=119) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 54 5 49 6 Pyrexia 24 0 36 0 Edema b 12 0 7 0 Gastrointestinal Diarrhea 43 2.7 45 3.4 Abdominal pain c 34 2.7 30 5 Nausea 34 1.4 26 0.8 Vomiting 28 4.1 20 1.7 Constipation 20 0 15 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 28 1.4 36 3.4 Arthralgia 19 0 14 0.8 Respiratory, Thoracic and Mediastinal Cough 26 0 19 0.8 Dyspnea 8 1 13 1.7 Skin and Subcutaneous Tissue Rash e 23 1.4 25 4.2 Pruritus 19 0 28 1.7 Dry Skin 7 0 11 0 Infections Upper respiratory tract infection f 20 0 9 0 Endocrine Hyperglycemia 19 2.7 6 1 Hypothyroidism 5 0 14 0.8 Hyperthyroidism 4 0 12 0 Nervous System Headache 16 0 17 1.7 Dizziness 14 0 11 0 Metabolism and Nutrition Decreased appetite 14 1.4 20 1.7 Psychiatric Insomnia 9 0 13 0.8 Investigations Weight decreased 8 0 10 0 Clinically important adverse reactions reported in <10% of patients receiving intravenous nivolumab with ipilimumab were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%). Table 36: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-142 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Number of evaluable patients ranges from 62 to 71 for the intravenous nivolumab cohort and from 87 to 114 for the intravenous nivolumab and ipilimumab cohort. Laboratory Abnormality Intravenous Nivolumab (n=74) Intravenous Nivolumab and Ipilimumab (n=119) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Anemia 50 7 42 9 Lymphopenia 36 7 25 6 Neutropenia 20 4.3 18 0 Thrombocytopenia 16 1.4 26 0.9 Chemistry Increased alkaline phosphatase 37 2.8 28 5 Increased lipase 33 19 39 12 Increased ALT 32 2.8 33 12 Increased AST 31 1.4 40 12 Hyponatremia 27 4.3 26 5 Hypocalcemia 19 0 16 0 Hypomagnesemia 17 0 18 0 Increased amylase 16 4.8 36 3.4 Increased bilirubin 14 4.2 21 5 Hypokalemia 14 0 15 1.8 Increased creatinine 12 0 25 3.6 Hyperkalemia 11 0 23 0.9 Hepatocellular Carcinoma Unresectable or Metastatic Hepatocellular Carcinoma (HCC) CHECKMATE-9DW The safety of intravenous nivolumab 1 mg/kg in combination with ipilimumab was evaluated in CHECKMATE-9DW, a randomized, open-label trial in adult patients with unresectable or metastatic HCC [see Clinical Studies (14.10) ] . Patients received intravenous nivolumab 1 mg/kg in combination with ipilimumab (n=332) or investigator’s choice of lenvatinib (n=275) or sorafenib (n=50) at the following dosage: • Intravenous nivolumab 1 mg/kg administered intravenously over 30 minutes in combination with ipilimumab 3 mg/kg administered intravenously over 30 minutes every 3 weeks, for a maximum of 4 doses, followed by single-agent intravenous nivolumab at 480 mg administered intravenously over 30 minutes every 4 weeks, or • Investigator’s choice: o Lenvatinib 8 mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight ≥60 kg), or o Sorafenib 400 mg orally twice daily In the intravenous nivolumab 1 mg/kg and ipilimumab arm, the median duration of exposure to intravenous nivolumab 1 mg/kg was 4.7 months (range: <0.1 to 24.4 months), 45% were exposed for >6 months and 30% were exposed for >1 year. Serious adverse reactions occurred in 53% of patients treated with intravenous nivolumab 1 mg/kg in combination with ipilimumab. The most frequent non liver-related serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab 1 mg/kg in combination with ipilimumab were diarrhea/colitis (4.5%), gastrointestinal hemorrhage (3%), and rash (2.4%). Liver-related serious adverse reactions occurred in 17% of patients treated with intravenous nivolumab 1 mg/kg in combination with ipilimumab, 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 who received intravenous nivolumab 1 mg/kg in combination with ipilimumab were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2.4%), ascites (2.4%), and hepatotoxicity (1.2%). Fatal adverse reactions occurred in 12 (3.6%) patients who received intravenous nivolumab 1 mg/kg in combination with ipilimumab; 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 discontinuations of intravenous nivolumab 1 mg/kg due to an adverse reaction occurred in 27% of patients. Adverse reactions leading to permanent discontinuation of intravenous nivolumab 1 mg/kg in >1% of patients included immune-mediated hepatitis (1.8%), diarrhea/colitis (1.8%), hepatic failure (1.2%). Dosage interruptions of intravenous nivolumab 1 mg/kg due to an adverse reaction occurred in 62% of patients. 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 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9DW. Table 37: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab 1 mg/kg in combination with Ipilimumab-Treated Patients - CHECKMATE-9DW Toxicity was graded per NCI CTCAE v5 a Represents a composite of multiple related terms. Adverse Reaction Intravenous Nivolumab 1 mg/kg and Ipilimumab (n=332) Lenvatinib or Sorafenib (n=325) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 36 3.6 15 1.2 Pruritus 34 1.5 7 0.3 General Fatigue a 33 2.4 39 4 Pyrexia a 15 0.6 9 1.5 Edema a 13 1.2 13 1.5 Gastrointestinal Diarrhea a 25 6 39 3.4 Abdominal pain a 14 1.2 27 2.5 Nausea 10 0.3 16 0.9 Musculoskeletal and Connective Tissue Musculoskeletal pain a 17 0.6 23 0.3 Arthralgia 12 0.3 13 0.6 Metabolism and Nutrition Decreased appetite 16 1.2 28 1.8 Endocrine Hypothyroidism a 14 0 27 0 Hyperthyroidism 11 0.6 1.5 0 Respiratory, Thoracic and Mediastinal Cough a 13 0 8 0 Clinically important adverse reactions reported in <10% of patients who received intravenous nivolumab 1 mg/kg with ipilimumab were hyperglycemia (8%), adrenal insufficiency (4.2%), pneumonitis (2.7%), and pancreatitis (2.4%). Table 38: Laboratory Values Worsening from Baseline a Occurring in ≥20% of intravenous Nivolumab 1 mg/kg in combination with Ipilimumab-Treated Patients - CHECKMATE-9DW a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab 1 mg/kg and ipilimumab group (range: 168 to 331 patients) and lenvatinib or sorafenib group (range: 145 to 315 patients). Laboratory Abnormality Intravenous Nivolumab 1 mg/kg and Ipilimumab (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 0.9 57 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 2.4 23 0.6 Hypokalemia 21 2.1 20 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 Previously Treated Hepatocellular Carcinoma CHECKMATE-040 The safety of intravenous nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg was evaluated in a subgroup comprising 49 patients with HCC and Child-Pugh Class A cirrhosis enrolled in Cohort 4 of CHECKMATE-040, a multicenter, multiple-cohort, open-label trial [see Clinical Studies (14.10) ] who progressed on or were intolerant to sorafenib. Intravenous nivolumab and ipilimumab were administered every 3 weeks for 4 doses, followed by single-agent intravenous nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity. During the intravenous nivolumab and ipilimumab combination period, 33 of 49 (67%) patients received all 4 planned doses of intravenous nivolumab and ipilimumab. During the entire treatment period, the median duration of exposure to intravenous nivolumab was 5.1 months (range: 0 to 35+ months) and to ipilimumab was 2.1 months (range: 0 to 4.5 months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction. The most frequent serious adverse reactions (reported in ≥4% of patients) were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. Tables 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-040. Table 39: Adverse Reactions Occurring in ≥10% of Patients Receiving Intravenous Nivolumab in Combination with Ipilimumab in Cohort 4 of CHECKMATE-040 Adverse Reaction Intravenous Nivolumab and Ipilimumab (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 who received intravenous nivolumab with ipilimumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%). Table 40: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients Receiving Intravenous Nivolumab in Combination with Ipilimumab in Cohort 4 of CHECKMATE-040 Laboratory Abnormality Intravenous Nivolumab and Ipilimumab (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 intravenous nivolumab with ipilimumab, 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. Esophageal Cancer Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer CHECKMATE-577 The safety of intravenous nivolumab was evaluated in CHECKMATE-577, a randomized, placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following chemoradiotherapy (CRT) [see Clinical Studies (14.11) ] . The trial excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Patients received either intravenous nivolumab 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Patients were treated until disease recurrence, unacceptable toxicity, or for up to 1‑year total duration. The median duration of exposure was 10.1 months (range: <0.1 to 14 months) in intravenous nivolumab-treated patients and 9 months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received intravenous nivolumab, 61% were exposed for >6 months and 54% were exposed for >9 months. Serious adverse reactions occurred in 33% of patients receiving intravenous nivolumab. A serious adverse reaction reported in ≥2% of patients who received intravenous nivolumab was pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who received intravenous nivolumab. Intravenous nivolumab was discontinued in 12% of patients and was delayed in 28% of patients for an adverse reaction. Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-577. Table 41: Adverse Reactions Occurring in ≥10% of Patients Receiving Intravenous Nivolumab - CHECKMATE-577 a Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort. b Includes gastroesophageal reflux. c Includes asthenia. d Includes productive cough. e Includes dyspnea exertional. f Includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, exfoliative rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic. g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, spinal pain. Adverse Reaction Intravenous Nivolumab (n=532) Placebo (n=260) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Adverse Reaction 96 34 93 32 Gastrointestinal Diarrhea 29 0.9 29 0.8 Nausea 23 0.8 21 0 Abdominal Pain a 17 0.8 20 1.5 Vomiting 15 0.6 16 1.2 Dysphagia 13 0.8 17 3.5 Dyspepsia b 12 0.2 16 0.4 Constipation 11 0 12 0 General Fatigue c 34 1.3 29 1.5 Respiratory, Thoracic and Mediastinal Cough d 20 0.2 21 0.4 Dyspnea e 12 0.8 12 0.4 Skin and Subcutaneous Tissue Rash f 21 0.9 10 0.4 Pruritus 13 0.4 6 0 Investigations Weight decreased 13 0.4 9 0 Musculoskeletal and Connective Tissue Musculoskeletal pain g 21 0.6 20 0.8 Arthralgia 10 0.2 8 0 Metabolism and Nutrition Decreased appetite 15 0.9 10 0.8 Endocrine Hypothyroidism 11 0 1.5 0 Table 42: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-577 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 163 to 526 patients) and Placebo group (range: 86 to 256 patients). b Includes alanine aminotransferase increased, aspartate aminotransferase increased. Laboratory Abnormality Intravenous Nivolumab (n=532) Placebo (n=260) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Increased AST 27 2.1 22 0.8 Increased alkaline phosphatase 25 0.8 18 0.8 Increased albumin 21 0.2 18 0 Increased ALT 20 1.9 16 1.2 Increased amylase 20 3.9 13 1.3 Hyponatremia 19 1.7 12 1.2 Hyperkalemia 17 0.8 15 1.6 Hypokalemia 12 1 11 1.2 Transaminases increased b 11 1.5 6 1.2 Hematology Lymphopenia 44 17 35 12 Anemia 27 0.8 21 0.4 Neutropenia 24 1.5 23 0.4 First-line Treatment of Unresectable Advanced or Metastatic ESCC CHECKMATE‑648 The safety of intravenous nivolumab in combination with chemotherapy or in combination with ipilimumab 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 (14.11) ] . Patients received one of the following treatments: • intravenous nivolumab 240 mg on days 1 and 15, 5-FU (fluorouracil) 800 mg/m 2 /day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m 2 intravenously on day 1 (of a 4‑week cycle). • intravenous nivolumab 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg every 6 weeks. • 5-FU (fluorouracil) 800 mg/m 2 /day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m 2 intravenously on day 1 (of a 4-week cycle). Among patients who received intravenous nivolumab with chemotherapy, the median duration of exposure was 5.7 months (range: 0.1 to 30.6 months). Among patients who received intravenous nivolumab and ipilimumab, the median duration of exposure was 2.8 months (range: 0 to 24 months). Serious adverse reactions occurred in 62% of patients receiving intravenous nivolumab in combination with chemotherapy and in 69% of patients receiving intravenous nivolumab in combination with ipilimumab. The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with ipilimumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%). Fatal adverse reactions occurred in 5 (1.6%) patients who received intravenous nivolumab in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury and in 5 (1.6%) patients who received intravenous nivolumab in combination with ipilimumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome. Intravenous nivolumab and/or chemotherapy were discontinued in 39% of patients and were delayed in 71% of patients for an adverse reaction. Intravenous nivolumab and/or ipilimumab were discontinued in 23% of patients and were delayed in 46% of patients for an adverse reaction. The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with chemotherapy were nausea, decreased appetite, fatigue, constipation, stomatitis, diarrhea, and vomiting. The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with ipilimumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation. Tables 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648. Table 43: Adverse Reactions in ≥10% of Patients - CHECKMATE-648 Toxicity was graded per NCI CTCAE v4. a Includes aphthous ulcer, mouth ulceration, and mucosal inflammation. b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper. c Includes asthenia and malaise. d Includes tumor associated fever. e Includes swelling, generalized edema, edema peripheral, and peripheral swelling. f Includes hyperesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy. g Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, and rash pruritic. h Includes productive cough. i Includes organizing pneumonia, pneumonia bacterial, and pneumonia pseudomonal. j Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, and spinal pain. Adverse Reaction Intravenous Nivolumab with Cisplatin and 5‑FU (n=310) Intravenous Nivolumab and Ipilimumab (n=322) Cisplatin and 5-FU (n=304) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3‑4 (%) Gastrointestinal Nausea 65 4.2 22 0.6 56 2.6 Constipation 44 1.0 20 0.3 43 1 Stomatitis a 44 9 11 0.6 35 3 Diarrhea 29 2.9 22 1.9 20 2 Vomiting 23 2.3 15 1.6 19 3 Dysphagia 14 7 12 5 12 4.9 Abdominal pain b 13 1.9 10 0.9 11 0.7 Metabolism and Nutrition Decreased appetite 51 7 17 4 50 6 General Fatigue c 47 3.5 28 2.5 41 4.9 Pyrexia d 19 0.3 23 0.9 12 0.3 Edema e 16 0 7 0 13 0 Nervous System Peripheral neuropathy f 18 1.3 2.8 0 13 1 Psychiatric Insomnia 16 0 8 0 10 0.3 Skin and Subcutaneous Tissue Rash g 16 0.6 31 3.1 7 0 Pruritus 11 0 17 0.9 3.6 0 Alopecia 10 0 11 0 Respiratory, Thoracic and Mediastinal Cough h 16 0.3 13 0.3 13 0.3 Infections and Infestations Pneumonia i 13 5 14 8 10 2.6 Endocrine Hypothyroidism 7 0 14 0 0.3 0 Investigations Weight decreased 12 0.6 12 1.9 11 1 Musculoskeletal and Connective Tissue Musculoskeletal pain j 11 0.3 14 0.6 8 0.3 Table 44: Laboratory Values Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-648 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab with cisplatin and 5-FU group (range: 60 to 305 patients), intravenous nivolumab and ipilimumab group (range: 59 to 307 patients) or cisplatin and 5-FU group (range: 56 to 283 patients). Laboratory Abnormality Intravenous Nivolumab with Cisplatin and 5‑FU (n=310) Intravenous Nivolumab and Ipilimumab (n=322) Cisplatin and 5-FU (n=304) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Anemia 81 21 52 7 66 14 Lymphopenia 67 23 50 13 44 8 Neutropenia 61 18 13 1.3 48 13 Leukopenia 53 11 39 5 Thrombocytopenia 43 3.3 12 1 29 2.8 Chemistry Hyponatremia 52 15 45 11 40 8 Hypocalcemia 43 3 32 0 23 0.7 Increased creatinine 41 2.3 15 0.7 31 0.7 Hypomagnesemia 35 1.7 15 0 25 1.8 Hyperglycemia 34 0 43 4.3 36 0.8 Hyperkalemia 33 2.3 23 1.6 24 0.7 Hypokalemia 29 9 19 5 17 6 Increased alkaline phosphatase 26 1.3 31 3.3 15 0 Increased AST 23 3.3 39 6 11 1.4 Increased ALT 23 2.3 33 6 8 0.7 Hypoglycemia 18 0.4 15 1.2 7 0 Hypercalcemia 11 2.6 15 2 8 0 Previously-Treated Unresectable Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma (ESCC) ATTRACTION-3 The safety of intravenous nivolumab was evaluated in ATTRACTION-3, a randomized, active-controlled, open‑label, multicenter trial in 209 patients with unresectable advanced, recurrent or metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum‑based chemotherapy [see Clinical Studies (14.11) ] . The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients received intravenous nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m 2 intravenously every 3 weeks (n=65) or paclitaxel 100 mg/m 2 intravenously once a week for 6 weeks followed by 1 week off (n=143). Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 2.6 months (range: 0 to 29.2 months) in intravenous nivolumab-treated patients and 2.6 months (range: 0 to 21.4 months) in docetaxel- or paclitaxel-treated patients. Among patients who received intravenous nivolumab, 26% were exposed for >6 months and 10% were exposed for >1 year. Serious adverse reactions occurred in 38% of patients receiving intravenous nivolumab. Serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab were pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse reactions occurred in patients who received intravenous nivolumab: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%). Intravenous nivolumab was discontinued in 13% of patients and was delayed in 27% of patients for an adverse reaction. Tables 45 and 46 summarize the adverse reactions and laboratory abnormalities, respectively, in ATTRACTION-3. Table 45: Adverse Reactions Occurring in ≥10% of Patients Receiving Intravenous Nivolumab - ATTRACTION-3 Toxicity was graded per NCI CTCAE v4. a Includes urticaria, drug eruption, eczema, eczema asteatotic, eczema nummular, palmar-plantar erythrodysesthesia syndrome, erythema, erythema multiforme, blister, skin exfoliation, Stevens-Johnson syndrome, dermatitis, dermatitis described as acneiform, bullous, or contact, and rash described as maculo-papular, generalized, or pustular. b Includes hypophagia, and food aversion. c Includes colitis. d Includes spondylolisthesis, periarthritis, musculoskeletal chest pain, neck pain, arthralgia, back pain, myalgia, pain in extremity, arthritis, bone pain, and periarthritis calcarea. e Includes influenza, influenza like illness, pharyngitis, nasopharyngitis, tracheitis, and bronchitis and upper respiratory infection with bronchitis. f Includes pneumonia aspiration, pneumonia bacterial, and lung infection. Two patients (1.0%) died of pneumonia in the intravenous nivolumab treatment arm. Two patients (1.0%) died of pneumonia in the chemotherapy treatment arm; these deaths occurred with paclitaxel only. g Includes productive cough. h Includes tumor-associated fever. i Includes asthenia. j Includes hemoglobin decreased, and iron deficiency anemia. k Includes blood thyroid stimulating hormone increased. Adverse Reaction Intravenous Nivolumab (n=209) Docetaxel or Paclitaxel (n=208) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 22 1.9 28 1 Pruritus 12 0 7 0 Metabolism and Nutrition Decreased appetite b 21 1.9 35 5 Gastrointestinal Diarrhea c 18 1.9 17 1.4 Constipation 17 0 19 0 Nausea 11 0 20 0.5 Musculoskeletal and Connective Tissue Musculoskeletal pain d 17 0 26 1.4 Infections Upper respiratory tract infection e 17 1 14 0 Pneumonia f 13 5 19 9 Respiratory, Thoracic and Mediastinal Cough g 16 0 14 0.5 General Pyrexia h 16 0.5 19 0.5 Fatigue i 12 1.4 27 4.8 Blood and Lymphatic System Anemia j 13 8 30 13 Endocrine Hypothyroidism k 11 0 1.4 0 Table 46: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Patients - ATTRACTION-3 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (209 patients) and Docetaxel or Paclitaxel group (range: 207 to 208 patients). Laboratory Abnormality Intravenous Nivolumab (n=209) Docetaxel or Paclitaxel (n=208) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Increased creatinine 78 0.5 68 0.5 Hyperglycemia 52 5 62 5 Hyponatremia 42 11 50 12 Increased AST 40 6 30 1 Increased alkaline phosphatase 33 4.8 24 1.0 Increased ALT 31 5 22 1.9 Hypercalcemia 22 6 14 2.9 Hyperkalemia 22 0.5 31 1 Hypoglycemia 14 1.4 14 0.5 Hypokalemia 11 2.9 13 3.4 Hematology Lymphopenia 46 19 72 43 Anemia 42 9 71 17 Leukopenia 11 0.5 79 45 Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma CHECKMATE-649 The safety of intravenous nivolumab in combination with chemotherapy was evaluated in CHECKMATE-649, a randomized, multicenter, open-label trial in patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma [see Clinical Studies (14.12) ] . The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive or had untreated central nervous system (CNS) metastases. Patients were randomized to receive intravenous nivolumab in combination with chemotherapy or chemotherapy. Patients received one of the following treatments: • intravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks. • intravenous nivolumab 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every 3 weeks or CapeOX every 3 weeks. Patients were treated with intravenous nivolumab in combination with chemotherapy or chemotherapy until disease progression, unacceptable toxicity, or up to 2 years. The median duration of exposure was 6.8 months (range: 0 to 33.5 months) in intravenous nivolumab and chemotherapy-treated patients. Among patients who received intravenous nivolumab and chemotherapy, 54% were exposed for >6 months and 28% were exposed for >1 year. Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with intravenous nivolumab in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. Serious adverse reactions occurred in 52% of patients treated with intravenous nivolumab in combination with chemotherapy. Intravenous nivolumab and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous nivolumab in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain. Tables 47 and 48 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-649. Table 47: Adverse Reactions in ≥10% of Patients Receiving Intravenous Nivolumab and Chemotherapy - CHECKMATE-649 Toxicity was graded per NCI CTCAE v4. a Includes dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy. b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper. c Includes aphthous ulcer, mouth ulceration, and mucosal inflammation. d Includes asthenia. e Includes tumor associated fever. f Includes swelling, generalized edema, edema peripheral, and peripheral swelling. g Includes blood albumin decreased. h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. i Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, nodular rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash vesicular. j Includes productive cough. k Includes nasopharyngitis, pharyngitis, and rhinitis. Adverse Reaction Intravenous Nivolumab and mFOLFOX6 or CapeOX (n=782) mFOLFOX6 or CapeOX (n=767) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Adverse Reaction 99 69 98 59 Nervous System Peripheral neuropathy a 53 7 46 4.8 Headache 11 0.8 6 0.3 Gastrointestinal Nausea 48 3.2 44 3.7 Diarrhea 39 5 34 3.7 Vomiting 31 4.2 29 4.2 Abdominal pain b 27 2.8 24 2.6 Constipation 25 0.6 21 0.4 Stomatitis c 17 1.8 13 0.8 General Fatigue d 44 7 40 5 Pyrexia e 19 1 11 0.4 Edema f 12 0.5 8 0.1 Metabolism and Nutrition Decreased appetite 29 3.6 26 2.5 Hypoalbuminemia g 14 0.3 9 0.3 Investigations Weight decreased 17 1.3 15 0.7 Increased lipase 14 7 8 3.7 Increased amylase 12 3.1 5 0.4 Musculoskeletal and Connective Tissue Musculoskeletal pain h 20 1.3 14 2 Skin and Subcutaneous Tissue Rash i 18 1.7 4.4 0.1 Palmar-plantar erythrodysesthesia syndrome 13 1.5 12 0.8 Respiratory, Thoracic and Mediastinal Cough j 13 0.1 9 0 Infections and Infestations Upper respiratory tract infection k 10 0.1 7 0.1 Table 48: Laboratory Values Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-649 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and mFOLFOX6 or CapeOX group (407 to 767 patients) or mFOLFOX6 or CapeOX group (range: 405 to 735 patients). Laboratory Abnormality Intravenous Nivolumab and mFOLFOX6 or CapeOX (n=782) mFOLFOX6 or CapeOX (n=767) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Neutropenia 73 29 62 23 Leukopenia 69 12 59 9 Thrombocytopenia 68 7 63 4.4 Anemia 59 14 60 10 Lymphopenia 59 12 49 9 Chemistry Increased AST 52 4.6 47 1.9 Hypocalcemia 42 1.6 37 1 Hyperglycemia 41 3.9 38 2.7 Increased ALT 37 3.4 30 1.9 Hyponatremia 34 6 24 5 Hypokalemia 27 7 24 4.8 Hyperbilirubinemia 24 2.8 21 2 Increased creatinine 15 1 9 0.5 Hyperkalemia 14 1.4 11 0.7 Hypoglycemia 12 0.7 9 0.2 Hypernatremia 11 0.5 7.1 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of intravenous nivolumab. 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. Eye: Vogt-Koyanagi-Harada (VKH) syndrome Complications of Intravenous Nivolumab Treatment After Allogeneic HSCT: Treatment refractory, severe acute and chronic GVHD Blood and lymphatic system disorders: Hemophagocytic lymphohistiocytosis (HLH) (including fatal cases), autoimmune hemolytic anemia (including fatal cases)