OPDIVO QVANTIG- nivolumab and hyaluronidase-nvhy_injection, solution

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0. Hyaluronidase increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidase in OPDIVO QVANTIG acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours. Exposure-Response Relationship The exposure-response relationship and time course of pharmacodynamics of OPDIVO QVANTIG have not been fully characterized. When comparing nivolumab exposures following OPDIVO QVANTIG to those of intravenous nivolumab in CHECKMATE-67T [see Clinical Studies (14. 1) avg min Steady state was achieved by 16 weeks. The systemic accumulation ratio was 2. Absorption The geometric mean bioavailability (CV%) of nivolumab is 74% (14%). Peak concentrations occurred by around 6 days. Distribution The geometric mean (CV%) volume of distribution at steady state is 6. Elimination Nivolumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of 24. 6%), resulting in a geometric mean steady-state clearance (CV%) of 8. 9%) in patients with metastatic tumors; this decrease in clearance is not considered clinically relevant. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady state. The geometric mean (CV%) elimination half-life is 25 days (78%). Specific Populations Body weight (35 to 153 kg), sex, eGFR (24 to 124 mL/min/1. 73 m 2 The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of OPDIVO QVANTIG or of other nivolumab products or hyaluronidase products. During the 2-year treatment period in CHECKMATE-67T [see Clinical Studies (14. 1) Nivolumab clearance increased by approximately 26% in patients who received OPDIVO QVANTIG and tested positive for ADA compared to patients who tested negative for ADA; this change in clearance is not considered clinically significant. Local injection-site reactions were reported in 15% (7/46) of patients who developed ADA to nivolumab and 7% (10/155) of patients who did not develop ADA to nivolumab; however, all events were Grade 1 or 2 and resolved. Because of low occurrence of anti-nivolumab or anti-hyaluronidase antibodies, the effect of ADA on the effectiveness of OPDIVO QVANTIG is unknown.

OPDIVO QVANTIG is a combination of nivolumab (a PD-1 blocking antibody) and hyaluronidase indicated for the treatment of multiple cancers, including renal cell carcinoma, melanoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma, used as monotherapy or in combination with chemotherapy or targeted agents in first-line, neoadjuvant, adjuvant, and previously treated settings, with certain indications requiring specific biomarker status, prior therapies, or being approved under accelerated approval based on response rate and duration.

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. 1) OPDIVO QVANTIG is for subcutaneous use only. 1) (2. 2) (2. 2) (2. 2) OPDIVO QVANTIG has different dosage and administration instructions than intravenously administered nivolumab products [see Dosage and Administration (2. 4) OPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. Do not 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. The recommended dosages of OPDIVO QVANTIG as monotherapy agent are presented in Table 1. Table 1: Recommended Dosages for OPDIVO QVANTIG as Monotherapy dagger Dosing recommendations for both monotherapy or following intravenous nivolumab and ipilimumab combination therapy. Indication Recommended OPDIVO QVANTIG Dosage Duration of Therapy Advanced renal cell carcinomadagger 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 Unresectable or metastatic melanomadagger Metastatic non-small cell lung cancer Squamous cell carcinoma of the head and neck Locally advanced or metastatic urothelial carcinoma Microsatellite instability-high or mismatch repair deficient metastatic colorectal cancerdagger Hepatocellular carcinomadagger Esophageal squamous cell carcinoma Adjuvant treatment of melanoma 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 urothelial carcinoma 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 * Administer over 3-5 minutes. 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 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 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 b c 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 b 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 b ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin >=2 times ULN Permanently discontinue a 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. 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. 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-25G (3/8”-5/8”) hypodermic injection needle or subcutaneous administration set (eg. , winged/butterfly). 600 mg nivolumab and 10,000 units hyaluronidase ∘ 900 mg nivolumab and 15,000 units hyaluronidase ∘ 1,200 mg nivolumab and 20,000 units hyaluronidase ∘ 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-25G (3/8”-5/8”) hypodermic injection needle to the syringe immediately prior to administration. Once withdrawn into the syringe, OPDIVO QVANTIG should be used immediately. If not used immediately, store the syringe: .

ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling. [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) ] Most common adverse reactions (>=10%) with OPDIVO QVANTIG as monotherapy in patients with Renal Cell Carcinoma were: (6. 1) (6. 1) (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. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared 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. 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. 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. 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 * a Adverse Reaction OPDIVO QVANTIG Intravenous Nivolumab All Grades Grades 3-4 All Grades Grades 3-4 General Fatigue a 20 2. 3 Injection site reaction a 8 0 0 0 Edema 5 0. 8 Musculoskeletal and Connective Tissue Musculoskeletal pain a 31 1. 3 Skin and Subcutaneous Tissue Pruritus 16 0. 4 21 0 Rash a 15 1. 2 Gastrointestinal Diarrhea a 11 0. 4 Abdominal pain a 10 0 10 0. 4 Nausea 8 0 9 0 Constipation 8 0 6 0 Vomiting 6 0. 9 0 Respiratory, Thoracic, and Mediastinal Cough 11 0 11 0 Endocrine Hypothyroidism a 12 0 17 0 Metabolism and Nutrition Hyperglycemia 9 2. 0 Decreased appetite 9 0 11 0. 8 Clinically important adverse reactions in <5% of patients who received OPDIVO QVANTIG include: Cardiac: Respiratory, thoracic, and mediastinal: Endocrine: Gastrointestinal: Hepatobiliary: Nervous system: Skin and subcutaneous tissue: Musculoskeletal and connective tissue: Blood and lymphatic system: Eye disorders: Immune system: Table 6: Laboratory Values Worsening from Baseline a a 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. 4 Sodium decreased 34 2. 5 Potassium increased 34 3. 9 Alkaline phosphatase increased 32 2. 0 Calcium increased 29 2. 1 Albumin decreased 25 1. 4 ALT increased 21 1. 1 The safety of OPDIVO QVANTIG for its approved indications [see Indications and Usage (1) 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) ] 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 b c d Adverse Reaction Intravenous Nivolumab and Ipilimumab Sunitinib 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. 6 Edema b 16 0. 6 Skin and Subcutaneous Tissue Rash c 39 3. 1 Pruritus/generalized pruritus 33 0. 5 11 0 Gastrointestinal Diarrhea 38 4. 6 58 6 Nausea 30 2 43 1. 5 Vomiting 20 0. 1 Abdominal pain 19 1. 9 Constipation 17 0. 4 18 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 37 4 40 2. 6 Arthralgia 23 1. 3 16 0 Respiratory, Thoracic and Mediastinal Cough/productive cough 28 0. 4 Dyspnea/exertional dyspnea 20 2. 1 Metabolism and Nutrition Decreased appetite 21 1. 9 Nervous System Headache 19 0. 9 Endocrine Hypothyroidism 18 0. 2 Table 8: Laboratory Values Worsening from Baseline a a 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. 7 Increased ALT 41 7 44 2. 7 Increased AST 40 4. 1 Increased amylase 39 12 33 7 Hyponatremia 39 10 36 7 Increased alkaline phosphatase 29 2 32 1 Hyperkalemia 29 2. 9 Hypocalcemia 21 0. 6 Hypomagnesemia 16 0. 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) ] 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 b c d e f g h i j k Adverse Reaction Intravenous Nivolumab and Cabozantinib Sunitinib Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Diarrhea 64 7 47 4. 4 Nausea 27 0. 3 Abdominal pain a 22 1. 3 Vomiting 17 1. 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 Rash f 36 3. 1 14 0 Pruritus 19 0. 4 0 Vascular Hypertension g 36 13 39 14 Endocrine Hypothyroidism h 34 0. 3 Musculoskeletal and Connective Tissue Musculoskeletal pain i 33 3. 1 Arthralgia 18 0. 3 Metabolism and Nutrition Decreased appetite 28 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. 4 0 Infections and Infestations Upper respiratory tract infection k 20 0. 3 Table 10: Laboratory Values Worsening from Baseline a a Laboratory Abnormality Intravenous Nivolumab and Cabozantinib Sunitinib Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased ALT 79 9. 5 Increased AST 77 7. 6 Hypophosphatemia 69 28 48 10 Hypocalcemia 54 1. 6 Hypomagnesemia 47 1. 3 Hyperglycemia 44 3. 7 Hyponatremia 43 11 36 12 Increased lipase 41 14 38 13 Increased amylase 41 10 28 6 Increased alkaline phosphatase 41 2. 6 Increased creatinine 39 1. 6 Hyperkalemia 35 4. 7 27 1 Hypoglycemia 26 0. 4 Hematology Lymphopenia 42 6. 6 45 10 Thrombocytopenia 41 0. 7 Anemia 37 2. 8 Leukopenia 37 0. 1 Neutropenia 35 3. 2 67 12 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) ] 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 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 b c d Adverse Reaction Intravenous Nivolumab Everolimus 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. 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. 8 Constipation 23 0. 5 Vomiting 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. 5 Musculoskeletal and Connective Tissue Arthralgia 20 1 14 0. 5 Back pain 21 3. 8 Other clinically important adverse reactions in CHECKMATE-025 were: General Disorders and Administration Site Conditions: Gastrointestinal Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Investigations: Skin Disorders: Table 12: Laboratory Values Worsening from Baseline a a 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. 6 Increased alkaline phosphatase 32 2. 8 Hyponatremia 32 7 26 6 Hyperkalemia 30 4 20 2. 1 Hypocalcemia 23 0. 3 Increased ALT 22 3. 8 Hypercalcemia 19 3. 3 Lipids Increased triglycerides 32 1. 5 67 11 Increased cholesterol 21 0. 4 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) 2 2 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. 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 b Adverse Reaction Intravenous Nivolumab Chemotherapy 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: Eye Disorders: General Disorders and Administration Site Conditions: Investigations: Nervous System Disorders: Skin and Subcutaneous Tissue Disorders: Table 14: Laboratory Abnormalities Worsening from Baseline a a 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. 1 Increased ALT 16 1. 6 5 0 Hyperkalemia 15 2 6 0 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) 2 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. 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. 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 b c d Adverse Reaction Intravenous Nivolumab Dacarbazine All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue 49 1. 4 Edema a 12 1. 9 0 Musculoskeletal and Connective Tissue Musculoskeletal pain b 32 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: Table 16: Laboratory Abnormalities Worsening from Baseline a a 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. 5 Increased alkaline phosphatase 21 2. 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) Patients were randomized to receive: 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. 6%), and pneumonitis (1. 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 b c d e Adverse Reaction Intravenous Nivolumab and (n=313) (n=311) All Grades (%) Grades All Grades (%) Grades All Grades (%) Grades General Fatigue a 62 7 59 1. 2 Pyrexia 40 1. 6 16 0 18 0. 6 Gastrointestinal Diarrhea 54 11 36 5 47 7 Nausea 44 3. 9 Vomiting 31 3. 8 20 1 17 1. 6 Skin and Subcutaneous Tissue Rash b 53 6 40 1. 5 Vitiligo 9 0 10 0. 3 5 0 Musculoskeletal and Connective Tissue Musculoskeletal pain c 32 2. 9 Arthralgia 21 0. 3 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. 6 22 0 Dyspnea/exertional dyspnea 24 2. 6 Infections Upper respiratory tract infection d 23 0 22 0. 3 17 0 Endocrine Hypothyroidism 19 0. 6 11 0 5 0 Hyperthyroidism 11 1. 3 6 0 1 0 Investigations Decreased weight 12 0 7 0 7 0. 3 Vascular Hypertension e 7 2. 3 Clinically important adverse reactions in <10% of patients who received intravenous nivolumab with ipilimumab or intravenous nivolumab as a single agent were: Gastrointestinal Disorders: Skin and Subcutaneous Tissue Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Table 18: Laboratory Abnormalities Worsening from Baseline a a Laboratory Abnormality Intravenous Nivolumab and Intravenous Nivolumab Ipilimumab All Grades (%) Grade All Grades (%) Grade All Grades (%) Grade 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 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. 7 Increased amylase 27 10 19 2. 6 Increased creatinine 26 2. 3 Hematology Anemia 52 2. 6 41 6 Lymphopenia 39 5 41 4. 9 29 4 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) 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. 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 b c d e f Adverse Reaction Intravenous Nivolumab Placebo All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 36 0. 4 Musculoskeletal and connective tissue Musculoskeletal pain b 30 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. 8 Table 20: Laboratory Abnormalities Worsening from Baseline a a 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. 7 Neutropenia 10 0 10 0. 4 Chemistry AST increased 25 2. 4 Lipase increased 22 2. 3 ALT increased 20 2. 4 Amylase increased 17 0. 4 9 0 Creatinine increased 15 0. 4 13 0 Sodium decreased 13 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) 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 b c d e f g Adverse Reaction Intravenous Nivolumab Ipilimumab 10 mg/kg All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 57 0. 4 Gastrointestinal Diarrhea 37 2. 4 55 11 Nausea 23 0. 2 28 0 Abdominal pain b 21 0. 9 Constipation 10 0 9 0 Skin and Subcutaneous Tissue Rash c 35 1. 3 Pruritus 28 0 37 1. 1 Musculoskeletal and Connective Tissue Musculoskeletal pain d 32 0. 4 Arthralgia 19 0. 4 Nervous System Headache 23 0. 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. 2 Endocrine Hypothyroidism g 12 0. 4 Table 22: Laboratory Abnormalities Worsening from Baseline a a Laboratory Abnormality Intravenous Nivolumab Ipilimumab 10 mg/kg All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Lymphopenia 27 0. 9 Anemia 26 0 34 0. 5 Leukopenia 14 0 2. 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. 1 Hyponatremia 16 1. 2 Hyperkalemia 12 0. 5 Increased Creatinine 12 0 13 0 Hypocalcemia 10 0. 5 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) The median age of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 en dash 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. 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 b c Adverse Reaction Intravenous Nivolumab and Platinum-Doublet Chemotherapy Platinum-Doublet Chemotherapy All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Gastrointestinal Nausea 38 0. 1 Constipation 34 0 32 1. 1 Vomiting 11 1. 6 General Fatigue a 26 2. 1 Malaise 15 0. 6 Metabolism and Nutrition Decreased appetite 20 1. 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 a 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. 8 Thrombocytopenia 24 2. 9 22 3 Chemistry Hyperglycemia 37 6 35 2. 9 Hypomagnesemia 25 1. 2 Hyponatremia 25 2. 8 Increased amylase 23 3. 8 Increased ALT 23 0 20 1. 2 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) 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. 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. 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. 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. 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) ] 2 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 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 Docetaxel 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. 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 a b 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. 8 Increased alkaline phosphatase 26 0. 8 Increased ALT 22 1. 5 Increased creatinine 18 0 12 0. 5 Increased TSH b 14 N/A 6 N/A 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) ] 2 2 2 2 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. 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) 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. 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 b c d e f g h i j k 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. 3 Pruritus 30 0 16 0 General Fatigue/Asthenia 36 1. 3 Pyrexia 10 0. 3 Gastrointestinal Diarrhea b 30 2. 7 Nausea 16 0. 6 13 0 Abdominal pain c 15 0. 6 Constipation 13 0. 3 Musculoskeletal and Connective Tissue Musculoskeletal pain d 28 0. 9 Arthralgia 11 0. 3 13 0 Infections Urinary tract infection e 22 6 23 9 Upper respiratory tract infection f 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. 9 Respiratory, Thoracic and Mediastinal Cough h 14 0 11 0 Dyspnea i 11 0. 3 Metabolism and Nutrition Decreased appetite 13 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 a Laboratory Abnormality Intravenous Nivolumab (n=351) Placebo (n=348) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Increased creatinine 36 1. 6 Increased amylase 34 8 23 3. 2 Increased lipase 33 12 31 10 Hyperkalemia 32 5 30 6 Increased alkaline phosphatase 24 2. 6 Increased AST 24 3. 9 Increased ALT 23 2. 6 Hyponatremia 22 4. 8 Hypocalcemia 17 1. 9 Hypomagnesemia 16 0 9 0 Hypercalcemia 12 0. 3 Hematology Lymphopenia 33 2. 5 Anemia 30 1. 9 Neutropenia 11 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) Among patients who received intravenous nivolumab with chemotherapy, the median duration of intravenous nivolumab exposure was 7. 4 months (range: 0. 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. 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 b c d e f g h i j k l Adverse Reaction Intravenous Nivolumab and Platinum-Doublet Chemotherapy 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. 1 Diarrhea a 19 2 14 0 Abdominal pain b 14 0. 3 General Fatigue c 48 3. 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 Pruritus 17 0. 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 a Laboratory Abnormality Intravenous Nivolumab and Platinum-Doublet Chemotherapy Platinum-Doublet Chemotherapy 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. 1 Hypomagnesemia 48 3. 5 Hyponatremia 43 13 39 8 Hyperglycemia 41 3. 2 Hypocalcemia 36 2. 1 Hyperkalemia 33 3. 1 Increased amylase 32 4. 6 Increased AST 31 2. 7 Increased ALT 29 2. 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) 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 b c d 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 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 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 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 33 and 34 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 33: Adverse Reactions Occurring in >=10% of Patients - CHECKMATE-142 Toxicity was graded per NCI CTCAE v4. a b c d e f Adverse Reaction Intravenous Nivolumab Intravenous Nivolumab and Ipilimumab 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. 4 Abdominal pain c 34 2. 7 30 5 Nausea 34 1. 8 Vomiting 28 4. 7 Constipation 20 0 15 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 28 1. 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. 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. 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. Table 34: Laboratory Abnormalities Worsening from Baseline a a Laboratory Abnormality Intravenous Nivolumab Intravenous Nivolumab and Ipilimumab 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. 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. 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 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) ] 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 35 and 36 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-040. Table 35: 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 36: 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. 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) ] 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 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-577. Table 37: Adverse Reactions Occurring in >=10% of Patients Receiving Intravenous Nivolumab - CHECKMATE-577 a b c d e f g 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. 8 Nausea 23 0. 8 21 0 Abdominal Pain a 17 0. 5 Vomiting 15 0. 2 Dysphagia 13 0. 5 Dyspepsia b 12 0. 4 Constipation 11 0 12 0 General Fatigue c 34 1. 5 Respiratory, Thoracic and Mediastinal Cough d 20 0. 4 Dyspnea e 12 0. 4 Skin and Subcutaneous Tissue Rash f 21 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. 8 Arthralgia 10 0. 2 8 0 Metabolism and Nutrition Decreased appetite 15 0. 8 Endocrine Hypothyroidism 11 0 1. 5 0 Table 38: Laboratory Abnormalities Worsening from Baseline a a b Laboratory Abnormality Intravenous Nivolumab (n=532) Placebo (n=260) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Increased AST 27 2. 8 Increased alkaline phosphatase 25 0. 8 Increased albumin 21 0. 2 18 0 Increased ALT 20 1. 2 Increased amylase 20 3. 3 Hyponatremia 19 1. 2 Hyperkalemia 17 0. 6 Hypokalemia 12 1 11 1. 2 Transaminases increased b 11 1. 2 Hematology Lymphopenia 44 17 35 12 Anemia 27 0. 4 Neutropenia 24 1. 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) ] 2 2 2 2 Among patients who received intravenous nivolumab with chemotherapy, the median duration of exposure was 5. 7 months (range: 0. 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. 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. 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 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648. Table 39: Adverse Reactions in >=10% of Patients - CHECKMATE-648 Toxicity was graded per NCI CTCAE v4. a b c d e f g h i j 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. 6 Constipation 44 1. 3 43 1 Stomatitis a 44 9 11 0. 6 35 3 Diarrhea 29 2. 9 20 2 Vomiting 23 2. 6 19 3 Dysphagia 14 7 12 5 12 4. 9 Abdominal pain b 13 1. 7 Metabolism and Nutrition Decreased appetite 51 7 17 4 50 6 General Fatigue c 47 3. 9 Pyrexia d 19 0. 3 Edema e 16 0 7 0 13 0 Nervous System Peripheral neuropathy f 18 1. 8 0 13 1 Psychiatric Insomnia 16 0 8 0 10 0. 3 Skin and Subcutaneous Tissue Rash g 16 0. 1 7 0 Pruritus 11 0 17 0. 6 0 Alopecia 10 0 11 0 Respiratory, Thoracic and Mediastinal Cough h 16 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. 9 11 1 Musculoskeletal and Connective Tissue Musculoskeletal pain j 11 0. 3 Table 40: Laboratory Values Worsening from Baseline a a Laboratory Abnormality Intravenous Nivolumab with Cisplatin and 5‑FU Intravenous Nivolumab and Ipilimumab (n=322) Cisplatin and 5-FU 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. 7 Hypomagnesemia 35 1. 7 15 0 25 1. 8 Hyperglycemia 34 0 43 4. 8 Hyperkalemia 33 2. 7 Hypokalemia 29 9 19 5 17 6 Increased alkaline phosphatase 26 1. 3 15 0 Increased AST 23 3. 3 39 6 11 1. 4 Increased ALT 23 2. 7 Hypoglycemia 18 0. 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) ] 2 2 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. Intravenous nivolumab was discontinued in 13% of patients and was delayed in 27% of patients for an adverse reaction. Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, in ATTRACTION-3. Table 41: Adverse Reactions Occurring in >=10% of Patients Receiving Intravenous Nivolumab - ATTRACTION-3 Toxicity was graded per NCI CTCAE v4. a b c d e f g h i j k 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. 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 Fatigue i 12 1. 8 Blood and Lymphatic System Anemia j 13 8 30 13 Endocrine Hypothyroidism k 11 0 1. 4 0 Table 42: Laboratory Abnormalities Worsening from Baseline a a 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 Hyperglycemia 52 5 62 5 Hyponatremia 42 11 50 12 Increased AST 40 6 30 1 Increased alkaline phosphatase 33 4. 0 Increased ALT 31 5 22 1. 9 Hypercalcemia 22 6 14 2. 9 Hyperkalemia 22 0. 5 31 1 Hypoglycemia 14 1. 5 Hypokalemia 11 2. 4 Hematology Lymphopenia 46 19 72 43 Anemia 42 9 71 17 Leukopenia 11 0. 5 79 45 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) ] 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. 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 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-649. Table 43: Adverse Reactions in >=10% of Patients Receiving Intravenous Nivolumab and Chemotherapy - CHECKMATE-649 Toxicity was graded per NCI CTCAE v4. a b c d e f g h i j k Adverse Reaction Intravenous Nivolumab and mFOLFOX6 or CapeOX (n=782) mFOLFOX6 or CapeOX 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. 3 Gastrointestinal Nausea 48 3. 7 Diarrhea 39 5 34 3. 7 Vomiting 31 4. 2 Abdominal pain b 27 2. 6 Constipation 25 0. 4 Stomatitis c 17 1. 8 General Fatigue d 44 7 40 5 Pyrexia e 19 1 11 0. 4 Edema f 12 0. 1 Metabolism and Nutrition Decreased appetite 29 3. 5 Hypoalbuminemia g 14 0. 3 Investigations Weight decreased 17 1. 7 Increased lipase 14 7 8 3. 7 Increased amylase 12 3. 4 Musculoskeletal and Connective Tissue Musculoskeletal pain h 20 1. 3 14 2 Skin and Subcutaneous Tissue Rash i 18 1. 1 Palmar-plantar erythrodysesthesia syndrome 13 1. 8 Respiratory, Thoracic and Mediastinal Cough j 13 0. 1 9 0 Infections and Infestations Upper respiratory tract infection k 10 0. 1 Table 44: Laboratory Values Worsening from Baseline a a Laboratory Abnormality Intravenous Nivolumab and mFOLFOX6 or CapeOX mFOLFOX6 or CapeOX 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. 9 Hypocalcemia 42 1. 6 37 1 Hyperglycemia 41 3. 7 Increased ALT 37 3. 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. 7 Hypoglycemia 12 0. 2 Hypernatremia 11 0. 1 0 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: Complications of Intravenous Nivolumab Treatment After Allogeneic HSCT: Blood and lymphatic system disorders:.
Adverse Reactions in Patients Treated with Intravenous Nivolumab
The safety of OPDIVO QVANTIG for its approved indications [see Indications and Usage (1) 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) ] 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 b c d Adverse Reaction Intravenous Nivolumab and Ipilimumab Sunitinib 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. 6 Edema b 16 0. 6 Skin and Subcutaneous Tissue Rash c 39 3. 1 Pruritus/generalized pruritus 33 0. 5 11 0 Gastrointestinal Diarrhea 38 4. 6 58 6 Nausea 30 2 43 1. 5 Vomiting 20 0. 1 Abdominal pain 19 1. 9 Constipation 17 0. 4 18 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 37 4 40 2. 6 Arthralgia 23 1. 3 16 0 Respiratory, Thoracic and Mediastinal Cough/productive cough 28 0. 4 Dyspnea/exertional dyspnea 20 2. 1 Metabolism and Nutrition Decreased appetite 21 1. 9 Nervous System Headache 19 0. 9 Endocrine Hypothyroidism 18 0. 2 Table 8: Laboratory Values Worsening from Baseline a a 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. 7 Increased ALT 41 7 44 2. 7 Increased AST 40 4. 1 Increased amylase 39 12 33 7 Hyponatremia 39 10 36 7 Increased alkaline phosphatase 29 2 32 1 Hyperkalemia 29 2. 9 Hypocalcemia 21 0. 6 Hypomagnesemia 16 0. 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) ] 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 b c d e f g h i j k Adverse Reaction Intravenous Nivolumab and Cabozantinib Sunitinib Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Diarrhea 64 7 47 4. 4 Nausea 27 0. 3 Abdominal pain a 22 1. 3 Vomiting 17 1. 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 Rash f 36 3. 1 14 0 Pruritus 19 0. 4 0 Vascular Hypertension g 36 13 39 14 Endocrine Hypothyroidism h 34 0. 3 Musculoskeletal and Connective Tissue Musculoskeletal pain i 33 3. 1 Arthralgia 18 0. 3 Metabolism and Nutrition Decreased appetite 28 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. 4 0 Infections and Infestations Upper respiratory tract infection k 20 0. 3 Table 10: Laboratory Values Worsening from Baseline a a Laboratory Abnormality Intravenous Nivolumab and Cabozantinib Sunitinib Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased ALT 79 9. 5 Increased AST 77 7. 6 Hypophosphatemia 69 28 48 10 Hypocalcemia 54 1. 6 Hypomagnesemia 47 1. 3 Hyperglycemia 44 3. 7 Hyponatremia 43 11 36 12 Increased lipase 41 14 38 13 Increased amylase 41 10 28 6 Increased alkaline phosphatase 41 2. 6 Increased creatinine 39 1. 6 Hyperkalemia 35 4. 7 27 1 Hypoglycemia 26 0. 4 Hematology Lymphopenia 42 6. 6 45 10 Thrombocytopenia 41 0. 7 Anemia 37 2. 8 Leukopenia 37 0. 1 Neutropenia 35 3. 2 67 12 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) ] 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 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 b c d Adverse Reaction Intravenous Nivolumab Everolimus 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. 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. 8 Constipation 23 0. 5 Vomiting 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. 5 Musculoskeletal and Connective Tissue Arthralgia 20 1 14 0. 5 Back pain 21 3. 8 Other clinically important adverse reactions in CHECKMATE-025 were: General Disorders and Administration Site Conditions: Gastrointestinal Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Investigations: Skin Disorders: Table 12: Laboratory Values Worsening from Baseline a a 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. 6 Increased alkaline phosphatase 32 2. 8 Hyponatremia 32 7 26 6 Hyperkalemia 30 4 20 2. 1 Hypocalcemia 23 0. 3 Increased ALT 22 3. 8 Hypercalcemia 19 3. 3 Lipids Increased triglycerides 32 1. 5 67 11 Increased cholesterol 21 0.

2) Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12. 1) (see Data) The background risk in the U. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data OPDIVO QVANTIG for subcutaneous injection contains nivolumab and hyaluronidase [see Description (11) ] Nivolumab A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab intravenously twice weekly from the onset of organogenesis through delivery, at exposure levels of between 4 and 15 times higher than those observed at the clinical dose of 600 mg once every 2 weeks, 900 mg once every 3 weeks, or 1,200 mg once every 4 weeks (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response, and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Hyaluronidase In an embryo-fetal development study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is at least 6,600 times higher than the human dose of 10,000 U once every 2 weeks, 15,000 U once every 3 weeks, or 20,000 U once every 4 weeks (U/kg basis), when administered with nivolumab. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is at least 1,080 times higher than the human dose of 10,000 U once every 2 weeks, 15,000 U once every 3 weeks, or 20,000 U once every 4 weeks (U/kg basis), when administered with nivolumab. Risk Summary There are no data on the presence of nivolumab or hyaluronidase in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for 5 months after the last dose of OPDIVO QVANTIG. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating OPDIVO QVANTIG [see Use in Specific Populations (8. 1) Contraception OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8. 1) The safety and effectiveness of OPDIVO QVANTIG have not been established in pediatric patients. Of the 248 patients who were randomized to monotherapy OPDIVO QVANTIG in clinical studies, 48% were 65 years and over and 14% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and esophageal or gastroesophageal junction cancer who were randomized to single agent intravenous nivolumab in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients [see Clinical Studies (14. 12) Clinical studies in patients with recurrent head and neck SCC, or dMMR or MSI-H metastatic CRC (mCRC) who were treated with single agent intravenous nivolumab did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients [see Clinical Studies (14. 9) Of the 179 patients with NSCLC who were randomized to intravenous nivolumab in combination with platinum-doublet chemotherapy, 48% were 65 years old or older and 6% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years [see Clinical Studies (14. 4) Of the 229 patients with NSCLC who were randomized to intravenous nivolumab 360 mg in combination with platinum-doublet chemotherapy every 3 weeks for up to 4 cycles, followed by intravenous nivolumab 480 mg every 4 weeks, 56% were 65 years old or older and 7% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years. Of the 1,110 patients with ESCC, GC, GEJC, or EAC who were randomized to intravenous nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy, 42% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14. 12) Of the 304 patients with UC who were treated with intravenous nivolumab in combination with gemcitabine and platinum-doublet chemotherapy, 40% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age and over and younger patients. Clinical studies of intravenous nivolumab with platinum-doublet chemotherapy did not include sufficient numbers of patients aged 75 years and over to determine whether safety and effectiveness differs compared to younger patients. [see Clinical Studies (14. 8) Of the 320 patients with renal cell carcinoma who were treated with intravenous nivolumab in combination with cabozantinib, 41% were 65 years or older and 9% were 75 years or older.

NONCLINICAL TOXICOLOGY
No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature. Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is at least 600 times higher than the human dose (U/kg basis), of 10,000 U once every 2 weeks, 15,000 U once every 3 weeks, or 20,000 U once every 4 weeks, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e. , semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data. In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis M. tuberculosis.
CLINICAL STUDIES
Previously Treated Renal Cell Carcinoma - OPDIVO QVANTIG The efficacy of OPDIVO QVANTIG was evaluated in CHECKMATE-67T (NCT04810078), a multicenter, randomized, open-label study in patients with advanced or metastatic clear cell renal cell carcinoma. Patients 18 years of age or older with histologically confirmed advanced or metastatic renal cell carcinoma with a clear cell component, including those with sarcomatoid features, and who received no more than 2 prior systemic treatment regimens were randomized to receive OPDIVO QVANTIG (containing 1,200 mg of nivolumab and 20,000 units of hyaluronidase) every 4 weeks subcutaneously, or nivolumab 3 mg/kg every 2 weeks intravenously. Patients with untreated, symptomatic central nervous system (CNS) metastases; leptomeningeal metastases; concurrent malignancies requiring treatment or history of prior malignancy within the previous 2 years; active, known, or suspected autoimmune disease; or who received prior treatment with a checkpoint inhibitor were excluded from the study. Patients with asymptomatic, stable CNS metastases that did not require immediate treatment were eligible if there was no evidence of progression within 28 days prior to the first dose of study drug administration. Stratification factors for randomization were weight (<80 kg vs >=80 kg) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification (favorable vs intermediate, vs poor risk). The primary objective was to assess the nivolumab exposure of subcutaneous administration of OPDIVO QVANTIG as compared to the intravenous administration of nivolumab. The secondary objective of the study was to evaluate overall response rate (ORR) by blinded independent central review (BICR). A total of 495 patients were randomized to receive either OPDIVO QVANTIG (n=248) or intravenous nivolumab (n=247). The median age was 65 years (range: 20 to 93), with 51% >=65 years of age and 14% >=75 years of age; 68% male; 85% White, 12. 5% not reported, 1% American Indian or Alaska Native, 0. 8% Asian, and 0. 4% Black; 36% Hispanic or Latino, 33% not Hispanic or Latino, and 31% not reported. Fifty-seven percent of patients weighed <80 kg and 43% weighed >=80 kg. Baseline Karnofsky performance status was 70 (7%), 80 (20%), 90 (34%), or 100 (39%). Patient distribution by IMDC risk categories was 21% favorable, 62% intermediate, and 17% poor. When comparing subcutaneous administration of OPDIVO QVANTIG to the intravenous administration of nivolumab, CHECKMATE-67T met the predefined acceptance margin for pharmacokinetic endpoints, with the lower boundary of 90% confidence interval of geometric mean ratios of not less than 0. 8 for both serum nivolumab C avg min [see Clinical Pharmacology 12. 3 Table 45: Efficacy Results - CHECKMATE-67T a OPDIVO QVANTIG N=248 Intravenous Nivolumab N=247 ORR per BICR, n (%) 60 (24) 45 (18) 95% CI a (19, 30) (14, 24) RCC Trials - Intravenous Nivolumab The effectiveness of OPDIVO QVANTIG has been established for the following: Use of OPDIVO QVANTIG for these RCC indications is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab in the CHECKMATE-67T trial [see Adverse Reactions (6. 1) Clinical Pharmacology (12. 3) Clinical Studies (14. 1) CHECKMATE-214 CHECKMATE-214 (NCT02231749) was a randomized (1:1), open-label trial in patients with previously untreated advanced RCC. Patients were included regardless of their PD-L1 status. CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and region. Efficacy was evaluated in intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the IMDC criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status 10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal). Patients were randomized to nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by nivolumab 3 mg/kg intravenously every two weeks (n=425), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=422). Treatment continued until disease progression or unacceptable toxicity. The trial population characteristics were: median age was 61 years (range: 21 to 85) with 38% >=65 years of age and 8% >=75 years of age. The majority of patients were male (73%) and White (87%) and 26% and 74% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. The major efficacy outcome measures were OS, PFS (independent radiographic review committee [IRRC]-assessed) and confirmed ORR (IRRC-assessed) in intermediate/poor risk patients. In this population, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to intravenous nivolumab and ipilimumab as compared with sunitinib (Table 46 and Figure 1). OS benefit was observed regardless of PD-L1 expression level. The trial did not demonstrate a statistically significant improvement in PFS. Efficacy results are shown in Table 46 and Figure 1. Table 46: Efficacy Results - CHECKMATE-214 a b c d e f g Intermediate/Poor-Risk Intravenous Nivolumab and Ipilimumab Sunitinib Overall Survival Deaths (%) 140 (32. 5) Median survival (months) NR a 25. 9 Hazard ratio (99. 89) p-value c,d <0. 0001 Confirmed Overall Response Rate (95% CI) 41. 0) p-value e,f <0. 0001 Complete response (CR) 40 (9. 2) Partial response (PR) 137 (32. 4) Median duration of response (months) (95% CI) NR a a 18. 8, NR a Progression-free Survival Disease progression or death (%) 228 (53. 0) Median (months) 11. 4 Hazard ratio (99. 05) p-value c NS g Figure 1: Overall Survival (Intermediate/Poor Risk Population) - CHECKMATE-214 CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to intravenous nivolumab and ipilimumab (n=125) or to sunitinib (n=124). These patients were not evaluated as part of the efficacy analysis population. OS in favorable risk patients receiving intravenous nivolumab and ipilimumab compared to sunitinib has a hazard ratio of 1. 45 (95% CI: 0. The efficacy of intravenous nivolumab and ipilimumab in previously untreated renal cell carcinoma with favorable-risk disease has not been established. CHECKMATE-9ER CHECKMATE-9ER (NCT03141177) was a randomized, open-label study of intravenous nivolumab combined with cabozantinib versus sunitinib in patients with previously untreated advanced RCC. CHECKMATE-9ER excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression. Patients were stratified by IMDC prognostic score (favorable vs. intermediate vs. poor), PD-L1 tumor expression (>=1% vs. <1% or indeterminate), and region (US/Canada/Western Europe/Northern Europe vs. Rest of World). Patients were randomized to nivolumab 240 mg intravenously every 2 weeks and cabozantinib 40 mg orally daily (n=323), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (4 weeks on treatment followed by 2 weeks off) (n=328). Treatment continued until disease progression per RECIST v1. 1 or unacceptable toxicity. Treatment beyond RECIST‑defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every 12 weeks thereafter. The trial population characteristics were: median age 61 years (range: 28 to 90) with 38% >=65 years of age and 10% >=75 years of age. The majority of patients were male (74%) and White (82%) and 23% and 77% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. Patient distribution by IMDC risk categories was 22% favorable, 58% intermediate, and 20% poor. The major efficacy outcome measure was PFS (BICR assessed). Additional efficacy outcome measures were OS and ORR (BICR assessed). The trial demonstrated a statistically significant improvement in PFS, OS, and ORR for patients randomized to intravenous nivolumab and cabozantinib compared with sunitinib. Consistent results for PFS were observed across pre-specified subgroups of IMDC risk categories and PD-L1 tumor expression status. An updated OS analysis was conducted when 271 deaths were observed based on the pre-specified number of deaths for the pre-planned final analysis of OS. Efficacy results are shown in Table 47 and Figures 2 and 3. Table 47: Efficacy Results - CHECKMATE-9ER a b c d e f g h Intravenous Nivolumab and Cabozantinib Sunitinib Progression-free Survival Disease progression or death (%) 144 (45) 191 (58) Median PFS (months) a 16. 7) Hazard ratio (95% CI) b 0. 64) p-value c,d <0. 0001 Overall Survival Deaths (%) 67 (21) 99 (30) Median OS (months) a NR e NR (22. 6, NR e Hazard ratio (98. 89% CI) b 0. 89) p-value c,d,f 0. 0010 Updated Overall Survival Deaths (%) 121 (37) 150 (46) Median OS (months) a 37. 0, NR) Hazard ratio (95% CI) b 0. 90) Confirmed Objective Response Rate (95% CI) g 55. 3) p-value h <0. 0001 Complete Response 26 (8%) 15 (4. 6%) Partial Response 154 (48%) 74 (23%) Median duration of response in months (95% CI) a 20. 4) Figure 2: Progression-free Survival - CHECKMATE-9ER Figure 3: Updated Overall Survival - CHECKMATE-9ER In an exploratory analysis, the updated analysis of OS in patients with IMDC favorable, intermediate, intermediate/poor, and poor risk demonstrated a HR (95% CI) of 1. 79), respectively. oq-os-checkmate-214 oq-pfs-checkmate-9er oq-updated-os-checkmate-9er CHECKMATE-025 CHECKMATE-025 (NCT01668784) was a randomized (1:1), open-label trial in patients with advanced RCC who had experienced disease progression during or after one or two prior anti-angiogenic therapy regimens. Patients had to have a Karnofsky Performance Score (KPS) >=70% and patients were included regardless of their PD-L1 status. The trial excluded patients with any history of or concurrent brain metastases, prior treatment with an mTOR inhibitor, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by region, Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group and the number of prior anti-angiogenic therapies. Patients were randomized to nivolumab 3 mg/kg by intravenous infusion every 2 weeks (n=410) or everolimus 10 mg orally daily (n=411). The first tumor assessments were conducted 8 weeks after randomization and continued every 8 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. The major efficacy outcome measure was overall survival (OS). The trial population characteristics were: median age was 62 years (range: 18 to 88) with 40% >=65 years of age and 9% >=75 years of age. The majority of patients were male (75%) and White (88%) and 34% and 66% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. The majority of patients (77%) were treated with one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 34% favorable, 47% intermediate, and 19% poor. The trial demonstrated a statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with everolimus at the prespecified interim analysis when 398 events were observed (70% of the planned number of events for final analysis). Efficacy results are shown in Table 48 and Figure 4. Table 48: Efficacy Results - CHECKMATE-025 a b c d Intravenous Nivolumab Everolimus Overall Survival Deaths (%) 183 (45) 215 (52) Median survival (months) (95% CI) 25. 1) Hazard ratio (95% CI) b 0. 89) p-value c,d 0. 0018 Confirmed Overall Response Rate (95% CI) 21. 2) Median duration of response (months) (95% CI) 23. 9) Median time to onset of confirmed response (months) (min, max) 3. 2) Figure 4: Overall Survival - CHECKMATE-025 oq-os-checkmate-025 Previously Treated Metastatic Melanoma The effectiveness of OPDIVO QVANTIG has been established for the treatment of previously treated unresectable or metastatic melanoma. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6. 3) OPDIVO QVANTIG is not indicated for the treatment of pediatric patients. CHECKMATE-037 CHECKMATE-037 (NCT01721746) was a multicenter, open-label trial that randomized (2:1) patients with unresectable or metastatic melanoma to receive nivolumab 3 mg/kg intravenously every 2 weeks or investigator’s choice of chemotherapy, either single-agent dacarbazine 1000 mg/m 2 2 Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received intravenous nivolumab in CHECKMATE-037 and in whom the minimum duration of follow-up was 6 months. The major efficacy outcome measures in this population were confirmed overall response rate (ORR) as measured by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST 1. 1) and duration of response. Among the 120 patients treated with intravenous nivolumab, the median age was 58 years (range: 25 to 88), 65% of patients were male, 98% were White, and the ECOG performance score was 0 (58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V600 mutation positive (22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic therapies for metastatic disease (68%). The ORR was 32% (95% confidence interval [CI]: 23, 41), consisting of 4 complete responses and 34 partial responses in intravenous nivolumab-treated patients. Of 38 patients with responses, 87% had ongoing responses with durations ranging from 2. 6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer. There were responses in patients with and without BRAF V600 mutation-positive melanoma. A total of 405 patients were randomized and the median duration of OS was 15. 7 months (95% CI: 12. 9) in nivolumab-treated patients compared to 14. 4 months (95% CI: 11. 24) in patients assigned to investigator’s choice of treatment. Figure 5 summarizes the OS results. Figure 5: Overall Survival - CHECKMATE-037* * The primary OS analysis was not adjusted to account for subsequent therapies, with 54 (40. 6%) patients in the chemotherapy arm subsequently receiving an anti-PD1 treatment. OS may be confounded by dropout, imbalance of subsequent therapies, and differences in baseline factors. The effectiveness of OPDIVO QVANTIG has been established for the treatment of previously untreated unresectable or metastatic melanoma. Use of OPDIVO QVANTIG for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6. CHECKMATE-066 CHECKMATE-066 (NCT01721772) was a multicenter, double-blind, randomized (1:1) trial in 418 patients with BRAF V600 wild-type unresectable or metastatic melanoma. Patients were randomized to receive either nivolumab 3 mg/kg by intravenous infusion every 2 weeks or dacarbazine 1000 mg/m 2 The trial population characteristics were: median age was 65 years (range: 18 to 87), 59% were male, and 99. 5% were White. Disease characteristics were M1c stage disease (61%), cutaneous melanoma (74%), mucosal melanoma (11%), elevated LDH level (37%), PD-L1 >=5% tumor cell membrane expression (35%), and history of brain metastasis (4%). More patients in the intravenous nivolumab arm had an ECOG performance status of 0 (71% vs. CHECKMATE-066 demonstrated a statistically significant improvement in OS for the intravenous nivolumab arm compared with the dacarbazine arm in an interim analysis based on 47% of the total planned events for OS. At the time of analysis, 88% (63/72) of intravenous nivolumab-treated patients had ongoing responses, which included 43 patients with ongoing response of 6 months or longer. Efficacy results are shown in Table 49 and Figure 6. Table 49: Efficacy Results - CHECKMATE-066 a b c d Intravenous Nivolumab Dacarbazine Overall Survival Deaths (%) 50 (24) 96 (46) Median (months) (95% CI) NR a 10. 60) p-value c,d <0. 0001 Progression-free Survival Disease progression or death (%) 108 (51) 163 (78) Median (months) (95% CI) 5. 4) Hazard ratio (95% CI) b 0. 56) p-value c,d <0. 0001 Overall Response Rate 34% 9% (95% CI) (28, 41) (5, 13) Complete response rate 4% 1% Partial response rate 30% 8% Figure 6: Overall Survival - CHECKMATE-066 CHECKMATE-067 CHECKMATE-067 (NCT01844505) was a multicenter, randomized (1:1:1), double-blind trial in 945 patients with previously untreated, unresectable or metastatic melanoma to one of the following arms: intravenous nivolumab and ipilimumab, intravenous nivolumab, or ipilimumab. Patients were required to have completed adjuvant or neoadjuvant treatment at least 6 weeks prior to randomization and have no prior treatment with anti-CTLA-4 antibody and no evidence of active brain metastasis, ocular melanoma, autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were randomized to receive: Randomization was stratified by PD-L1 expression (>=5% vs. <5% tumor cell membrane expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M stage per the AJCC staging system (M0, M1a, M1b vs. Tumor assessments were conducted 12 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. The major efficacy outcome measures were investigator-assessed PFS per RECIST v1. Additional efficacy outcome measures were confirmed ORR and duration of response. The trial population characteristics were: median age 61 years (range: 18 to 90); 65% male; 97% White; ECOG performance score 0 (73%) or 1 (27%). Disease characteristics were: AJCC Stage IV disease (93%); M1c disease (58%); elevated LDH (36%); history of brain metastases (4%); BRAF V600 mutation-positive melanoma (32%); PD-L1 >=5% tumor cell membrane expression as determined by the clinical trials assay (46%); and prior adjuvant therapy (22%). CHECKMATE-067 demonstrated statistically significant improvements in OS and PFS for patients randomized to either intravenous nivolumab-containing arm as compared with the ipilimumab arm. The trial was not designed to assess whether adding ipilimumab to intravenous nivolumab improves PFS or OS compared to intravenous nivolumab as a single agent. Efficacy results are shown in Table 50 and Figure 7. Table 50: Efficacy Results - CHECKMATE-067 a b c d e f + Censored observation Intravenous Nivolumab and Intravenous Nivolumab Ipilimumab Overall Survival a Deaths (%) 128 (41) 142 (45) 197 (63) Hazard ratio b (95% CI) 0. 78) p-value c, d <0. 0001 Progression-free Survival a Disease progression or death 151 (48%) 174 (55%) 234 (74%) Median (months) (95% CI) 11. 9 Hazard ratio b (95% CI) 0. 69) p-value c, e <0. 0001 Confirmed Overall Response Rate a 50% 40% 14% (95% CI) (44, 55) (34, 46) (10, 18) p-value f <0. 0001 Complete response 8. 9% Partial response 41% 31% 12% Duration of Response Proportion >=6 months in duration 76% 74% 63% Range (months) 1. 8+ Figure 7: Overall Survival - CHECKMATE-067 Based on a minimum follow-up of 48 months, the median OS was not reached (95% CI: 38. 2, NR) in the intravenous nivolumab and ipilimumab arm. The median OS was 36. 9 months (95% CI: 28. 3, NR) in the intravenous nivolumab arm and 19. 9 months (95% CI: 16. 6) in the ipilimumab arm. Based on a minimum follow-up of 28 months, the median PFS was 11. 7 months (95% CI: 8. 9) in the intravenous nivolumab and ipilimumab arm, 6. 9 months (95% CI: 4. 5) in the intravenous nivolumab arm, and 2. 9 months (95% CI: 2. 2) in the ipilimumab arm. Based on a minimum follow-up of 28 months, the proportion of responses lasting >=24 months was 55% in the intravenous nivolumab and ipilimumab arm, 56% in the intravenous nivolumab arm, and 39% in the ipilimumab arm. oq-os-checkmate-066 oq-os-checkmate-067 oq-os-checkmate-037 The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. Use of OPDIVO QVANTIG for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab [see Adverse Reactions (6. CHECKMATE-76K CHECKMATE-76K (NCT04099251) was a randomized, double-blind trial in 790 patients with completely resected Stage IIB/C melanoma. Patients were randomized (2:1) to receive nivolumab 480 mg or placebo by intravenous infusion every 4 weeks for up to 1 year or until disease recurrence or unacceptable toxicity. Enrollment required complete resection of the primary melanoma with negative margins and a negative sentinel lymph node within 12 weeks prior to randomization, and ECOG performance status of 0 or 1. The trial excluded patients with ocular/uveal or mucosal melanoma, autoimmune disease, any condition requiring systemic treatment with either corticosteroids (>=10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery. Randomization was stratified by AJCC 8 th The trial population characteristics were: median age 62 years (range: 19 to 92), 61% were male, 98% were White, 0. 4% Black or African American, 0. 1% Asian, and 1. 1% race unknown, 2. 2% Hispanic or Latino, 58% Not Hispanic or Latino, 40% ethnicity unknown, and 94% had an ECOG performance status of 0. Sixty one percent had stage IIB and 39% had stage IIC melanoma. CHECKMATE-76K demonstrated a statistically significant improvement in RFS for patients randomized to the intravenous nivolumab arm compared with the placebo arm. Efficacy results are shown in Table 51 and Figure 8. Table 51: Efficacy Results - CHECKMATE-76K a b c d Intravenous Nivolumab Placebo Recurrence-free Survival Number of events, n (%) 66 (13%) 69 (26%) Median (months) b (95% CI) NR a (28. 5, NR) NR a (21. 6, NR) Hazard ratio c (95% CI) d 0. 42 Figure 8: Recurrence-free Survival - CHECKMATE-76K CHECKMATE-238 CHECKMATE-238 (NCT02388906) was a randomized, double-blind trial in 906 patients with completely resected Stage IIIB/C or Stage IV melanoma. Patients were randomized (1:1) to receive nivolumab 3 mg/kg by intravenous infusion every 2 weeks or ipilimumab 10 mg/kg intravenously every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year. Enrollment required complete resection of melanoma with margins negative for disease within 12 weeks prior to randomization. The trial excluded patients with a history of ocular/uveal melanoma, autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (>=10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed >=6 months prior to randomization. Randomization was stratified by PD-L1 status (positive [based on 5% level] vs. negative/indeterminate) and AJCC stage (Stage IIIB/C vs. Stage IV M1a-M1b vs. Stage IV M1c). The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause, whichever occurs first and as assessed by the investigator. Patients underwent imaging for tumor recurrence every 12 weeks for the first 2 years then every 6 months thereafter. The trial population characteristics were: median age was 55 years (range: 18 to 86), 58% were male, 95% were White, and 90% had an ECOG performance status of 0. Disease characteristics were AJCC Stage IIIB (34%), Stage IIIC (47%), Stage IV (19%), M1a-b (14%), BRAF V600 mutation positive (42%), BRAF wild-type (45%), elevated LDH (8%), PD-L1 >=5% tumor cell membrane expression determined by clinical trial assay (34%), macroscopic lymph nodes (48%), and tumor ulceration (32%). CHECKMATE-238 demonstrated a statistically significant improvement in RFS for patients randomized to the intravenous nivolumab arm compared with the ipilimumab 10 mg/kg arm. Efficacy results are shown in Table 52 and Figure 9. Table 52: Efficacy Results - CHECKMATE-238 a b c d e Intravenous Nivolumab Ipilimumab 10 mg/kg Recurrence-free Survival Number of events, n (%) 154 (34%) 206 (45%) Median (months) (95% CI) NR a NR a a Hazard ratio b (95% CI) c,d 0. 65 Overall Survival Number of events, n (%) e 100 (22%) 111 (25%) Median (months) (95% CI) NR a NR a Hazard ratio b (95% CI) 0. 3148 Figure 9: Recurrence-free Survival - CHECKMATE-238 oq-rfs-checkmate-76k oq-rfs-checkmate-238 The effectiveness of OPDIVO QVANTIG has been established for the neoadjuvant treatment of resectable (tumors >=4 cm or node positive) NSCLC in combination with platinum doublet chemotherapy. Use of OPDIVO QVANTIG for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab (CHECKMATE-816, NCT02998528), and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6. 3) CHECKMATE-816 CHECKMATE-816 (NCT02998528) was a randomized, open label trial in patients with resectable NSCLC. The trial included patients with resectable, histologically confirmed Stage IB (>=4 cm), II, or IIIA NSCLC (per the 7th edition American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging criteria), ECOG performance status 0 or 1, and measurable disease (per RECIST version 1. Patients with unresectable or metastatic NSCLC, known EGFR mutations or ALK translocations, Grade 2 or greater peripheral neuropathy, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients were randomized to receive either: Platinum-doublet chemotherapy consisted of paclitaxel 175 mg/m 2 2 2 2 2 2 2 2 2 2 2 2 2 Stratification factors for randomization were tumor PD-L1 expression level (>=1% versus <1% or non-quantifiable), disease stage (IB/II versus IIIA), and sex (male versus female). Tumor assessments were performed at baseline, within 14 days of surgery, every 12 weeks after surgery for 2 years, then every 6 months for 3 years, and every year for 5 years until disease recurrence or progression. The major efficacy outcome measures were event-free survival (EFS) based on blinded independent central review (BICR) assessment and pathologic complete response (pCR) as evaluated by blinded independent pathology review (BIPR). Additional efficacy outcome measures included OS. A total of 358 patients were randomized to receive either intravenous nivolumab in combination with platinum‑doublet chemotherapy (n=179) or platinum-doublet chemotherapy (n=179). The median age was 65 years (range: 34 to 84) with 51% of patients >=65 years and 7% of patients >=75 years, 50% were Asian, 47% were White, 2% were Black, and 71% were male. Baseline ECOG performance status was 0 (67%) or 1 (33%); 50% had tumors with PD-L1 expression >=1%; 35% had stage IB/II and 64% had stage IIIA disease; 51% had tumors with squamous histology and 49% had tumors with non-squamous histology; and 89% were former/current smokers. Eighty-three percent of patients in the intravenous nivolumab in combination with platinum-doublet chemotherapy arm had definitive surgery compared to 75% of patients in the platinum-doublet chemotherapy arm. The study demonstrated statistically significant improvements in EFS and pCR. Efficacy results are presented in Table 53 and Figure 10. Table 53: Efficacy Results - CHECKMATE-816 Minimum follow-up for EFS was 21 months. a b c d e f Intravenous Nivolumab and Platinum-Doublet Chemotherapy Platinum-Doublet Chemotherapy Event-free Survival (EFS) per BICR Events (%) 64 (35. 6) Median (months) a (95% CI) 31. 7) Hazard Ratio b (95% CI) 0. 87) Stratified log-rank p-value c 0. 0052 Pathologic Complete Response (pCR) per BIPR Number of patients with pCR 43 4 pCR Rate (%), (95% CI) d 24. 6) Estimated treatment difference (95% CI) e 21. 2) p-value f <0. 0001 Figure 10: Event-Free Survival - CHECKMATE-816 At the time of the EFS analysis, 26% of the patients had died. A prespecified interim analysis for OS resulted in a HR of 0. 57 (95% CI: 0. 87), which did not cross the boundary for statistical significance. oq-efs-checkmate-816 The effectiveness of OPDIVO QVANTIG has been established for neoadjuvant treatment of resectable (tumors >=4 cm or node positive) NSCLC and no EGFR mutations or ALK rearrangements in combination with platinum doublet chemotherapy followed by adjuvant treatment with intravenous nivolumab. Use of OPDIVO QVANTIG for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab (CHECKMATE-77T, NCT04025879), and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6. 3) CHECKMATE-77T The efficacy of intravenous nivolumab, in combination with platinum-doublet chemotherapy, followed by surgery, and continued adjuvant treatment with intravenous nivolumab as a single agent, was investigated in CHECKMATE-77T (NCT04025879), a randomized, double-blind trial in 461 patients with resectable NSCLC. The trial included patients with resectable, suspected or histologically confirmed Stage IIA (>4 cm) to IIIB (T3-T4 N2) NSCLC (per the 8th edition American Joint Committee on Cancer (AJCC) Staging Manual), and ECOG performance status 0 or 1. Patients with unresectable or metastatic NSCLC, EGFR mutations or known ALK translocations, brain metastasis, Grade 2 or greater peripheral neuropathy, interstitial lung disease or active, non-infectious pneumonitis (symptomatic and/or requiring treatment), active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Randomization was stratified by tumor PD-L1 expression level (>=1% versus <1% versus indeterminate/not evaluable), disease stage (Stage II versus Stage III), and tumor histology (squamous versus nonsquamous). Patients were randomized (1:1) to receive either: ∘ 2 2 ∘ 2 2 ∘ 2 2 or (see above) All study medications were administered via intravenous infusion. Treatment continued until disease progression, recurrence, or unacceptable toxicity for up to 13 cycles (1 year). Tumor assessments were performed every 12 weeks for 2 years, then every 24 weeks for up to 5 years or until disease recurrence or progression was confirmed by BICR. The trial was not designed to isolate the effect of intravenous nivolumab in each phase (neoadjuvant or adjuvant) of treatment. The major efficacy outcome measure was event-free survival (EFS) based on BICR assessment. Additional efficacy outcome measures included overall survival (OS), pathologic complete response (pCR), and major pathologic response (MPR). The median age was 66 years (range: 35 to 86); 71% were male; 72% were White, 25% were Asian, 1. 7% were Black, and 1. 5% were mixed race/ race unknown/ not reported; and 6% were Hispanic or Latino. Baseline ECOG performance status was 0 (62%) or 1 (38%); 56% had tumors with PD-L1 expression >=1% and 40% had tumors with PD-L1 expression <1%; 35% had stage II and 64% had stage III disease; 23% had N1 disease and 39% had N2 disease; 51% had tumors with squamous histology and 49% had tumors with nonsquamous histology; and 90% were former/current smokers. Seventy-eight percent of patients in the neoadjuvant intravenous nivolumab in combination with platinum-doublet chemotherapy followed by adjuvant intravenous nivolumab arm had definitive surgery compared to 77% of patients in the neoadjuvant placebo and platinum-doublet chemotherapy followed by placebo arm. The study demonstrated a statistically significant improvement in EFS for patients treated with neoadjuvant intravenous nivolumab in combination with platinum-doublet chemotherapy followed by single agent intravenous nivolumab compared with patients randomized to placebo in combination with platinum-doublet chemotherapy followed by placebo. Efficacy results are presented in Table 54 and Figure 11. Table 54: Efficacy Results - CHECKMATE-77T a b c Neoadjuvant Intravenous Nivolumab and Platinum-Doublet Chemotherapy/Adjuvant Intravenous Nivolumab (n=229) Neoadjuvant Placebo and Platinum-Doublet Chemotherapy/Adjuvant Placebo (n=232) Event-free Survival (EFS) per BICR Events (%) 76 (33%) 113 (49%) Median (months) a (95% CI) NR (28. 1) Hazard Ratio b (95% CI) 0. 78) Stratified log-rank p-value c 0. 00025 Figure 11: Event-Free Survival - CHECKMATE-77T In a pre-specified descriptive analysis, the pCR rate was 25% (95% CI: 20, 31) in the intravenous nivolumab arm and 4. 7% (95% CI: 2. 4, 8) in the placebo arm. At the time of the EFS analysis, OS data were immature. oq-efs-checkmate-77t The effectiveness of OPDIVO QVANTIG has been established for the treatment of NSCLC previously treated with 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. 3) CHECKMATE-017 CHECKMATE-017 (NCT01642004) was a randomized (1:1), open-label trial in 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks (n=135) or docetaxel 75 mg/m 2 The trial population characteristics were: median age was 63 years (range: 39 to 85) with 44% >=65 years of age and 11% >=75 years of age. The majority of patients were White (93%) and male (76%); the majority of patients were enrolled in Europe (57%) with the remainder in US/Canada (32%) and the rest of the world (11%). Baseline ECOG performance status was 0 (24%) or 1 (76%) and 92% were former/current smokers. Baseline disease characteristics of the population as reported by investigators were Stage IIIb (19%), Stage IV (80%), and brain metastases (6%). All patients received prior therapy with a platinum-doublet regimen and 99% of patients had tumors of squamous-cell histology. The trial demonstrated a statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with docetaxel at the prespecified interim analysis when 199 events were observed (86% of the planned number of events for final analysis). Efficacy results are shown in Table 55 and Figure 12. Table 55: Efficacy Results - CHECKMATE-017 a b c d e Intravenous Nivolumab Docetaxel Overall Survival Deaths (%) 86 (64%) 113 (82%) Median (months) (95% CI) 9. 0 Hazard ratio (95% CI) a 0. 79) p-value b,c 0. 0002 Overall Response Rate 27 (20%) 12 (9%) (95% CI) (14, 28) (5, 15) p-value d 0. 0083 Complete response 1 (0. 7%) 0 Median duration of response (months) (95% CI) NR e e 8. 4 Progression-free Survival Disease progression or death (%) 105 (78%) 122 (89%) Median (months) 3. 8 Hazard ratio (95% CI) a 0. 81) p-value b 0. 0004 Figure 12: Overall Survival - CHECKMATE-017 Archival tumor specimens were retrospectively evaluated for PD-L1 expression. Across the trial population, 17% of 272 patients had non-quantifiable results. Among the 225 patients with quantifiable results, 47% had PD-L1 negative squamous NSCLC, defined as <1% of tumor cells expressing PD-L1 and 53% had PD-L1 positive squamous NSCLC defined as >=1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratios for survival were 0. 58 (95% CI: 0. 92) in the PD-L1 negative subgroup and 0. 69 (95% CI: 0. 05) in the PD-L1 positive subgroup. CHECKMATE-057 CHECKMATE-057 (NCT01673867) was a randomized (1:1), open-label trial in 582 patients with metastatic non-squamous NSCLC who had experienced disease progression during or after one prior platinum doublet‑based chemotherapy regimen. Appropriate prior targeted therapy in patients with known sensitizing EGFR mutation or ALK translocation was allowed. Patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks (n=292) or docetaxel 75 mg/m 2 The trial population characteristics: median age was 62 years (range: 21 to 85) with 42% of patients >=65 years and 7% of patients >=75 years. The majority of patients were White (92%) and male (55%); the majority of patients were enrolled in Europe (46%) followed by the US/Canada (37%) and the rest of the world (17%). Baseline ECOG performance status was 0 (31%) or 1 (69%), 79% were former/current smokers, 3. 6% had NSCLC with ALK rearrangement, 14% had NSCLC with EGFR mutation, and 12% had previously treated brain metastases. Prior therapy included platinum-doublet regimen (100%) and 40% received maintenance therapy as part of the first-line regimen. Histologic subtypes included adenocarcinoma (93%), large cell (2. 4%), and bronchoalveolar (0. CHECKMATE-057 demonstrated a statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with docetaxel at the prespecified interim analysis when 413 events were observed (93% of the planned number of events for final analysis). Efficacy results are shown in Table 56 and Figure 13. Table 56: Efficacy Results - CHECKMATE-057 a b c d e Intravenous Nivolumab Docetaxel Overall Survival Deaths (%) 190 (65%) 223 (77%) Median (months) (95% CI) 12. 4 Hazard ratio (95% CI) a 0. 89) p-value b,c 0. 0015 Overall Response Rate 56 (19%) 36 (12%) (95% CI) (15, 24) (9, 17) p-value d 0. 02 Complete response 4 (1. 3%) Median duration of response (months) (95% CI) 17 e 6 (4. 0) Progression-free Survival Disease progression or death (%) 234 (80%) 245 (84%) Median (months) 2. 2 Hazard ratio (95% CI) a 0. 11) p-value b 0. 39 Figure 13: Overall Survival - CHECKMATE-057 Archival tumor specimens were evaluated for PD-L1 expression following completion of the trial. Across the trial population, 22% of 582 patients had non-quantifiable results. Of the remaining 455 patients, the proportion of patients in retrospectively determined subgroups based on PD-L1 testing using the PD-L1 IHC 28-8 pharmDx assay were: 46% PD-L1 negative, defined as <1% of tumor cells expressing PD-L1 and 54% had PD-L1 expression, defined as >=1% of tumor cells expressing PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% had >=1% but <5% tumor cells with positive staining, 7% had >=5% but <10% tumor cells with positive staining, and 67% had >=10% tumor cells with positive staining. Figures 14 and 15 summarize the results of prespecified analyses of OS and PFS in subgroups determined by percentage of tumor cells expressing PD-L1. Figure 14: Forest Plot: OS Based on PD-L1 Expression - CHECKMATE-057 Figure 15: Forest Plot: PFS Based on PD-L1 Expression - CHECKMATE-057 oq-os-checkmate-017 oq-os-checkmate-057 oq-forest-plot-os-checkmate-057 oq-forest-plot-pfs-checkmate-057 The effectiveness of OPDIVO QVANTIG has been established for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after platinum-based therapy. 3) CHECKMATE-141 CHECKMATE-141 (NCT02105636) was a randomized (2:1), active-controlled, open-label trial enrolling patients with metastatic or recurrent SCCHN who had experienced disease progression during or within 6 months of receiving platinum-based therapy administered in either the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. The trial excluded patients with autoimmune disease, medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e. , mucosal melanoma), or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. Patients were randomized to receive nivolumab 3 mg/kg by intravenous infusion every 2 weeks or investigator’s choice of cetuximab (400 mg/m 2 2 2 2 Randomization was stratified by prior cetuximab treatment (yes/no). The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and ORR. A total of 361 patients were randomized; 240 patients to the intravenous nivolumab arm and 121 patients to the investigator’s choice arm (docetaxel: 45%; methotrexate: 43%; and cetuximab: 12%). The trial population characteristics were: median age was 60 years (range: 28 to 83) with 31% >=65 years of age, 83% were White, 12% Asian, and 4% were Black, and 83% male. Baseline ECOG performance status was 0 (20%) or 1 (78%), 76% were former/current smokers, 90% had Stage IV disease, 45% of patients received only one prior line of systemic therapy, the remaining 55% received two or more prior lines of systemic therapy, and 25% had HPVp16-positive tumors, 24% had HPV p16-negative tumors, and 51% had unknown status. The trial demonstrated a statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with investigator’s choice at a pre-specified interim analysis (78% of the planned number of events for final analysis). There were no statistically significant differences between the two arms for PFS (HR=0. 89; 95% CI: 0. 13) or ORR (13. 3% [95% CI: 9. 8% [95% CI: 2. 6] for nivolumab and investigator’s choice, respectively). Efficacy results are shown in Table 57 and Figure 16. Table 57: Overall Survival - CHECKMATE-141 a b c Intravenous Nivolumab Cetuximab, Methotrexate or Docetaxel Overall Survival Deaths (%) 133 (55%) 85 (70%) Median (months) (95% CI) 7. 0) Hazard ratio (95% CI) a 0. 92) p-value b,c 0. 0101 Figure 16: Overall Survival - CHECKMATE-141 Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1 IHC 28-8 pharmDx assay. Across the trial population, 28% (101/361) of patients had non-quantifiable results. Among the 260 patients with quantifiable results, 43% (111/260) had PD-L1 negative SCCHN, defined as <1% of tumor cells expressing PD-L1, and 57% (149/260) had PD-L1 positive SCCHN, defined as >=1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratio for survival was 0. 89 (95% CI: 0. 45) with median survivals of 5. 8 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 negative subgroup. The HR for survival was 0. 55 (95% CI: 0. 83) with median survivals of 8. 6 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 positive SCCHN subgroup. oq-os-checkmate-141 The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of UC at high risk of recurrence. 3) CHECKMATE-274 CHECKMATE-274 (NCT02632409) was a randomized, double-blind, placebo‑controlled study of adjuvant intravenous nivolumab in patients who were within 120 days of radical resection (R0) of UC of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence. High risk of recurrence was defined as either 1) ypT2-ypT4a or ypN + + The trial population characteristics were: median age of 67 years (range: 30 to 92); 76% male; 76% White, 22% Asian, 0. 7% Black, and 0. 1% American Indian or Alaska Native. Of the 335 (47%) of patients with node-positive UC, 44 (6%) had nonen dashmuscle-invasive (=1% in 40% of patients, and 21% of patients had upper tract UC. The major efficacy outcome measures were investigator-assessed DFS in all randomized patients and in patients with tumors expressing PD-L1 >=1%. DFS was defined as time to first recurrence (local urothelial tract, local non-urothelial tract, or distant metastasis), or death. At the pre-specified interim analysis, CHECKMATE-274 demonstrated a statistically significant improvement in DFS for patients randomized to intravenous nivolumab vs. placebo in the all randomized patient population, as well as in the subpopulation of patients with PD-L1 >=1%, as shown in Table 58 and Figure 17. In exploratory subgroup analyses in patients with upper tract UC (n=149), no improvement in DFS was observed in the nivolumab arm compared to the placebo arm. The unstratified DFS hazard ratio estimate was 1. 15 (95% CI: 0. In an exploratory subgroup analysis in patients with PD-L1 expression of <1% (n=414), the unstratified DFS hazard ratio estimate was 0. 83 (95% CI: 0. OS data is immature with 33% of deaths in the overall randomized population. In the UTUC subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm). Table 58: Efficacy Results - CHECKMATE-274 N. Not reached, N. Not estimable a b c d e All Randomized PD-L1 >=1% Intravenous Nivolumab (n=353) Placebo (n=356) Intravenous Nivolumab (n=140) Placebo (n=142) Disease-free Survival Events a Local recurrence Distant recurrence Death 170 (48) 47 (13) 108 (31) 14 (4) 204 (57) 64 (18) 127 (36) 10 (3) 55 (39) 10 (7) 40 (29) 5 (4) 81 (57) 24 (17) 52 (37) 5 (4) Median DFS (months) b (95% CI) 20. 2) Hazard ratio c (95% CI) 0. 77) p-value 0. 0005 e Figure 17: Disease-free Survival in All Randomized Patients - CHECKMATE-274 oq-dfs-checkmate-274 The effectiveness of OPDIVO QVANTIG has been established for the first-line treatment of unresectable or metastatic UC in combination with cisplatin and gemcitabine. 3) CHECKMATE-901 CHECKMATE-901 (NCT 03036098) was a randomized, open-label study in patients with previously untreated unresectable or metastatic UC. Prior neoadjuvant or adjuvant chemotherapy were permitted as long as the disease recurrence took place >=12 months from completion of therapy. Patients who were ineligible for cisplatin and those with active CNS metastases were excluded. Stratification factors for randomization were PD-L1 status (>=1% vs. <1% or indeterminate) and liver metastasis. Patients were randomized 1:1 to receive either: 2 2 2 2 The major efficacy outcome measures were OS and PFS as assessed by BICR using RECIST v1. Additional efficacy outcome measures included ORR as assessed by BICR. The median age was 65 years of age (range: 32 to 86) with 51% of patients >=65 years of age and 12% of patients >=75 years of age, 23% were Asian, 72% were White, 0. 3% were Black, 0. 3% were American Indian or Alaska Native, 4. 9% were Other, 12% were Hispanic or Latino, and 77% were male. Baseline ECOG performance status was 0 (53%) or 1 (46%). At baseline, 87% of patients had metastatic UC, including 20% with liver metastases, 11% had locally advanced UC, and 51% had UC histologic variants. Forty-nine (16%) in the intravenous nivolumab in combination with cisplatin-based chemotherapy arm and 43 (14%) in the cisplatin-based chemotherapy arm switched from cisplatin to carboplatin after at least one cycle of cisplatin. Efficacy results are presented in Table 59 and Figures 18 and 19. Table 59: Efficacy Results en dash CHECKMATE-901 a b c d Intravenous Nivolumab and Cisplatin and Gemcitabine Cisplatin and Gemcitabine (n=304) Overall Survival (OS) Events, n (%) 172 (56. 5) Median (months) (95% CI) a 21. 9 Hazard ratio (95% CI) b 0. 78 p-value c 0. 0171 Progression-free Survival (PFS) d Events, n (%) 211 (69. 8) Median (months) (95% CI) a 7. 6 Hazard ratio (95% CI) b 0. 72 p-value c 0. 0012 Objective Response Rate (ORR) d Response rate, n (%) (95% CI) 175 (57. 9) Complete response rate, n (%) 66 (22%) 36 (12%) Partial response rate, n (%) 109 (36%) 95 (31%) Duration of Response (DoR) Median (months) (95% CI) a 9. 3 Figure 18: Overall Survival - CHECKMATE-901 Figure 19: Progression-free Survival - CHECKMATE-901 oq-os-checkmate-901 oq-pfs-checkmate-901 The effectiveness of OPDIVO QVANTIG has been established for the treatment of patients with locally advanced or metastatic UC and disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 3) CHECKMATE-275 CHECKMATE-275 (NCT02387996) was a single-arm trial in 270 patients with locally advanced or metastatic UC who had disease progression during or following platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients were excluded for active brain or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, and ECOG performance status >1. Patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 8 weeks for the first 48 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed ORR as assessed by IRRC using RECIST v1. The median age was 66 years (range: 38 to 90), 78% were male, 86% were White. Twenty-seven percent had non-bladder urothelial carcinoma and 84% had visceral metastases. Thirty-four percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy. Twenty-nine percent of patients had received >=2 prior systemic regimens in the metastatic setting. Thirty-six percent of patients received prior cisplatin only, 23% received prior carboplatin only, and 7% were treated with both cisplatin and carboplatin in the metastatic setting. Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent of patients had a hemoglobin <10 g/dL, and twenty-eight percent of patients had liver metastases at baseline. Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 270 patients, 46% were defined as having PD-L1 expression of >=1% (defined as >=1% of tumor cells expressing PD-L1). The remaining 54% of patients were classified as having PD-L1 expression of <1% (defined as <1% of tumor cells expressing PD-L1). Confirmed ORR in all patients and the two PD-L1 subgroups are shown in Table 60. Median time to response was 1. 9 months (range: 1. In 77 patients who received prior systemic therapy only in the neoadjuvant or adjuvant setting, the ORR was 23. 4% (95% CI: 14. Table 60: Efficacy Results - CHECKMATE-275 a b All Patients N=270 PD-L1 <1% N=146 PD-L1 >=1% N=124 Confirmed Overall Response Rate, n (%) (95% CI) 53 (19. 6) Complete response rate 7 (2. 8%) Partial response rate 46 (17. 2%) Median Duration of Response a 10. 0+) NR b The effectiveness of OPDIVO QVANTIG has been established for the treatment of microsatellite instability-high or mismatch repair deficient colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of OPDIVO QVANTIG for this indication is supported by evidence from an adequate and well-controlled study conducted with intravenous nivolumab (CHECKMATE-142, NCT02060188), and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6. CHECKMATE-142 CHECKMATE-142 (NCT02060188) was a multicenter, non-randomized, multiple parallel-cohort, open-label trial conducted in patients with locally determined dMMR or MSI-H metastatic CRC (mCRC) who had disease progression during or after prior treatment with fluoropyrimidine‑ , oxaliplatin‑ , or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line of treatment for metastatic disease, ECOG performance status 0 or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients enrolled in the single agent intravenous nivolumab MSI-H mCRC cohort received nivolumab 3 mg/kg by intravenous infusion (IV) every 2 weeks. Patients enrolled in the intravenous nivolumab and ipilimumab MSI-H mCRC cohort received nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses, followed by nivolumab as a single agent at a dose of 3 mg/kg as intravenous infusion every 2 weeks. Treatment in both cohorts continued until unacceptable toxicity or radiographic progression. Tumor assessments were conducted every 6 weeks for the first 24 weeks and every 12 weeks thereafter. Efficacy outcome measures included ORR and DOR as assessed by BICR using RECIST v1. A total of 74 patients were enrolled in the single-agent MSI-H mCRC intravenous nivolumab cohort. The median age was 53 years (range: 26 to 79) with 23% >=65 years of age and 5% >=75 years of age, 59% were male and 88% were White. Baseline ECOG performance status was 0 (43%), 1 (55%), or 3 (1. 4%) and 36% were reported to have Lynch Syndrome. Across the 74 patients, 72% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 7%, 30%, 28%, 19%, and 16% received 0, 1, 2, 3, or >=4 prior lines of therapy for metastatic disease, respectively, and 42% of patients had received an anti-EGFR antibody. A total of 119 patients were enrolled in the intravenous nivolumab and ipilimumab MSI-H mCRC cohort. The median age was 58 years (range: 21 to 88), with 32% >=65 years of age and 9% >=75 years of age; 59% were male and 92% were White. Baseline ECOG performance status was 0 (45%) and 1 (55%), and 29% were reported to have Lynch Syndrome. Across the 119 patients, 69% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%, 24%, and 15% received 1, 2, 3, or >=4 prior lines of therapy for metastatic disease, respectively, and 29% had received an anti-EGFR antibody. Efficacy results for each of these single-arm cohorts are shown in Table 61. Table 61: Efficacy Results - CHECKMATE-142 a b c Intravenous Nivolumab a MSI-H/dMMR Cohort Intravenous Nivolumab and Ipilimumab b MSI-H/dMMR Cohort All Patients Prior Treatment (Fluoropyrimidine, Oxaliplatin, and Irinotecan) All Patients Prior Treatment (Fluoropyrimidine, Oxaliplatin, and Irinotecan) Overall Response Rate per BICR; n (%) 28 (38%) 17 (32%) 71 (60%) 46 (56%) (95% CI) c (27, 50) (20, 46) (50, 69) (45, 67) Complete Response (%) 8 (11%) 5 (9%) 17 (14%) 11 (13%) Partial Response (%) 20 (27%) 12 (23%) 54 (45%) 35 (43%) Duration of Response Proportion of responders with >=6 months response duration 86% 94% 89% 87% Proportion of responders with >=12 months response duration 82% 88% 77% 74% The effectiveness of OPDIVO QVANTIG has been established for the treatment of hepatocellular carcinoma in patients who have been previously treated with sorafenib and following treatment with intravenous nivolumab and ipilimumab. 3) CHECKMATE-040 CHECKMATE-040 (NCT01658878) was a multicenter, multiple cohort, open-label trial that evaluated the efficacy of intravenous nivolumab as a single agent and in combination with ipilimumab in patients with hepatocellular carcinoma (HCC) who progressed on or were intolerant to sorafenib. Additional eligibility criteria included histologic confirmation of HCC and Child‑Pugh Class A cirrhosis. The trial excluded patients with active autoimmune disease, brain metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co‑infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible. Tumor assessments were conducted every 6 weeks for 48 weeks and then every 12 weeks thereafter. The major efficacy outcome measure was confirmed overall response rate as assessed by BICR using RECIST v1. 1 and modified RECIST (mRECIST) for HCC. Duration of response was also assessed. The efficacy of intravenous nivolumab in combination with ipilimumab was evaluated in 49 patients (Cohort 4) who received intravenous nivolumab 1 mg/kg and ipilimumab 3 mg/kg administered every 3 weeks for 4 doses, followed by single-agent intravenous nivolumab at 240 mg every 2 weeks until disease progression or unacceptable toxicity. The median age was 60 years (range: 18 to 80), 88% were male, 74% were Asian, and 25% were White. Baseline ECOG performance status was 0 (61%) or 1 (39%). Fifty-seven (57%) percent of patients had active HBV infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The etiology for HCC was alcoholic liver disease in 16% and non‑alcoholic fatty liver disease in 6% of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had extrahepatic spread; 35% had vascular invasion; and 51% had AFP levels >=400 µg/L. Prior cancer treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of patients had received 2 or more prior systemic therapies. Efficacy results are shown in Table 62. The results for intravenous nivolumab in combination with ipilimumab in Cohort 4 are based on a minimum follow-up of 28 months. Table 62: Efficacy Results - Cohort 4 of CHECKMATE-040 a b Intravenous Nivolumab and Ipilimumab Overall Response Rate per BICR, a 16 (33%) (95% CI) b (20, 48) Complete response 4 (8%) Partial response 12 (24%) Duration of Response per BICR, a n=16 Range (months) 4. 5+ Percent with duration >=6 months 88% Percent with duration >=12 months 56% Percent with duration >=24 months 31% Overall Response Rate per BICR, a 17 (35%) (95% CI) b (22, 50) Complete response 6 (12%) Partial response 11 (22%) The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of resected esophageal or gastroesophageal junction cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy (CRT). 3) CHECKMATE-577 CHECKMATE-577 (NCT02743494) was a randomized, multicenter, double-blind trial in 794 patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following concurrent chemoradiotherapy (CRT). Patients were randomized (2:1) to receive either 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. Treatment was until disease recurrence, unacceptable toxicity, or for up to 1 year in total duration. Enrollment required complete resection within 4 to 16 weeks prior to randomization. The trial excluded patients who did not receive 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. Randomization was stratified by tumor PD-L1 status (>=1% vs. <1% or indeterminate or non-evaluable), pathologic lymph node status (positive >=ypN1 vs. negative ypN0), and histology (squamous vs. adenocarcinoma). The major efficacy outcome measure was disease-free survival (DFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant from the primary resected site) or death, from any cause, whichever occurred first as assessed by the investigator prior to subsequent anti-cancer therapy. Patients on treatment underwent imaging for tumor recurrence every 12 weeks for 2 years, and a minimum of one scan every 6 to 12 months for years 3 to 5. The trial population characteristics were: median age 62 years (range: 26 to 86), 36% were >=65 years of age, 85% were male, 15% were Asian, 82% were White, and 1. 1% were Black. Disease characteristics were AJCC Stage II (35%) or Stage III (65%) at initial diagnosis carcinoma, EC (60%) or GEJC (40%) at initial diagnosis, with pathologic positive lymph node status (58%) at study entry and histological confirmation of predominant adenocarcinoma (71%) or squamous cell carcinoma (29%). The baseline Tumor PD-L1 status >=1% was positive for 16% of patients and negative for 72% of patients. Baseline ECOG performance status was 0 (58%) or 1 (42%). CHECKMATE-577 demonstrated a statistically significant improvement in DFS for patients randomized to the intravenous nivolumab arm as compared with the placebo arm. DFS benefit was observed regardless of tumor PD-L1 expression and histology. Efficacy results are shown in Table 63 and Figure 20. Table 63: Efficacy Results - CHECKMATE-577 a b Intravenous Nivolumab Placebo Disease-free Survival Number of events, n (%) 241 (45%) 155 (59%) Median (months) (95% CI) 22. 3) Hazard ratio a (95% CI) 0. 85) p-value b 0. 0003 Figure 20: Disease-free Survival - CHECKMATE-577 oq-dfs-checkmate-577 The effectiveness of OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapy has been established for the first-line treatment of unresectable advanced or metastatic ESCC. 3) CHECKMATE-648 CHECKMATE-648 (NCT03143153) was a randomized, active-controlled, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC (squamous or adenosquamous histology). The trial enrolled patients whose tumor was evaluable for tumor cell (TC) PD-L1 expression [also called PD-L1 tumor proportion score (TPS)], which was evaluated using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. A retrospective scoring of a patient’s tumor PD-L1 status using Combined Positive Score (CPS), was also conducted using the PD-L1-stained tumor specimens used for randomization. Patients were not amenable to chemoradiation or surgery with curative intent. Prior treatment with curative intent was allowed if completed more than six months prior to trial enrollment. The trial excluded patients with brain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to apparent invasion of tumor to organs adjacent to the esophageal tumor. Patients were randomized to receive one of the following treatments: 2 2 2 2 Patients received intravenous nivolumab until disease progression, unacceptable toxicity, or up to 2 years. In patients who received intravenous nivolumab in combination with chemotherapy and in whom either fluorouracil and/or cisplatin were discontinued, other components of the treatment regimen were allowed to be continued. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue intravenous nivolumab as a single agent. Randomization was stratified by TC PD-L1 expression (>=1% vs. <1% or indeterminate), region (East Asia vs. Rest of Asia vs. Rest of World), ECOG performance status (0 vs. 1), and number of organs with metastases (<=1 vs. The major efficacy outcome measures were OS and BICR-assessed PFS in patients with TC PD-L1 expression >=1%. Additional efficacy measures included OS in all randomized patients, BICR-assessed PFS in all randomized patients, and ORR assessed by BICR in TC PD-L1 expression >=1% and in all randomized patients. The tumor assessments per RECIST v1. 1 were conducted every 6 weeks up to and including week 48, then every 12 weeks thereafter. A total of 970 patients were randomized in CHECKMATE-648 study among whom 965 and 906 patients had quantifiable TC PD-L1 expression and CPS at baseline, respectively. The trial population characteristics for all randomized patients were median age 64 years (range: 26 to 90), 47% were >=65 years of age, 82% were male, 71% were Asian, 26% were White, and 1. 1% were Black or African American. Patients had histological confirmation of squamous cell carcinoma (98%) or adenosquamous cell carcinoma (1. 9%) in the esophagus. Baseline ECOG performance status was 0 (47. 0%) or 1 (53%). Efficacy results are shown in Table 64 and Figures 21 and 22. Table 64: Efficacy Results - CHECKMATE-648 a b c S1, S2, S3, S4, S5 NS: Not Statistically significant, NT: Not evaluated for statistical significance as per pre-specified hierarchical testing procedure Intravenous Nivolumab with Cisplatin and Fluorouracil Intravenous Nivolumab and Ipilimumab Cisplatin and Fluorouracil Intravenous Nivolumab with Cisplatin and Fluorouracil Intravenous Nivolumab and Ipilimumab Cisplatin and Fluorouracil All Patients TC PD-L1 expression >=1% Overall Survival Deaths (%) 209 (65) 216 (66) 232 (72) 98 (62) 106 (67) 121 (77) Median (months) (95% CI) 13. 7, 10) Hazard ratio b 0. 84) - p-value c 0. 0110 S2 - <0. 0010 S4 - Progression-free Survival a Disease progression or death (%) 235 (73) 258 (79) 210 (65) 117 (74) 123 (78) 100 (64) Median (months) (95% CI) 5. 8) Hazard ratio (95% CI) b 0. 34) - p-value c NS NT - 0. 0023 S5 NS - Overall Response Rate, n (%) a, NT 152 (47. 7) (95% CI) (41. 8) Complete response (%) 43 (13. 1) Partial response (%) 109 (34. 6) Duration of Response (months) a Median (95% CI) 8. 8+ Figure 21: Overall Survival en dash CHECKMATE-648 (A) OS in All Randomized Patients (B) OS in TC PD-L1 >=1% Figure 22: Progression-free Survival en dash CHECKMATE-648 (A) PFS in All Randomized Patients (B) PFS in TC PD-L1 >=1% Exploratory subgroup analyses of patients with TC PD-L1 expression <1% (n=492) were conducted. OS results for each intravenous nivolumab containing arm compared to chemotherapy were: Exploratory subgroup analyses were also conducted by PD-L1 status per CPS (>=1 and <1) for each intravenous nivolumab containing arm compared to chemotherapy. Among the 906 patients with quantifiable PD-L1 CPS at baseline, 278 in the intravenous nivolumab with chemotherapy arm, 266 in the intravenous nivolumab with ipilimumab arm, and 280 in the chemotherapy arm had PD-L1 CPS >=1. A total of 27 patients in the intravenous nivolumab with chemotherapy arm, 31 patients in the intravenous nivolumab with ipilimumab arm, and 24 patients in the chemotherapy arm had PD-L1 CPS <1. OS results for each comparison by PD-L1 CPS status were: oq-os-checkmate-648a oq-os-checkmate-648b oq-pfs-checkmate-648a oq-pfs-checkmate-648b The effectiveness of OPDIVO QVANTIG has been established for the treatment of unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy. 3) ATTRACTION-3 ATTRACTION-3 (NCT02569242) was a multicenter, randomized (1:1), active-controlled, open‑label trial in patients with unresectable advanced, recurrent, or metastatic ESCC, who were refractory or intolerant to at least one fluoropyrimidine- and platinum‑based regimen. The trial enrolled patients regardless of PD-L1 status, but tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. 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, or had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients were randomized to receive nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks or investigator’s choice of taxane chemotherapy consisting of docetaxel (75 mg/m 2 2 Randomization was stratified by region (Japan vs. Rest of World), number of organs with metastases (<=1 vs. >=2), and PD-L1 status (>=1% vs. <1% or indeterminate). Patients were treated until disease progression, assessed by the investigator per RECIST v1. 1, or unacceptable toxicity. The tumor assessments were conducted every 6 weeks for 1 year, and every 12 weeks thereafter. Additional efficacy outcome measures were ORR and PFS as assessed by the investigator using RECIST v1. A total of 419 patients were randomized; 210 to the intravenous nivolumab arm and 209 to the investigator’s choice arm (docetaxel: 31%, paclitaxel: 69%). The trial population characteristics were: median age 65 years (range: 33 to 87), 53% were >=65 years of age, 87% were male, 96% were Asian and 4% were White. Sixty-seven percent of patients had received one prior systemic therapy regimen and 26% had received two prior systemic therapy regimens prior to enrolling in ATTRACTION‑3. Baseline ECOG performance status was 0 (50%) or 1 (50%). ATTRACTION-3 demonstrated a statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with investigator’s choice of taxane chemotherapy. The minimum follow-up was 17. Efficacy results are shown in Table 65 and Figure 23. Table 65: Efficacy Results - ATTRACTION-3 a b c d e f Intravenous Nivolumab Docetaxel or Paclitaxel Overall Survival a Deaths (%) 160 (76%) 173 (83%) Median (months) (95% CI) 10. 9) Hazard ratio (95% CI) b 0. 96) p-value c 0. 0189 Overall Response Rate d 33 (19. 5) (95% CI) (13. 8) Complete response (%) 1 (0. 3) Partial response (%) 32 (18. 3) Median duration of response (months) (95% CI) 6. 2) p-value e 0. 6323 Progression-free Survival a, f Disease progression or death (%) 187 (89) 176 (84) Median (months) (95% CI) 1. 2) Hazard ratio (95% CI) b 1. 3) Figure 23: Overall Survival - ATTRACTION-3 Of the 419 patients, 48% had PD-L1 positive ESCC, defined as >=1% of tumor cells expressing PD-L1. The remaining 52% had PD-L1 negative ESCC defined as <1% of tumor cells expressing PD-L1. In a pre-specified exploratory analysis by PD-L1 status, the hazard ratio (HR) for OS was 0. 94) with median survivals of 10. 1 months for the intravenous nivolumab and investigator’s choice arms, respectively, in the PD-L1 positive subgroup. In the PD-L1 negative subgroup, the HR for OS was 0. 84 (95% CI: 0. 14) with median survivals of 10. 3 months for the intravenous nivolumab and investigator’s choice arms, respectively. oq-os-attraction-3 The effectiveness of OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapy has been established for the treatment of gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. 3) CHECKMATE-649 CHECKMATE-649 (NCT02872116) was a randomized, multicenter, open-label trial in patients (n=1581) with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. The trial enrolled patients regardless of PD-L1 status, and tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive, or had untreated CNS metastases. Patients were randomized to receive intravenous nivolumab in combination with chemotherapy (n=789) or chemotherapy (n=792). Patients received one of the following treatments: Patients were treated until disease progression, unacceptable toxicity, or up to 2 years. In patients who received intravenous nivolumab in combination with chemotherapy and in whom chemotherapy was discontinued, intravenous nivolumab monotherapy was allowed to be given at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks up to 2 years after treatment initiation. Randomization was stratified by tumor cell PD-L1 status (>=1% vs. <1% or indeterminate), region (Asia vs. 1), and chemotherapy regimen (mFOLFOX6 vs. The major efficacy outcome measures, assessed in patients with PD-L1 CPS >=5, were PFS assessed by BICR and OS. Additional efficacy outcome measures included OS and PFS in patients with PD-L1 CPS >=1 and in all randomized patients, and ORR and DOR as assessed by BICR in patients with PD-L1 CPS >=1 and >=5, and in all randomized patients. Tumor assessments were conducted per RECIST v1. 1 every 6 weeks up to and including week 48, then every 12 weeks thereafter. The trial population characteristics were: median age 61 years (range: 18 to 90), 39% were >=65 years of age, 70% were male, 24% were Asian, and 69% were White, and 1% were Black. Baseline ECOG performance status was 0 (42%) or 1 (58%). Seventy percent of patients had adenocarcinoma tumors in the stomach, 16% in the gastroesophageal junction, and 13% in the esophagus. CHECKMATE-649 demonstrated a statistically significant improvement in OS and PFS for patients with PD-L1 CPS >=5. Statistically significant improvement in OS was also demonstrated for all randomized patients. The minimum follow-up was 12. Efficacy results are shown in Table 66 and Figures 24, 25, and 26. Table 66: Efficacy Results - CHECKMATE-649 a b c d e Intravenous Nivolumab and mFOLFOX6 mFOLFOX6 Intravenous Nivolumab and mFOLFOX6 mFOLFOX6 Intravenous Nivolumab and mFOLFOX6 mFOLFOX6 All Patients PD-L1 CPS >=1 PD-L1 CPS >=5 Overall Survival Deaths (%) 544 (69) 591 (75) 434 (68) 492 (75) 309 (65) 362 (75) Median (months) (95% CI) 13. 1) Hazard ratio (95% CI) a 0. 83) p-value b 0. 0001 Progression-free Survival c Disease progression or death (%) 559 (70. 6) Median (months) (95% CI) 7. 9) Hazard ratio (95% CI) a 0. 79) p-value b - e - e <0. 0001 Overall Response Rate, n (%) c,d 370 (47) 293 (37) 314 (49) 249 (38) 237 (50) 184 (38) (95% CI) (43, 50) (34, 40) (45, 53) (34, 42) (46, 55) (34, 43) Complete response (%) 78 (10) 52 (7) 65 (10) 42 (6) 55 (12) 34 (7) Partial response (%) 292 (37) 241 (30) 249 (39) 207 (32) 182 (38) 150 (31) Duration of Response (months) c,d Median (95% CI) Range 8. 8+ In an exploratory analysis in patients with PD-L1 CPS <1 (n=265), the median OS was 13. 1 months (95% CI: 9. 7) for the intravenous nivolumab and chemotherapy arm and 12. 5 months (95% CI: 10. 8) for the chemotherapy arm, with a stratified HR of 0. 85 (95% CI: 0. In an exploratory analysis in patients with PD-L1 CPS <5 (n=606), the median OS was 12. 4 months (95% CI: 10. 3) for the intravenous nivolumab and chemotherapy arm and 12. 3 months (95% CI: 11. 2) for the chemotherapy arm, with a stratified HR of 0. 94 (95% CI: 0. Figure 24: Overall Survival (All Patients) - CHECKMATE-649 Figure 25: Overall Survival (PD-L1 CPS >=1) - CHECKMATE-649 Figure 26: Overall Survival (PD-L1 CPS >=5) - CHECKMATE-649 oq-os-checkmate-649 oq-os-pd-l1-cps-greater-than-1-checkmate-649 oq-os-pd-l1-cps-greater-than-5-checkmate-649.
Medication Guide
MEDICATION GUIDE OPDIVO QVANTIGtrademark (op-DEE-voh cue-VAN-tig) (nivolumab and hyaluronidase-nvhy) injection, for subcutaneous use Read this Medication Guide before you start receiving OPDIVO QVANTIG and before each injection. There may be new information. If your healthcare provider prescribes OPDIVO QVANTIG in combination with cabozantinib, also read the Patient Information that comes with cabozantinib. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about OPDIVO QVANTIG? OPDIVO QVANTIG is a medicine that may treat certain cancers by working with your immune system. OPDIVO QVANTIG can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. You may have more than one of these problems at the same time. Some of these problems may happen more often when OPDIVO QVANTIG is used in combination with another therapy. Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including: Lung problems. Intestinal problems. Liver problems. Hormone gland problems. Kidney problems. Skin problems. Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with OPDIVO QVANTIG. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include: Rejection of a transplanted organ or tissue. Getting medical treatment right away may help keep these problems from becoming more serious. What is OPDIVO QVANTIG? OPDIVO QVANTIG is a prescription medicine used to treat adults with: a type of kidney cancer that has spread called advanced renal cell carcinoma (RCC). ∘ ∘ ∘ a type of skin cancer called melanoma. ∘ ∘ ∘ a type of lung cancer called non-small cell lung cancer (NSCLC). ∘ ∘ ▪ and ▪ ∘ ▪ and ▪ ▪ and head and neck cancer (squamous cell carcinoma). ∘ ▪ and ▪ cancer of the lining of the urinary tract (urothelial carcinoma). ∘ ∘ ∘ and: ▪ or ▪ a type of colon or rectal cancer (colorectal cancer or CRC). ∘ ▪ and ▪ and ▪ a type of liver cancer called hepatocellular carcinoma (HCC). ∘ cancer of the tube that connects your throat to your stomach (esophageal cancer). ∘ ▪ but ▪ ∘ ▪ and ▪ or ▪ ∘ ▪ and ▪ cancer of the stomach (gastric cancer), cancer where the esophagus joins the stomach (gastroesophageal junction cancer), and a type of cancer in the esophagus called esophageal adenocarcinoma. ∘ ▪ or ▪ It is not known if OPDIVO QVANTIG is safe and effective in children. Before receiving OPDIVO QVANTIG, tell your healthcare provider about all of your medical conditions, including if you: Females who are able to become pregnant: ∘ ∘ ∘ Tell your healthcare provider about all the medicines you take, How will I receive OPDIVO QVANTIG? What are the possible side effects of OPDIVO QVANTIG? OPDIVO QVANTIG can cause serious side effects, including: See “What is the most important information I should know about OPDIVO QVANTIG?” Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). The most common side effects of OPDIVO QVANTIG when used alone in people with renal cell carcinoma include: The most common side effects observed with nivolumab given into the vein (intravenous nivolumab), which may be experienced with OPDIVO QVANTIG, are shown below. The most common side effects of intravenous nivolumab when used alone include: The most common side effects of intravenous nivolumab when used in combination with cabozantinib as the first treatment for advanced RCC include: The most common side effects of intravenous nivolumab when used in combination with platinum-containing chemotherapy and another chemotherapy medicine before having surgery for NSCLC include: The most common side effects of intravenous nivolumab when used in combination with cisplatin and gemcitabine to treat urothelial cancer include: The most common side effects of intravenous nivolumab when used in combination with fluoropyrimidine and platinum-containing chemotherapy to treat esophageal cancer and gastric cancer include: These are not all the possible side effects of OPDIVO QVANTIG. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of OPDIVO QVANTIG. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about OPDIVO QVANTIG that is written for health professionals. What are the ingredients in OPDIVO QVANTIG? Active ingredients: Inactive ingredients: Manufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA U.S. License No. 1713 Halozyme Therapeutics, Inc., 12390 El Camino Real, San Diego, CA 92130, U.S. License No. 2187 OPDIVO QVANTIG trademark For more information, call 1-855-673-4861 or go to www.Qvantig.com. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: December 2024

E.R. Squibb & Sons, L.L.C.

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