OPDIVO QVANTIG Dailymed

The following clinically significant adverse reactions are described elsewhere in the labeling.

• •Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
• •Complications of Allogeneic HSCT [see Warnings and Precautions (5.2) ]

• • Most common adverse reactions (≥10%) with OPDIVO QVANTIG as monotherapy in patients with Renal Cell Carcinoma were: musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain. (6.1)
• •Safety of OPDIVO QVANTIG for the following indications is based on safety of intravenous nivolumab in these populations. The most common adverse reactions with intravenous nivolumab for these indications are presented below.
• •As monotherapy for the treatment of advanced renal cell carcinoma; adjuvant treatment of completely resected Stage IIB, IIC, III, or IV melanoma; unresectable or metastatic melanoma; adjuvant treatment of NSCLC, metastatic NSCLC; squamous cell carcinoma of the head and neck; urothelial carcinoma; MSI-H or dMMR mCRC; hepatocellular carcinoma; esophageal cancer: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection. (6.1)

• •In combination with cabozantinib for the first-line treatment of advanced renal cell carcinoma: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1)

• •In combination with platinum-doublet chemotherapy for the neoadjuvant treatment of NSCLC: nausea, constipation, fatigue, decreased appetite, and rash. (6.1)
• •In combination with cisplatin and gemcitabine for the treatment of urothelial cancer: nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. (6.1)
• •In combination with fluoropyrimidine- and platinum- containing chemotherapy for the treatment of esophageal cancer and gastric cancer: nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO QVANTIG as a single agent in 247 patients enrolled in CHECKMATE-67T, with additional data from intravenous nivolumab single-agent (1994 patients), and from intravenous nivolumab in combination with cabozantinib (320 patients) for select adverse reactions.

CHECKMATE-67T was a multicenter, randomized, open-label study in adult patients with advanced or metastatic RCC. Patients received OPDIVO QVANTIG dose of 1,200 mg of nivolumab and 20,000 units of hyaluronidase subcutaneously every 4 weeks (n=247) or 3 mg/kg of nivolumab intravenously every 2 weeks (n=245). Among patients who received OPDIVO QVANTIG, 52% were exposed for 6 months or longer and 20% were exposed for greater than 1 year.

Serious adverse reactions occurred in 28% of patients who received OPDIVO QVANTIG. Serious adverse reactions in >1% of patients included pleural effusion (1.6%), pneumonitis (1.6%), hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). Fatal adverse reactions occurred in 3 patients (1.2%) who received OPDIVO QVANTIG and included myocarditis, myositis, and colitis complications.

Permanent discontinuation of OPDIVO QVANTIG due to an adverse reaction occurred in 10% of patients. The most common adverse reaction which resulted in permanent discontinuation was pneumonitis (2%).

Dosage interruptions of OPDIVO QVANTIG due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in >2% of patients included COVID-19 (4.5%), increased blood creatinine (2.8%), anemia, diarrhea, and fatigue (2.4% each).

The most common adverse reactions (≥10%) were musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain.

Tables 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-67T.

Table 5: Adverse Reactions* in ≥5% of Adult Patients with RCC Receiving OPDIVO QVANTIG in CHECKMATE-67T

*   Toxicity was graded per NCI CTCAE v5. a   Includes multiple related terms
Adverse Reaction	OPDIVO QVANTIG(n=247)		Intravenous Nivolumab(n=245)
	All Grades(%)	Grades 3-4(%)	All Grades(%)	Grades 3-4(%)
General
Fatiguea	20	2.4	25	3.3
Injection site reactiona	8	0	0	0
Edema	5	0.4	11	0.8
Musculoskeletal and Connective Tissue
Musculoskeletal paina	31	1.6	39	3.3
Skin and Subcutaneous Tissue
Pruritus	16	0.4	21	0
Rasha	15	1.2	13	1.2
Gastrointestinal
Diarrheaa	11	0.4	14	0.4
Abdominal paina	10	0	10	0.4
Nausea	8	0	9	0
Constipation	8	0	6	0
Vomiting	6	0.4	4.9	0
Respiratory, Thoracic, and Mediastinal
Cough	11	0	11	0
Endocrine
Hypothyroidisma	12	0	17	0
Metabolism and Nutrition
Hyperglycemia	9	2.4	13	2.0
Decreased appetite	9	0	11	0.8

Clinically important adverse reactions in <5% of patients who received OPDIVO QVANTIG include:

Cardiac: myocarditis

Respiratory, thoracic, and mediastinal: pneumonitis, dyspnea

Endocrine: adrenal insufficiency, hyperthyroidism, thyroiditis

Gastrointestinal: colitis, pancreatitis

Hepatobiliary: hepatitis

Nervous system: peripheral neuropathy

Skin and subcutaneous tissue: psoriasis, erythema

Musculoskeletal and connective tissue: arthritis

Blood and lymphatic system: eosinophilia

Eye disorders: uveitis

Immune system: hypersensitivity

Table 6: Laboratory Values Worsening from Baseline^a (≥20%) in Patients with RCC Receiving OPDIVO QVANTIG in CHECKMATE-67T

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO QVANTIG group (range: 232 to 235 patients) and intravenous nivolumab group (range: 240 to 244 patients).
Laboratory Abnormality	OPDIVO QVANTIG		Intravenous Nivolumab
	All Grades(%)	Grades 3-4(%)	All Grades(%)	Grades 3-4(%)
Hematology
Hemoglobin decreased	46	7	48	9
Lymphocytes decreased	36	6	45	9
Chemistry
Creatinine increased	38	1.3	43	0.4
Sodium decreased	34	2.6	40	2.5
Potassium increased	34	3.0	45	2.9
Alkaline phosphatase increased	32	2.1	33	2.0
Calcium increased	29	2.1	31	4.1
Albumin decreased	25	1.7	35	0.4
ALT increased	21	1.3	26	4.1

Adverse Reactions in Patients Treated with Intravenous Nivolumab

The safety of OPDIVO QVANTIG for its approved indications [see Indications and Usage (1)] has been established in adequate and well-controlled clinical studies of intravenous nivolumab. Below is a description of adverse reactions in these adequate and well-controlled clinical studies.

First-line Renal Cell Carcinoma

CHECKMATE-214

The safety of intravenous nivolumab with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC; patients received intravenous nivolumab 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=535) [see Clinical Studies (14.1) ]. The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in intravenous nivolumab and ipilimumab-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the intravenous nivolumab and ipilimumab arm were exposed to treatment for >6 months and 38% of patients were exposed to treatment for >1 year.

Serious adverse reactions occurred in 59% of patients receiving intravenous nivolumab and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of intravenous nivolumab and ipilimumab patients. Fifty-four percent (54%) of patients receiving intravenous nivolumab and ipilimumab had a dose interruption for an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous nivolumab and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in ≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of intravenous nivolumab and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia.

Tables 7 and 8 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of intravenous nivolumab and ipilimumab‑treated patients in CHECKMATE-214.

Table 7: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab and Ipilimumab - CHECKMATE-214

Toxicity was graded per NCI CTCAE v4. a   Includes asthenia. b   Includes peripheral edema, peripheral swelling. c   Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption. d   Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.
Adverse Reaction	Intravenous Nivolumab and Ipilimumab (n=547)		Sunitinib(n=535)
	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Adverse Reaction	99	65	99	76
General
Fatiguea	58	8	69	13
Pyrexia	25	0.7	17	0.6
Edemab	16	0.5	17	0.6
Skin and Subcutaneous Tissue
Rashc	39	3.7	25	1.1
Pruritus/generalized pruritus	33	0.5	11	0
Gastrointestinal
Diarrhea	38	4.6	58	6
Nausea	30	2	43	1.5
Vomiting	20	0.9	28	2.1
Abdominal pain	19	1.6	24	1.9
Constipation	17	0.4	18	0
Musculoskeletal and Connective Tissue
Musculoskeletal paind	37	4	40	2.6
Arthralgia	23	1.3	16	0
Respiratory, Thoracic and Mediastinal
Cough/productive cough	28	0.2	25	0.4
Dyspnea/exertional dyspnea	20	2.4	21	2.1
Metabolism and Nutrition
Decreased appetite	21	1.8	29	0.9
Nervous System
Headache	19	0.9	23	0.9
Endocrine
Hypothyroidism	18	0.4	27	0.2

Table 8: Laboratory Values Worsening from Baseline^a Occurring in >15% of Patients on Intravenous Nivolumab and Ipilimumab - CHECKMATE-214

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and ipilimumab group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients).
Laboratory Abnormality	Intravenous Nivolumab and Ipilimumab		Sunitinib
	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Chemistry
Increased lipase	48	20	51	20
Increased creatinine	42	2.1	46	1.7
Increased ALT	41	7	44	2.7
Increased AST	40	4.8	60	2.1
Increased amylase	39	12	33	7
Hyponatremia	39	10	36	7
Increased alkaline phosphatase	29	2	32	1
Hyperkalemia	29	2.4	28	2.9
Hypocalcemia	21	0.4	35	0.6
Hypomagnesemia	16	0.4	26	1.6
Hematology
Anemia	43	3	64	9
Lymphopenia	36	5	63	14

In addition, among patients with TSH ≤ ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the intravenous nivolumab and ipilimumab group compared to the sunitinib group (31% and 61%, respectively).

CHECKMATE-9ER

The safety of intravenous nivolumab with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received intravenous nivolumab 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320) [see Clinical Studies (14.1) ]. Cabozantinib could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in intravenous nivolumab and cabozantinib-treated patients. In this trial, 82% of patients in the intravenous nivolumab and cabozantinib arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year.

Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab and cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.

Adverse reactions leading to discontinuation of either intravenous nivolumab or cabozantinib occurred in 20% of patients: 7% intravenous nivolumab only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either intravenous nivolumab or cabozantinib occurred in 83% of patients: 3% intravenous nivolumab only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially.

The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

Tables 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER.

Table 9: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab and Cabozantinib - CHECKMATE-9ER

Toxicity was graded per NCI CTCAE v4. a   Includes abdominal discomfort, abdominal pain lower, abdominal pain upper. b   Includes gastroesophageal reflux disease. c   Includes asthenia. d   Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure. e   Includes mucosal inflammation, aphthous ulcer, mouth ulceration. f   Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic.
g   Includes blood pressure increased, blood pressure systolic increased. h   Includes primary hypothyroidism. i   Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.
j   Includes productive cough. k   Includes nasopharyngitis, pharyngitis, rhinitis.
Adverse Reaction	Intravenous Nivolumab and Cabozantinib(n=320)		Sunitinib(n=320)
	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Gastrointestinal
Diarrhea	64	7	47	4.4
Nausea	27	0.6	31	0.3
Abdominal paina	22	1.9	15	0.3
Vomiting	17	1.9	21	0.3
Dyspepsiab	15	0	22	0.3
General
Fatiguec	51	8	50	8
Hepatobiliary
Hepatotoxicityd	44	11	26	5
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome	40	8	41	8
Stomatitise	37	3.4	46	4.4
Rashf	36	3.1	14	0
Pruritus	19	0.3	4.4	0
Vascular
Hypertensiong	36	13	39	14
Endocrine
Hypothyroidismh	34	0.3	30	0.3
Musculoskeletal and Connective Tissue
Musculoskeletal paini	33	3.8	29	3.1
Arthralgia	18	0.3	9	0.3
Metabolism and Nutrition
Decreased appetite	28	1.9	20	1.3
Nervous System
Dysgeusia	24	0	22	0
Headache	16	0	12	0.6
Respiratory, Thoracic and Mediastinal
Coughj	20	0.3	17	0
Dysphonia	17	0.3	3.4	0
Infections and Infestations
Upper respiratory tract infectionk	20	0.3	8	0.3

Table 10: Laboratory Values Worsening from Baseline^a Occurring in >20% of Patients on Intravenous Nivolumab and Cabozantinib - CHECKMATE-9ER

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and cabozantinib group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients).
Laboratory Abnormality	Intravenous Nivolumab and Cabozantinib		Sunitinib
	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Chemistry
Increased ALT	79	9.8	39	3.5
Increased AST	77	7.9	57	2.6
Hypophosphatemia	69	28	48	10
Hypocalcemia	54	1.9	24	0.6
Hypomagnesemia	47	1.3	25	0.3
Hyperglycemia	44	3.5	44	1.7
Hyponatremia	43	11	36	12
Increased lipase	41	14	38	13
Increased amylase	41	10	28	6
Increased alkaline phosphatase	41	2.8	37	1.6
Increased creatinine	39	1.3	42	0.6
Hyperkalemia	35	4.7	27	1
Hypoglycemia	26	0.8	14	0.4
Hematology
Lymphopenia	42	6.6	45	10
Thrombocytopenia	41	0.3	70	9.7
Anemia	37	2.5	61	4.8
Leukopenia	37	0.3	66	5.1
Neutropenia	35	3.2	67	12

Previously Treated Renal Cell Carcinoma

CHECKMATE-025

The safety of intravenous nivolumab was evaluated in CHECKMATE-025, a randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received intravenous nivolumab 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.1) ]. The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in intravenous nivolumab-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients.

Rate of death on treatment or within 30 days of the last dose was 4.7% on the intravenous nivolumab arm. Serious adverse reactions occurred in 47% of patients receiving intravenous nivolumab. Study therapy was discontinued for adverse reactions in 16% of intravenous nivolumab patients. Forty-four percent (44%) of patients receiving intravenous nivolumab had a dose interruption for an adverse reaction.

The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the intravenous nivolumab group compared to the everolimus group (26% and 14%, respectively).

Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025.

Table 11: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab - CHECKMATE-025

Toxicity was graded per NCI CTCAE v4.
a   Includes asthenia, decreased activity, fatigue, and malaise.
b   Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI).
c   Includes colitis, enterocolitis, and gastroenteritis.
d   Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema.
Adverse Reaction	Intravenous Nivolumab(n=406)		Everolimus(n=397)
	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Adverse Reaction	98	56	96	62
General
Fatiguea	56	6	57	7
Pyrexia	17	0.7	20	0.8
Respiratory, Thoracic and Mediastinal
Cough/productive cough	34	0	38	0.5
Dyspnea/exertional dyspnea	27	3	31	2
Upper respiratory infectionb	18	0	11	0
Gastrointestinal
Nausea	28	0.5	29	1
Diarrheac	25	2.2	32	1.8
Constipation	23	0.5	18	0.5
Vomiting	16	0.5	16	0.5
Skin and Subcutaneous Tissue
Rashd	28	1.5	36	1
Pruritus/generalized pruritus	19	0	14	0
Metabolism and Nutrition
Decreased appetite	23	1.2	30	1.5
Musculoskeletal and Connective Tissue
Arthralgia	20	1	14	0.5
Back pain	21	3.4	16	2.8

Other clinically important adverse reactions in CHECKMATE-025 were:

General Disorders and Administration Site Conditions: peripheral edema/edema

Gastrointestinal Disorders: abdominal pain/discomfort

Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain

Nervous System Disorders: headache/migraine, peripheral neuropathy

Investigations: weight decreased

Skin Disorders: palmar-plantar erythrodysesthesia

Table 12: Laboratory Values Worsening from Baseline^a Occurring in >15% of Patients on Intravenous Nivolumab - CHECKMATE-025

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients).
Laboratory Abnormality	Intravenous Nivolumab		Everolimus
	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Hematology
Lymphopenia	42	6	53	11
Anemia	39	8	69	16
Chemistry
Increased creatinine	42	2	45	1.6
Increased AST	33	2.8	39	1.6
Increased alkaline phosphatase	32	2.3	32	0.8
Hyponatremia	32	7	26	6
Hyperkalemia	30	4	20	2.1
Hypocalcemia	23	0.9	26	1.3
Increased ALT	22	3.2	31	0.8
Hypercalcemia	19	3.2	6	0.3
Lipids
Increased triglycerides	32	1.5	67	11
Increased cholesterol	21	0.3	55	1.4

Previously Treated Metastatic Melanoma

CHECKMATE-037

The safety of intravenous nivolumab was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.2)]. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m² intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m² intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in intravenous nivolumab‑treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received intravenous nivolumab for >6 months and 3% of patients received intravenous nivolumab for >1 year.

The population characteristics in the intravenous nivolumab group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the intravenous nivolumab group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%).

Serious adverse reactions occurred in 41% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving intravenous nivolumab had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving intravenous nivolumab. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving intravenous nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of patients) was rash.

Tables 13 and 14 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037.

Table 13: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037

Toxicity was graded per NCI CTCAE v4.
a   Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis.
b   Includes rhinitis, pharyngitis, and nasopharyngitis.
Adverse Reaction	Intravenous Nivolumab(n=268)		Chemotherapy(n=102)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rasha	21	0.4	7	0
Pruritus	19	0	3.9	0
Respiratory, Thoracic and Mediastinal
Cough	17	0	6	0
Infections
Upper respiratory tract infectionb	11	0	2	0
General
Peripheral edema	10	0	5	0

Clinically important adverse reactions in <10% of patients who received intravenous nivolumab were:

Cardiac Disorders: ventricular arrhythmia

Eye Disorders: iridocyclitis

General Disorders and Administration Site Conditions: infusion-related reactions

Investigations: increased amylase, increased lipase

Nervous System Disorders: dizziness, peripheral and sensory neuropathy

Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis

Table 14: Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients).
Laboratory Abnormality	Intravenous Nivolumab		Chemotherapy
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Increased AST	28	2.4	12	1
Hyponatremia	25	5	18	1.1
Increased alkaline phosphatase	22	2.4	13	1.1
Increased ALT	16	1.6	5	0
Hyperkalemia	15	2	6	0

Previously Untreated Metastatic Melanoma

CHECKMATE-066

The safety of intravenous nivolumab was also evaluated in CHECKMATE-066, a randomized, double-blind, active‑controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.2)]. The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206) or dacarbazine 1000 mg/m² intravenously every 3 weeks (n=205). The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in intravenous nivolumab-treated patients. In this trial, 47% of patients received intravenous nivolumab for >6 months and 12% of patients received intravenous nivolumab for >1 year.

The trial population characteristics in the intravenous nivolumab group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the intravenous nivolumab group with ECOG performance status 0 (71% vs. 59%).

Serious adverse reactions occurred in 36% of patients receiving intravenous nivolumab. Adverse reactions led to permanent discontinuation of intravenous nivolumab in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of intravenous nivolumab discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving intravenous nivolumab.

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.

Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.

Table 15: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066

Toxicity was graded per NCI CTCAE v4.
a   Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema.
b   Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain.
c   Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and skin reaction.
d   Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis.
Adverse Reaction	Intravenous Nivolumab(n=206)		Dacarbazine(n=205)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
General
Fatigue	49	1.9	39	3.4
Edemaa	12	1.5	4.9	0
Musculoskeletal and Connective Tissue
Musculoskeletal painb	32	2.9	25	2.4
Skin and Subcutaneous Tissue
Rashc	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 infectiond	17	0	6	0

Clinically important adverse reactions in <10% of patients who received intravenous nivolumab were:

Nervous System Disorders: peripheral neuropathy

Table 16: Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients).
Laboratory Abnormality	Intravenous Nivolumab		Dacarbazine
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Increased ALT	25	3	19	0.5
Increased AST	24	3.6	19	0.5
Increased alkaline phosphatase	21	2.6	14	1.6
Increased bilirubin	13	3.1	6	0

CHECKMATE-067

The safety of intravenous nivolumab, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.2)]. The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV.

Patients were randomized to receive:

• •Intravenous nivolumab 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (nivolumab and ipilimumab arm; n=313), or
• •Intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (nivolumab arm; n=313), or
• •Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab arm; n=311).

The median duration of exposure to intravenous nivolumab was 2.8 months (range: 1 day to 36.4 months) for the intravenous nivolumab and ipilimumab arm and 6.6 months (range: 1 day to 36.0 months) for the intravenous nivolumab arm. In the intravenous nivolumab and ipilimumab arm, 39% were exposed to intravenous nivolumab for ≥6 months and 30% exposed for >1 year. In the intravenous nivolumab arm, 53% were exposed for ≥6 months and 40% for >1 year.

The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC) Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy.

Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the intravenous nivolumab and ipilimumab arm relative to the intravenous nivolumab arm.

The most frequent (≥10%) serious adverse reactions in the intravenous nivolumab and ipilimumab arm and the intravenous nivolumab arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1%). The most frequent adverse reactions leading to discontinuation of both drugs in the intravenous nivolumab and ipilimumab arm and of intravenous nivolumab in the intravenous nivolumab arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%).

The most common (≥20%) adverse reactions in the intravenous nivolumab and ipilimumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. The most common (≥20%) adverse reactions in the intravenous nivolumab arm were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract infection, decreased appetite, headache, constipation, arthralgia, and vomiting.

Tables 17 and 18 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.

Table 17: Adverse Reactions Occurring in ≥10% of Patients on the Intravenous Nivolumab and Ipilimumab Arm or the Intravenous Nivolumab Arm and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067

Toxicity was graded per NCI CTCAE v4.
a   Includes asthenia and fatigue.
b   Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash.
c   Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
d   Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
e   Includes hypertension and blood pressure increased.
Adverse Reaction	Intravenous Nivolumab andIpilimumab(n=313)		Intravenous Nivolumab (n=313)		Ipilimumab (n=311)
	All Grades (%)	Grades3-4 (%)	All Grades (%)	Grades3-4 (%)	All Grades (%)	Grades3-4 (%)
General
Fatiguea	62	7	59	1.6	51	4.2
Pyrexia	40	1.6	16	0	18	0.6
Gastrointestinal
Diarrhea	54	11	36	5	47	7
Nausea	44	3.8	30	0.6	31	1.9
Vomiting	31	3.8	20	1	17	1.6
Skin and Subcutaneous Tissue
Rashb	53	6	40	1.9	42	3.5
Vitiligo	9	0	10	0.3	5	0
Musculoskeletal and Connective Tissue
Musculoskeletal painc	32	2.6	42	3.8	36	1.9
Arthralgia	21	0.3	21	1	16	0.3
Metabolism and Nutrition
Decreased appetite	29	1.9	22	0	24	1.3
Respiratory, Thoracic and Mediastinal
Cough/productive cough	27	0.3	28	0.6	22	0
Dyspnea/exertional dyspnea	24	2.9	18	1.3	17	0.6
Infections
Upper respiratory tract infectiond	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
Hypertensione	7	2.2	11	5	9	2.3

Clinically important adverse reactions in <10% of patients who received intravenous nivolumab with ipilimumab or intravenous nivolumab as a single agent were:

Gastrointestinal Disorders: stomatitis, intestinal perforation

Skin and Subcutaneous Tissue Disorders: vitiligo

Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis)

Nervous System Disorders: neuritis, peroneal nerve palsy

Table 18: Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥20% of Patients Treated with Intravenous Nivolumab with Ipilimumab or Single-Agent Intravenous Nivolumab and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and ipilimumab (range: 75 to 297); intravenous nivolumab (range: 81 to 306); ipilimumab (range: 61 to 301).
Laboratory Abnormality	Intravenous Nivolumab andIpilimumab		Intravenous Nivolumab		Ipilimumab
	All Grades (%)	Grade3-4 (%)	All Grades (%)	Grade3-4 (%)	All Grades (%)	Grade3-4 (%)
Chemistry
Increased ALT	55	16	25	3	29	2.7
Hyperglycemia	53	5.3	46	7	26	0
Increased AST	52	13	29	3.7	29	1.7
Hyponatremia	45	10	22	3.3	26	7
Increased lipase	43	22	32	12	24	7
Increased alkaline phosphatase	41	6	27	2	23	2
Hypocalcemia	31	1.1	15	0.7	20	0.7
Increased amylase	27	10	19	2.7	15	1.6
Increased creatinine	26	2.7	19	0.7	17	1.3
Hematology
Anemia	52	2.7	41	2.6	41	6
Lymphopenia	39	5	41	4.9	29	4

CHECKMATE-76K

The safety of intravenous nivolumab as a single agent was evaluated in CHECKMATE-76K, a randomized (2:1), double-blind trial in 788 patients with completely resected Stage IIB/C melanoma who received intravenous nivolumab 480 mg by intravenous infusion over 30 minutes every 4 weeks (n=524) or placebo by intravenous infusion over 30 minutes every 4 weeks (n=264) for up to 1 year [see Clinical Studies (14.3)]. The median duration of exposure was 11 months in patients treated with intravenous nivolumab and 11 months in patients treated with placebo.

Serious adverse reactions occurred in 18% of patients treated with intravenous nivolumab. A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). Permanent discontinuation of intravenous nivolumab due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of intravenous nivolumab in >1% of patients included diarrhea (1.1%), arthralgia (1.7%), and rash (1.7%).

Dosage interruptions of intravenous nivolumab due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dosage interruption in >1% of patients included COVID-19 infection, infusion related reaction, diarrhea, arthralgia, and increased ALT.

The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, rash, diarrhea, and pruritus.

Tables 19 and 20 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-76K.

Table 19: Adverse Reactions Occurring in ≥10% of Patients Treated with Intravenous Nivolumab - CHECKMATE-76K

Toxicity was graded per NCI CTCAE v5.
a   Includes asthenia.
b   Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, spinal pain, pain in extremity.
c   Includes dermatitis, dermatitis acneiform, dyshidrotic eczema, eczema, eczema asteatotic, eyelid rash, genital rash, pemphigoid, penile rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, toxic skin eruption.
d   Includes autoimmune colitis, colitis, diarrhea, enteritis, enterocolitis
e   Includes autoimmune hypothyroidism, blood thyroid stimulating hormone increased.
f   Includes cluster headache, migraine.
Adverse Reaction	Intravenous Nivolumab(n=524)		Placebo(n=264)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
General
Fatiguea	36	0.4	34	0.4
Musculoskeletal and connective tissue
Musculoskeletal painb	30	0.4	26	0.4
Skin and Subcutaneous Tissue
Rashc	28	1.1	15	0.4
Pruritus	20	0.2	11	0
Gastrointestinal
Diarrhead	23	1.3	16	0
Nausea	14	0	11	0
Endocrine
Hypothyroidisme	14	0	2.3	0
Nervous system
Headachef	12	0.2	14	0.8

Table 20: Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients - CHECKMATE-76K

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 262 to 513 patients) and placebo group (range: 138 to 261 patients).
Laboratory Abnormality	Intravenous Nivolumab (n=524)		Placebo (n=264)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Hematology
Anemia	19	0	14	0
Lymphopenia	17	1.1	17	1.7
Neutropenia	10	0	10	0.4
Chemistry
AST increased	25	2.2	16	0.4
Lipase increased	22	2.9	21	2.3
ALT increased	20	2.1	15	0.4
Amylase increased	17	0.4	9	0
Creatinine increased	15	0.4	13	0
Sodium decreased	13	0.6	11	0.4
Potassium increased	13	1	15	1.1

CHECKMATE-238

The safety of intravenous nivolumab as a single agent was evaluated in CHECKMATE-238, a randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year (n=453) [see Clinical Studies (14.3)]. The median duration of exposure was 11.5 months in intravenous nivolumab‑treated patients and was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received intravenous nivolumab for >6 months.

Serious adverse reactions occurred in 18% of intravenous nivolumab-treated patients. Study therapy was discontinued for adverse reactions in 9% of intravenous nivolumab-treated patients and 42% of ipilimumab-treated patients. Twenty-eight percent of intravenous nivolumab-treated patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions occurred in 25% of intravenous nivolumab-treated patients.

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of intravenous nivolumab-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).

Tables 21 and 22 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238.

Table 21: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-Treated Patients - CHECKMATE-238

Toxicity was graded per NCI CTCAE v4.
a   Includes asthenia.
b   Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness.
c   Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized, erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption.
d   Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity.
e   Includes postural dizziness and vertigo.
f   Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis.
g   Includes secondary hypothyroidism and autoimmune hypothyroidism.
Adverse Reaction	Intravenous Nivolumab(n=452)		Ipilimumab 10 mg/kg(n=453)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
General
Fatiguea	57	0.9	55	2.4
Gastrointestinal
Diarrhea	37	2.4	55	11
Nausea	23	0.2	28	0
Abdominal painb	21	0.2	23	0.9
Constipation	10	0	9	0
Skin and Subcutaneous Tissue
Rashc	35	1.1	47	5.3
Pruritus	28	0	37	1.1
Musculoskeletal and Connective Tissue
Musculoskeletal paind	32	0.4	27	0.4
Arthralgia	19	0.4	13	0.4
Nervous System
Headache	23	0.4	31	2.0
Dizzinesse	11	0	8	0
Infections
Upper respiratory tract infectionf	22	0	15	0.2
Respiratory, Thoracic and Mediastinal
Cough/productive cough	19	0	19	0
Dyspnea/exertional dyspnea	10	0.4	10	0.2
Endocrine
Hypothyroidismg	12	0.2	7.5	0.4

Table 22: Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients - CHECKMATE-238

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 400 to 447 patients) and ipilimumab 10 mg/kg group (range: 392 to 443 patients).
Laboratory Abnormality	Intravenous Nivolumab		Ipilimumab 10 mg/kg
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Hematology
Lymphopenia	27	0.4	12	0.9
Anemia	26	0	34	0.5
Leukopenia	14	0	2.7	0.2
Neutropenia	13	0	6	0.5
Chemistry
Increased Lipase	25	7	23	9
Increased ALT	25	1.8	40	12
Increased AST	24	1.3	33	9
Increased Amylase	17	3.3	13	3.1
Hyponatremia	16	1.1	22	3.2
Hyperkalemia	12	0.2	9	0.5
Increased Creatinine	12	0	13	0
Hypocalcemia	10	0.7	16	0.5

Neoadjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell Lung Cancer

CHECKMATE-816

The safety of intravenous nivolumab in combination with platinum-doublet chemotherapy was evaluated in CHECKMATE-816, a randomized, open-label, multicenter trial in patients with resectable NSCLC [see Clinical Studies (14.4)]. Patients received either intravenous nivolumab 360 mg administered in combination with platinum-doublet chemotherapy administered every 3 weeks for 3 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 3 cycles.

The median age of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 – 84); 72% male; 47% White, 50% Asian, and 2% Black/African American.

Serious adverse reactions occurred in 30% of patients who were treated with intravenous nivolumab in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy.

Study therapy with intravenous nivolumab in combination with platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one treatment withheld for an adverse reaction. The most common adverse reactions (≥1%) resulting in permanent discontinuation of intravenous nivolumab in combination with platinum-doublet chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and fatigue (1.1%).

The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased appetite, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were neutropenia, hyperglycemia, leukopenia, lymphopenia, increased amylase, anemia, thrombocytopenia, and hyponatremia.

Tables 23 and 24 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-816.

Table 23: Adverse Reactions in >10% of Patients with Early-Stage NSCLC Receiving Neoadjuvant Intravenous Nivolumab and Platinum-Doublet Chemotherapy in CHECKMATE-816

Toxicity was graded per NCI CTCAE v4.
a   Includes fatigue and asthenia
b   Includes rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, drug eruption, maculopapular rash, and pruritic rash.
c   Includes peripheral neuropathy, dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensory neuropathy.
Adverse Reaction	Intravenous Nivolumab and Platinum-Doublet Chemotherapy(n=176)		Platinum-Doublet Chemotherapy(n=176)
	All Grades (%)	Grades 3 or 4 (%)	All Grades (%)	Grades 3 or 4 (%)
Gastrointestinal
Nausea	38	0.6	45	1.1
Constipation	34	0	32	1.1
Vomiting	11	1.1	13	0.6
General
Fatiguea	26	2.3	23	1.1
Malaise	15	0.6	14	0.6
Metabolism and Nutrition
Decreased appetite	20	1.1	23	2.3
Skin and Subcutaneous Tissue
Rashb	20	2.3	7	0
Alopecia	11	0	15	0
Nervous System
Peripheral neuropathyc	13	0	6	0

Table 24: Select Laboratory Values Worsening from Baseline^a Occurring in >20% of Patients with Early-Stage NSCLC Receiving Neoadjuvant Intravenous Nivolumab and Platinum-Doublet Chemotherapy in CHECKMATE-816

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and platinum-doublet chemotherapy group (range: 73 to 171 patients) and platinum-doublet chemotherapy group (range: 68 to 171 patients).
Laboratory Abnormality	Intravenous Nivolumab and Platinum-Doublet Chemotherapya		Platinum-Doublet Chemotherapya
	All Grades (%)	Grades 3 or 4 (%)	All Grades (%)	Grades 3 or 4 (%)
Hematology
Anemia	63	3.5	70	6
Neutropenia	58	22	58	27
Leukopenia	53	5	51	11
Lymphopenia	38	4.7	31	1.8
Thrombocytopenia	24	2.9	22	3
Chemistry
Hyperglycemia	37	6	35	2.9
Hypomagnesemia	25	1.2	29	1.2
Hyponatremia	25	2.4	28	1.8
Increased amylase	23	3.6	13	1.8
Increased ALT	23	0	20	1.2

Neoadjuvant and Adjuvant Treatment of Resectable (Tumors 4 cm or Node Positive) Non-Small Cell Lung Cancer

CHECKMATE-77T

The safety of intravenous nivolumab in combination with neoadjuvant platinum-doublet chemotherapy followed by surgery and continued adjuvant treatment with intravenous nivolumab as a single agent after surgery was evaluated in CHECKMATE-77T, a randomized, double-blind, multicenter trial in patients with previously untreated resectable Stage IIA (>4 cm) to IIIB (T3N2 or T4N2) NSCLC (per the AJCC Cancer Staging Manual 8th Edition) [see Clinical Studies (14.5)]. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. The median duration of exposure to intravenous nivolumab was 10.3 months (range: 1 day to 22.3 months).

The study population characteristics were: median age 66 years (range: 35 - 86); 71% male; 72% White, 25% Asian, 1.7% Black/African American, and 1.5% other race; and 6% Hispanic or Latino.

Adverse reactions occurring in patients with resectable NSCLC receiving intravenous nivolumab in combination with platinum-doublet chemotherapy, given as neoadjuvant treatment and followed as a single agent adjuvant treatment after surgery, were generally similar to those occurring in patients in other clinical trials across tumor types receiving intravenous nivolumab in combination with chemotherapy.

Neoadjuvant Phase of CHECKMATE-77T

A total of 228 patients received at least 1 dose of intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment and 230 patients received at least 1 dose of placebo in combination with platinum-doublet chemotherapy as neoadjuvant treatment.

Serious adverse reactions occurred in 21% of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent (≥2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis (0.4% each).

Permanent discontinuation of any study drug due to an adverse reaction occurred in 13% of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent (≥1%) adverse reaction that led to permanent discontinuation of any study drug was peripheral sensory neuropathy (2.2%).

Of the 228 intravenous nivolumab-treated patients and 230 placebo-treated patients who received neoadjuvant treatment, 5.3% (n=12) and 3.5% (n=8), respectively, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in intravenous nivolumab-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2 patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19, and myositis (1 patient each).

Of the 178 intravenous nivolumab-treated patients who received surgery, 4.5% (n=8) experienced delay of surgery (surgery more than 6 weeks from last neoadjuvant treatment) due to adverse reactions. Of the 178 placebo-treated patients who received surgery, 3.9% (n=7) experienced delay of surgery due to adverse reactions.

Of the 178 intravenous nivolumab-treated patients who received surgery, 7% (n=13) did not receive adjuvant treatment due to adverse reactions. Of the 178 placebo-treated patients who received surgery, 2.8% (n=5) did not receive adjuvant treatment due to adverse reactions.

Adjuvant Phase of CHECKMATE-77T

A total of 142 patients in the intravenous nivolumab arm and 152 patients in the placebo arm received at least 1 dose of adjuvant treatment.

Of the patients who received single agent intravenous nivolumab as adjuvant treatment, 22% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. Permanent discontinuation of adjuvant intravenous nivolumab due to an adverse reaction occurred in 14% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant intravenous nivolumab were pneumonitis (4.2%) and diarrhea (1.4%).

Second-line Treatment of Metastatic NSCLC

CHECKMATE-017 and CHECKMATE-057

The safety of intravenous nivolumab was evaluated in CHECKMATE-017, a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies (14.6) ]. These trials excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received intravenous nivolumab 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks or docetaxel 75 mg/m² intravenously every 3 weeks. The median duration of therapy in intravenous nivolumab-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to 21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In CHECKMATE-017, 36% of patients received intravenous nivolumab for at least 6 months and 18% of patients received intravenous nivolumab for at least 1 year and in CHECKMATE-057, 30% of patients received intravenous nivolumab for >6 months and 20% of patients received intravenous nivolumab for >1 year.

Across both trials, the median age of intravenous nivolumab-treated patients was 61 years (range: 37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were White. Ten percent of patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%).

In CHECKMATE-057, in the intravenous nivolumab arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued in 11% of patients and was delayed in 28% of patients for an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions (≥20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

Tables 25 and 26 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057.

Table 25: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-017 and CHECKMATE-057

Toxicity was graded per NCI CTCAE v4.
Adverse Reaction	Intravenous Nivolumab(n=418)		Docetaxel(n=397)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Respiratory, Thoracic and Mediastinal
Cough	31	0.7	24	0
Metabolism and Nutrition
Decreased appetite	28	1.4	23	1.5
Skin and Subcutaneous Tissue
Pruritus	10	0.2	2	0

Other clinically important adverse reactions observed in intravenous nivolumab-treated patients and which occurred at a similar incidence in docetaxel-treated patients and not uled elsewhere in section 6 include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades).

Table 26: Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients for all NCI CTCAE Grades and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-017 and CHECKMATE-057

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients), except for TSH: intravenous nivolumab group n=314 and docetaxel group n=297.
b   Not graded per NCI CTCAE v4.
Laboratory Abnormality	Intravenous Nivolumab		Docetaxel
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Chemistry
Hyponatremia	35	7	34	4.9
Increased AST	27	1.9	13	0.8
Increased alkaline phosphatase	26	0.7	18	0.8
Increased ALT	22	1.7	17	0.5
Increased creatinine	18	0	12	0.5
Increased TSHb	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) ]. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma). Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either cetuximab (400 mg/m² initial dose intravenously followed by 250 mg/m² weekly), or methotrexate (40 to 60 mg/m² intravenously weekly), or docetaxel (30 to 40 mg/m² intravenously weekly). The median duration of exposure to nivolumab was 1.9 months (range: 1 day to 16.1+ months) in intravenous nivolumab-treated patients. In this trial, 18% of patients received intravenous nivolumab for >6 months and 2.5% of patients received intravenous nivolumab for >1 year.

The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the intravenous nivolumab group were ≥65 years of age and 37% in the comparator group were ≥65 years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and 90% had prior radiation therapy.

Serious adverse reactions occurred in 49% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC.

The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in ≥10% of intravenous nivolumab-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea. The most common laboratory abnormalities occurring in ≥10% of intravenous nivolumab-treated patients and at a higher incidence than investigator’s choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH.

Adjuvant Treatment of Urothelial Carcinoma (UC)

CHECKMATE-274

The safety of intravenous nivolumab was evaluated in CHECKMATE-274, a randomized, double‑blind, multicenter trial of adjuvant intravenous nivolumab versus placebo in adult patients who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal pelvis or ureter) and were at high risk of recurrence [see Clinical Studies (14.8)]. Patients received intravenous nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=351) or placebo (n=348) until recurrence or unacceptable toxicity for a maximum of 1 year. The median duration of intravenous nivolumab treatment was 8.8 months (range: 0 to 12.5).

Serious adverse reactions occurred in 30% of intravenous nivolumab patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). Intravenous nivolumab was discontinued for adverse reactions in 18% of patients. Intravenous nivolumab was delayed for adverse reaction in 33% of patients.

The most common adverse reactions (reported in ≥20% of patients) were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection.

Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-274.

Table 27: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-274

Toxicity was graded per NCI CTCAE v4.
a   Includes acne, buler, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis contact, eczema, eczema asteatotic, eczema nummular, erythema, erythema multiforme, lichen sclerosus, lichenoid keratosis, pemphigoid, photosensitivity reaction, pigmentation disorder, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rosacea, skin exfoliation, skin lesion, skin reaction, toxic skin eruption, and urticaria.
b   Includes colitis, colitis microscopic, diarrhea, duodenitis, enteritis, immune-mediated enterocolitis
c   Includes abdominal pain, abdominal discomfort, abdominal tenderness, lower and upper abdominal pain.
d   Includes musculoskeletal pain, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.
e   Includes cystitis, escherichia urinary tract infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, urethritis, urinary tract infection, urinary tract infection bacterial, urinary tract infection staphylococcal, and urosepsis.
f   Includes upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis.
g   Includes acute kidney injury, autoimmune nephritis, blood creatinine increased, glomerular filtration rate decreased, immune-mediated nephritis, nephritis, renal failure, and renal impairment.
h   Includes cough, productive cough, and upper-airway cough syndrome.
i   Includes dyspnea and exertional dyspnea.
j   Includes dizziness, postural dizziness and vertigo.
k   Includes aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, cholangitis, drug-induced liver injury, hepatic failure, hepatic function abnormal, hepatitis, hepatocellular injury, hyperbilirubinemia, gamma-glutamyl transferase increased, liver injury, and transaminases increased.
Adverse Reaction	Intravenous Nivolumab (n=351)		Placebo (n=348)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rasha	36	1.7	19	0.3
Pruritus	30	0	16	0
General
Fatigue/Asthenia	36	1.1	32	0.3
Pyrexia	10	0.3	10	0.3
Gastrointestinal
Diarrheab	30	2.8	27	1.7
Nausea	16	0.6	13	0
Abdominal painc	15	0.9	15	0.6
Constipation	13	0.3	15	0.3
Musculoskeletal and Connective Tissue
Musculoskeletal paind	28	0.6	24	0.9
Arthralgia	11	0.3	13	0
Infections
Urinary tract infectione	22	6	23	9
Upper respiratory tract infectionf	16	0.3	16	0.6
Endocrine
Hyperthyroidism	11	0	1.1	0
Hypothyroidism	11	0	2.3	0
Renal and Urinary Disorders
Renal dysfunctiong	17	1.7	16	0.9
Respiratory, Thoracic and Mediastinal
Coughh	14	0	11	0
Dyspneai	11	0.3	6	0.3
Metabolism and Nutrition
Decreased appetite	13	0.9	7	0.3
Nervous System Disorders
Dizzinessj	11	0.3	9	0
Hepatobiliary
Hepatitisk	11	4	8	0.6

Table 28: Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥10% of Patients - CHECKMATE-274

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 322 to 348 patients) and placebo group (range: 312 to 341 patients).
Laboratory Abnormality	Intravenous Nivolumab (n=351)		Placebo (n=348)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Chemistry
Increased creatinine	36	1.7	36	2.6
Increased amylase	34	8	23	3.2
Increased lipase	33	12	31	10
Hyperkalemia	32	5	30	6
Increased alkaline phosphatase	24	2.3	15	0.6
Increased AST	24	3.5	16	0.9
Increased ALT	23	2.9	15	0.6
Hyponatremia	22	4.1	17	1.8
Hypocalcemia	17	1.2	11	0.9
Hypomagnesemia	16	0	9	0
Hypercalcemia	12	0.3	8	0.3
Hematology
Lymphopenia	33	2.9	27	1.5
Anemia	30	1.4	28	0.9
Neutropenia	11	0.6	10	0.3

First-line Treatment of Unresectable or Metastatic UC

CHECKMATE-901

The safety of intravenous nivolumab was evaluated in CHECKMATE-901, a randomized, open-label trial in cisplatin-eligible patients with unresectable or metastatic UC [see Clinical Studies (14.8)]. Patients received either intravenous nivolumab 360 mg with cisplatin and gemcitabine every 3 weeks for up to 6 cycles followed by single-agent intravenous nivolumab 480 mg every 4 weeks up to 2 years (n=304), or cisplatin and gemcitabine chemotherapy every 3 weeks for up to 6 cycles (n=288). Patients discontinuing cisplatin alone were permitted to switch to carboplatin.

Among patients who received intravenous nivolumab with chemotherapy, the median duration of intravenous nivolumab exposure was 7.4 months (range: 0.03 to 47.9 months). Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab in combination with chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). The most common adverse reactions (reported in ≥20% of patients) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy.

Fatal adverse reactions occurred in 3.6% of patients who received intravenous nivolumab in combination with chemotherapy; these included sepsis (1%).

Intravenous nivolumab and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction.

Tables 29 and 30 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-901.

Table 29: Adverse Reactions Occurring in ≥10% of Treated Patients - CHECKMATE-901

Toxicity was graded per NCI CTCAE v4.
a   Includes colitis, immune-mediated enterocolitis.
b   Includes upper abdominal pain, lower abdominal pain, abdominal discomfort, epigastric discomfort, gastrointestinal pain, and hepatic pain.
c   Includes asthenia.
d   Includes peripheral edema, swelling, peripheral swelling, localized edema, swelling, face edema, testicular edema, gravitational edema, and edema genital.
e   Includes hyperthermia, body temperature increased and hyperpyrexia.
f   Includes back pain, arthralgia, bone pain, arthritis, musculoskeletal chest pain, non-cardiac chest pain, myalgia, neck pain, pain in extremity, and spinal pain.
g   Includes maculopapular rash, erythematous rash, macular rash, papular rash, pustular rash, acneiform dermatitis, dermatitis, allergic dermatitis, atopic dermatitis, exfoliative rash, eczema asteatotic, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, eczema, dermatitis exfoliative generalized, and skin exfoliation.
h   Includes paresthesia, peripheral sensory neuropathy, hypoesthesia, dysesthesia, neuralgia, hyperesthesia, peripheral motor neuropathy, polyneuropathy.
i   Includes occipital neuralgia.
j   Includes urosepsis, cystitis, pyelonephritis, pyelonephritis acute, urinary tract infection enterococcal, escherichia urinary tract infection.
k   Includes blood stimulating hormone increased.
l   Includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, anuria, azotemia.
Adverse Reaction	Intravenous Nivolumab and Platinum-Doublet Chemotherapy(n=304)		Platinum-Doublet Chemotherapy (n=288)
	All Grades(%)	Grades 3-4 (%)	All Grades(%)	Grades 3-4 (%)
Gastrointestinal disorders
Nausea	52	0.3	53	1
Constipation	30	0	28	0.7
Vomiting	23	1.3	19	2.1
Diarrheaa	19	2	14	0
Abdominal painb	14	0.3	9	0.3
General
Fatiguec	48	3.9	43	4.2
Edemad	18	0	9	0.3
Pyrexiae	14	1	14	0
Musculoskeletal and Connective Tissue
Musculoskeletal painf	33	3	21	0.3
Metabolism and Nutrition
Decreased appetite	30	1.6	19	1
Skin and Subcutaneous Tissue
Rashg	25	2.3	7	0.3
Pruritus	17	0.7	3.5	0
Nervous System Disorders
Peripheral neuropathyh	20	0.7	14	0
Headachei	11	0	5	0
Infections
Urinary tract infectionj	19	8	18	8
Endocrine disorders
Hypothyroidismk	17	0	0.3	0
Renal and Urinary Disorders
Renal dysfunctionl	14	6	11	1.7
Hematuria	11	1	7	1.4
Investigations
Weight decreased	11	0.3	6	0

Table 30: Selected Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥20% of Patients - CHECKMATE-901

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 289-301 patients) and chemotherapy group (range: 265-281 patients).
Laboratory Abnormality	Intravenous Nivolumab and Platinum-Doublet Chemotherapy(n=304)		Platinum-Doublet Chemotherapy(n=288)
	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Hematology
Anemia	88	21	80	21
Neutropenia	82	35	76	28
Lymphopenia	71	17	56	13
Thrombocytopenia	60	13	51	8
Chemistry
Increased creatinine	53	2.4	42	1.1
Hypomagnesemia	48	3.8	39	1.5
Hyponatremia	43	13	39	8
Hyperglycemia	41	3.9	37	3.2
Hypocalcemia	36	2.1	24	1.1
Hyperkalemia	33	3.0	32	1.1
Increased amylase	32	4.2	23	3.6
Increased AST	31	2.4	17	0.7
Increased ALT	29	2.4	19	0.7

Previously Treated Advanced or Metastatic UC

CHECKMATE-275

The safety of intravenous nivolumab was evaluated in CHECKMATE-275, a single arm trial in which 270 patients with locally advanced or metastatic UC had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies (14.8)]. Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a dose interruption for an adverse reaction.

Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with intravenous nivolumab. Serious adverse reactions occurred in 54% of patients. Intravenous nivolumab was discontinued for adverse reactions in 17% of patients.

The most frequent serious adverse reactions reported in ≥2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite.

Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275.

Table 31: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-275

Toxicity was graded per NCI CTCAE v4.
a   Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.
b   Includes abdominal discomfort, lower and upper abdominal pain.
c   Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular, maculopapular, or pruritic.
d   Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism, hypothyroidism, thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased, tri-iodothyronine increased.
Adverse Reaction	Intravenous Nivolumab (n=270)
	All Grades (%)	Grades 3-4 (%)
Adverse Reaction	99	51
General
Asthenia/fatigue/malaise	46	7
Pyrexia/tumor associated fever	17	0.4
Edema/peripheral edema/peripheral swelling	13	0.4
Musculoskeletal and Connective Tissue
Musculoskeletal paina	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 painb	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
Rashc	16	1.5
Pruritus	12	0
Endocrine
Thyroid disordersd	15	0

Table 32: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients - CHECKMATE-275

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: range: 84 to 256 patients.
Laboratory Abnormality	Intravenous Nivolumaba
	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 CHECKMATE-142, 74 patients with mCRC received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or until intolerable toxicity and 119 patients with mCRC received intravenous nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses, then intravenous nivolumab 3 mg/kg every 2 weeks until disease progression or until unacceptable toxicity.

In the intravenous nivolumab with ipilimumab cohort, serious adverse reactions occurred in 47% of patients. Treatment was discontinued in 13% of patients and delayed in 45% of patients for an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting.

Tables 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   Includes asthenia.
b   Includes peripheral edema and peripheral swelling.
c   Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
d   Includes back pain, pain in extremity, myalgia, neck pain, and bone pain.
e   Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized.
f   Includes nasopharyngitis and rhinitis.
Adverse Reaction	Intravenous Nivolumab(n=74)		Intravenous Nivolumab and Ipilimumab(n=119)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
General
Fatiguea	54	5	49	6
Pyrexia	24	0	36	0
Edemab	12	0	7	0
Gastrointestinal
Diarrhea	43	2.7	45	3.4
Abdominal painc	34	2.7	30	5
Nausea	34	1.4	26	0.8
Vomiting	28	4.1	20	1.7
Constipation	20	0	15	0
Musculoskeletal and Connective Tissue
Musculoskeletal paind	28	1.4	36	3.4
Arthralgia	19	0	14	0.8
Respiratory, Thoracic and Mediastinal
Cough	26	0	19	0.8
Dyspnea	8	1	13	1.7
Skin and Subcutaneous Tissue
Rashe	23	1.4	25	4.2
Pruritus	19	0	28	1.7
Dry Skin	7	0	11	0
Infections
Upper respiratory tract infectionf	20	0	9	0
Endocrine
Hyperglycemia	19	2.7	6	1
Hypothyroidism	5	0	14	0.8
Hyperthyroidism	4	0	12	0
Nervous System
Headache	16	0	17	1.7
Dizziness	14	0	11	0
Metabolism and Nutrition
Decreased appetite	14	1.4	20	1.7
Psychiatric
Insomnia	9	0	13	0.8
Investigations
Weight decreased	8	0	10	0

Clinically important adverse reactions reported in <10% of patients receiving intravenous nivolumab with ipilimumab were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%).

Table 34: Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥10% of Patients - CHECKMATE-142

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Number of evaluable patients ranges from 62 to 71 for the intravenous nivolumab cohort and from 87 to 114 for the intravenous nivolumab and ipilimumab cohort.
Laboratory Abnormality	Intravenous Nivolumab(n=74)		Intravenous Nivolumab and Ipilimumab(n=119)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Hematology
Anemia	50	7	42	9
Lymphopenia	36	7	25	6
Neutropenia	20	4.3	18	0
Thrombocytopenia	16	1.4	26	0.9
Chemistry
Increased alkaline phosphatase	37	2.8	28	5
Increased lipase	33	19	39	12
Increased ALT	32	2.8	33	12
Increased AST	31	1.4	40	12
Hyponatremia	27	4.3	26	5
Hypocalcemia	19	0	16	0
Hypomagnesemia	17	0	18	0
Increased amylase	16	4.8	36	3.4
Increased bilirubin	14	4.2	21	5
Hypokalemia	14	0	15	1.8
Increased creatinine	12	0	25	3.6
Hyperkalemia	11	0	23	0.9

CHECKMATE-040

The safety of intravenous nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg was evaluated in a subgroup comprising 49 patients with HCC and Child-Pugh Class A cirrhosis enrolled in Cohort 4 of CHECKMATE-040, a multicenter, multiple-cohort, open-label trial [see Clinical Studies (14.10) ] who progressed on or were intolerant to sorafenib. Intravenous nivolumab and ipilimumab were administered every 3 weeks for 4 doses, followed by single-agent intravenous nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity. During the intravenous nivolumab and ipilimumab combination period, 33 of 49 (67%) patients received all 4 planned doses of intravenous nivolumab and ipilimumab. During the entire treatment period, the median duration of exposure to intravenous nivolumab was 5.1 months (range: 0 to 35+ months) and to ipilimumab was 2.1 months (range: 0 to 4.5 months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction.

The most frequent serious adverse reactions (reported in ≥4% of patients) were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis.

Tables 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) ]. The trial excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Patients received either intravenous nivolumab 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Patients were treated until disease recurrence, unacceptable toxicity, or for up to 1‑year total duration. The median duration of exposure was 10.1 months (range: <0.1 to 14 months) in intravenous nivolumab-treated patients and 9 months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received intravenous nivolumab, 61% were exposed for >6 months and 54% were exposed for >9 months.

Serious adverse reactions occurred in 33% of patients receiving intravenous nivolumab. A serious adverse reaction reported in ≥2% of patients who received intravenous nivolumab was pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who received intravenous nivolumab.

Intravenous nivolumab was discontinued in 12% of patients and was delayed in 28% of patients for an adverse reaction.

Tables 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   Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
b   Includes gastroesophageal reflux.
c   Includes asthenia.
d   Includes productive cough.
e   Includes dyspnea exertional.
f   Includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, exfoliative rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic.
g   Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, spinal pain.
Adverse Reaction	Intravenous Nivolumab (n=532)		Placebo (n=260)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Adverse Reaction	96	34	93	32
Gastrointestinal
Diarrhea	29	0.9	29	0.8
Nausea	23	0.8	21	0
Abdominal Paina	17	0.8	20	1.5
Vomiting	15	0.6	16	1.2
Dysphagia	13	0.8	17	3.5
Dyspepsiab	12	0.2	16	0.4
Constipation	11	0	12	0
General
Fatiguec	34	1.3	29	1.5
Respiratory, Thoracic and Mediastinal
Coughd	20	0.2	21	0.4
Dyspneae	12	0.8	12	0.4
Skin and Subcutaneous Tissue
Rashf	21	0.9	10	0.4
Pruritus	13	0.4	6	0
Investigations
Weight decreased	13	0.4	9	0
Musculoskeletal and Connective Tissue
Musculoskeletal paing	21	0.6	20	0.8
Arthralgia	10	0.2	8	0
Metabolism and Nutrition
Decreased appetite	15	0.9	10	0.8
Endocrine
Hypothyroidism	11	0	1.5	0

Table 38: Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥10% of Patients - CHECKMATE-577

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 163 to 526 patients) and Placebo group (range: 86 to 256 patients).
b   Includes alanine aminotransferase increased, aspartate aminotransferase increased.
Laboratory Abnormality	Intravenous Nivolumab (n=532)		Placebo (n=260)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Chemistry
Increased AST	27	2.1	22	0.8
Increased alkaline phosphatase	25	0.8	18	0.8
Increased albumin	21	0.2	18	0
Increased ALT	20	1.9	16	1.2
Increased amylase	20	3.9	13	1.3
Hyponatremia	19	1.7	12	1.2
Hyperkalemia	17	0.8	15	1.6
Hypokalemia	12	1	11	1.2
Transaminases increasedb	11	1.5	6	1.2
Hematology
Lymphopenia	44	17	35	12
Anemia	27	0.8	21	0.4
Neutropenia	24	1.5	23	0.4

First-line Treatment of Unresectable Advanced or Metastatic ESCC

CHECKMATE‑648

The safety of intravenous nivolumab in combination with chemotherapy or in combination with ipilimumab was evaluated in CHECKMATE‑648, a randomized, active-controlled, multicenter, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC [see Clinical Studies (14.11) ]. Patients received one of the following treatments:

• •intravenous nivolumab 240 mg on days 1 and 15, 5-FU (fluorouracil) 800 mg/m²/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m² intravenously on day 1 (of a 4‑week cycle).
• •intravenous nivolumab 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg every 6 weeks.
• •5-FU (fluorouracil) 800 mg/m²/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m² intravenously on day 1 (of a 4-week cycle).

Among patients who received intravenous nivolumab with chemotherapy, the median duration of exposure was 5.7 months (range: 0.1 to 30.6 months). Among patients who received intravenous nivolumab and ipilimumab, the median duration of exposure was 2.8 months (range: 0 to 24 months).

Serious adverse reactions occurred in 62% of patients receiving intravenous nivolumab in combination with chemotherapy and in 69% of patients receiving intravenous nivolumab in combination with ipilimumab. The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with ipilimumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%).

Fatal adverse reactions occurred in 5 (1.6%) patients who received intravenous nivolumab in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury and in 5 (1.6%) patients who received intravenous nivolumab in combination with ipilimumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome.

Intravenous nivolumab and/or chemotherapy were discontinued in 39% of patients and were delayed in 71% of patients for an adverse reaction. Intravenous nivolumab and/or ipilimumab were discontinued in 23% of patients and were delayed in 46% of patients for an adverse reaction.

The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with chemotherapy were nausea, decreased appetite, fatigue, constipation, stomatitis, diarrhea, and vomiting. The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with ipilimumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation.

Tables 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   Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
b   Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
c   Includes asthenia and malaise.
d   Includes tumor associated fever.
e   Includes swelling, generalized edema, edema peripheral, and peripheral swelling.
f   Includes hyperesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy.
g   Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, and rash pruritic.
h   Includes productive cough.
i   Includes organizing pneumonia, pneumonia bacterial, and pneumonia pseudomonal.
j   Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, and spinal pain.
Adverse Reaction	Intravenous Nivolumab with Cisplatin and 5‑FU (n=310)		Intravenous Nivolumab and Ipilimumab (n=322)		Cisplatin and 5-FU (n=304)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3‑4 (%)
Gastrointestinal
Nausea	65	4.2	22	0.6	56	2.6
Constipation	44	1.0	20	0.3	43	1
Stomatitisa	44	9	11	0.6	35	3
Diarrhea	29	2.9	22	1.9	20	2
Vomiting	23	2.3	15	1.6	19	3
Dysphagia	14	7	12	5	12	4.9
Abdominal painb	13	1.9	10	0.9	11	0.7
Metabolism and Nutrition
Decreased appetite	51	7	17	4	50	6
General
Fatiguec	47	3.5	28	2.5	41	4.9
Pyrexiad	19	0.3	23	0.9	12	0.3
Edemae	16	0	7	0	13	0
Nervous System
Peripheral neuropathyf	18	1.3	2.8	0	13	1
Psychiatric
Insomnia	16	0	8	0	10	0.3
Skin and Subcutaneous Tissue
Rashg	16	0.6	31	3.1	7	0
Pruritus	11	0	17	0.9	3.6	0
Alopecia	10	0			11	0
Respiratory, Thoracic and Mediastinal
Coughh	16	0.3	13	0.3	13	0.3
Infections and Infestations
Pneumoniai	13	5	14	8	10	2.6
Endocrine
Hypothyroidism	7	0	14	0	0.3	0
Investigations
Weight decreased	12	0.6	12	1.9	11	1
Musculoskeletal and Connective Tissue
Musculoskeletal painj	11	0.3	14	0.6	8	0.3

Table 40: Laboratory Values Worsening from Baseline^a Occurring in ≥10% of Patients - CHECKMATE-648

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab with cisplatin and 5-FU group (range: 60 to 305 patients), intravenous nivolumab and ipilimumab group (range: 59 to 307 patients) or cisplatin and 5-FU group (range: 56 to 283 patients).
Laboratory Abnormality	Intravenous Nivolumab with Cisplatin and 5‑FU(n=310)		Intravenous Nivolumab and Ipilimumab (n=322)		Cisplatin and 5-FU(n=304)
	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Hematology
Anemia	81	21	52	7	66	14
Lymphopenia	67	23	50	13	44	8
Neutropenia	61	18	13	1.3	48	13
Leukopenia	53	11			39	5
Thrombocytopenia	43	3.3	12	1	29	2.8
Chemistry
Hyponatremia	52	15	45	11	40	8
Hypocalcemia	43	3	32	0	23	0.7
Increased creatinine	41	2.3	15	0.7	31	0.7
Hypomagnesemia	35	1.7	15	0	25	1.8
Hyperglycemia	34	0	43	4.3	36	0.8
Hyperkalemia	33	2.3	23	1.6	24	0.7
Hypokalemia	29	9	19	5	17	6
Increased alkaline phosphatase	26	1.3	31	3.3	15	0
Increased AST	23	3.3	39	6	11	1.4
Increased ALT	23	2.3	33	6	8	0.7
Hypoglycemia	18	0.4	15	1.2	7	0
Hypercalcemia	11	2.6	15	2	8	0

Previously-Treated Unresectable Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)

ATTRACTION-3

The safety of intravenous nivolumab was evaluated in ATTRACTION-3, a randomized, active-controlled, open‑label, multicenter trial in 209 patients with unresectable advanced, recurrent or metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum‑based chemotherapy [see Clinical Studies (14.11) ]. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients received intravenous nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m² intravenously every 3 weeks (n=65) or paclitaxel 100 mg/m² intravenously once a week for 6 weeks followed by 1 week off (n=143). Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 2.6 months (range: 0 to 29.2 months) in intravenous nivolumab-treated patients and 2.6 months (range: 0 to 21.4 months) in docetaxel- or paclitaxel-treated patients. Among patients who received intravenous nivolumab, 26% were exposed for >6 months and 10% were exposed for >1 year.

Serious adverse reactions occurred in 38% of patients receiving intravenous nivolumab. Serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab were pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse reactions occurred in patients who received intravenous nivolumab: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

Intravenous nivolumab was discontinued in 13% of patients and was delayed in 27% of patients for an adverse reaction.

Tables 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   Includes urticaria, drug eruption, eczema, eczema asteatotic, eczema nummular, palmar-plantar erythrodysesthesia syndrome, erythema, erythema multiforme, buler, skin exfoliation, Stevens-Johnson syndrome, dermatitis, dermatitis described as acneiform, bullous, or contact, and rash described as maculo-papular, generalized, or pustular.
b   Includes hypophagia, and food aversion.
c   Includes colitis.
d   Includes spondyloulhesis, periarthritis, musculoskeletal chest pain, neck pain, arthralgia, back pain, myalgia, pain in extremity, arthritis, bone pain, and periarthritis calcarea.
e   Includes influenza, influenza like illness, pharyngitis, nasopharyngitis, tracheitis, and bronchitis and upper respiratory infection with bronchitis.
f   Includes pneumonia aspiration, pneumonia bacterial, and lung infection. Two patients (1.0%) died of pneumonia in the intravenous nivolumab treatment arm. Two patients (1.0%) died of pneumonia in the chemotherapy treatment arm; these deaths occurred with paclitaxel only.
g   Includes productive cough.
h   Includes tumor-associated fever.
i   Includes asthenia.
j   Includes hemoglobin decreased, and iron deficiency anemia.
k   Includes blood thyroid stimulating hormone increased.
Adverse Reaction	Intravenous Nivolumab (n=209)		Docetaxel or Paclitaxel (n=208)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rasha	22	1.9	28	1
Pruritus	12	0	7	0
Metabolism and Nutrition
Decreased appetiteb	21	1.9	35	5
Gastrointestinal
Diarrheac	18	1.9	17	1.4
Constipation	17	0	19	0
Nausea	11	0	20	0.5
Musculoskeletal and Connective Tissue
Musculoskeletal paind	17	0	26	1.4
Infections
Upper respiratory tract infectione	17	1	14	0
Pneumoniaf	13	5	19	9
Respiratory, Thoracic and Mediastinal
Coughg	16	0	14	0.5
General
Pyrexiah	16	0.5	19	0.5
Fatiguei	12	1.4	27	4.8
Blood and Lymphatic System
Anemiaj	13	8	30	13
Endocrine
Hypothyroidismk	11	0	1.4	0

Table 42: Laboratory Abnormalities Worsening from Baseline^a Occurring in ≥10% of Patients - ATTRACTION-3

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (209 patients) and Docetaxel or Paclitaxel group (range: 207 to 208 patients).
Laboratory Abnormality	Intravenous Nivolumab (n=209)		Docetaxel or Paclitaxel (n=208)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Chemistry
Increased creatinine	78	0.5	68	0.5
Hyperglycemia	52	5	62	5
Hyponatremia	42	11	50	12
Increased AST	40	6	30	1
Increased alkaline phosphatase	33	4.8	24	1.0
Increased ALT	31	5	22	1.9
Hypercalcemia	22	6	14	2.9
Hyperkalemia	22	0.5	31	1
Hypoglycemia	14	1.4	14	0.5
Hypokalemia	11	2.9	13	3.4
Hematology
Lymphopenia	46	19	72	43
Anemia	42	9	71	17
Leukopenia	11	0.5	79	45

CHECKMATE-649

The safety of intravenous nivolumab in combination with chemotherapy was evaluated in CHECKMATE-649, a randomized, multicenter, open-label trial in patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma [see Clinical Studies (14.12) ]. The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive or had untreated central nervous system (CNS) metastases. Patients were randomized to receive intravenous nivolumab in combination with chemotherapy or chemotherapy. Patients received one of the following treatments:

• •intravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
• •intravenous nivolumab 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every 3 weeks or CapeOX every 3 weeks.

Patients were treated with intravenous nivolumab in combination with chemotherapy or chemotherapy until disease progression, unacceptable toxicity, or up to 2 years. The median duration of exposure was 6.8 months (range: 0 to 33.5 months) in intravenous nivolumab and chemotherapy-treated patients. Among patients who received intravenous nivolumab and chemotherapy, 54% were exposed for >6 months and 28% were exposed for >1 year.

Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with intravenous nivolumab in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. Serious adverse reactions occurred in 52% of patients treated with intravenous nivolumab in combination with chemotherapy. Intravenous nivolumab and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous nivolumab in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.

Tables 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   Includes dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy.
b   Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
c   Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
d   Includes asthenia.
e   Includes tumor associated fever.
f   Includes swelling, generalized edema, edema peripheral, and peripheral swelling.
g   Includes blood albumin decreased.
h   Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
i   Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, nodular rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash vesicular.
j   Includes productive cough.
k   Includes nasopharyngitis, pharyngitis, and rhinitis.
Adverse Reaction	Intravenous Nivolumab and mFOLFOX6 or CapeOX (n=782)		mFOLFOX6 or CapeOX(n=767)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4(%)
Adverse Reaction	99	69	98	59
Nervous System
Peripheral neuropathya	53	7	46	4.8
Headache	11	0.8	6	0.3
Gastrointestinal
Nausea	48	3.2	44	3.7
Diarrhea	39	5	34	3.7
Vomiting	31	4.2	29	4.2
Abdominal painb	27	2.8	24	2.6
Constipation	25	0.6	21	0.4
Stomatitisc	17	1.8	13	0.8
General
Fatigued	44	7	40	5
Pyrexiae	19	1	11	0.4
Edemaf	12	0.5	8	0.1
Metabolism and Nutrition
Decreased appetite	29	3.6	26	2.5
Hypoalbuminemiag	14	0.3	9	0.3
Investigations
Weight decreased	17	1.3	15	0.7
Increased lipase	14	7	8	3.7
Increased amylase	12	3.1	5	0.4
Musculoskeletal and Connective Tissue
Musculoskeletal painh	20	1.3	14	2
Skin and Subcutaneous Tissue
Rashi	18	1.7	4.4	0.1
Palmar-plantar erythrodysesthesia syndrome	13	1.5	12	0.8
Respiratory, Thoracic and Mediastinal
Coughj	13	0.1	9	0
Infections and Infestations
Upper respiratory tract infectionk	10	0.1	7	0.1

Table 44: Laboratory Values Worsening from Baseline^a Occurring in ≥10% of Patients - CHECKMATE-649

a   Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and mFOLFOX6 or CapeOX group (407 to 767 patients) or mFOLFOX6 or CapeOX group (range: 405 to 735 patients).
Laboratory Abnormality	Intravenous Nivolumab and mFOLFOX6 or CapeOX(n=782)		mFOLFOX6 or CapeOX(n=767)
	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Hematology
Neutropenia	73	29	62	23
Leukopenia	69	12	59	9
Thrombocytopenia	68	7	63	4.4
Anemia	59	14	60	10
Lymphopenia	59	12	49	9
Chemistry
Increased AST	52	4.6	47	1.9
Hypocalcemia	42	1.6	37	1
Hyperglycemia	41	3.9	38	2.7
Increased ALT	37	3.4	30	1.9
Hyponatremia	34	6	24	5
Hypokalemia	27	7	24	4.8
Hyperbilirubinemia	24	2.8	21	2
Increased creatinine	15	1	9	0.5
Hyperkalemia	14	1.4	11	0.7
Hypoglycemia	12	0.7	9	0.2
Hypernatremia	11	0.5	7.1	0

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of intravenous nivolumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye: Vogt-Koyanagi-Harada (VKH) syndrome

Complications of Intravenous Nivolumab Treatment After Allogeneic HSCT: Treatment refractory, severe acute and chronic GVHD

Blood and lymphatic system disorders: Hemophagocytic lymphohistiocytosis (HLH) (including fatal cases), autoimmune hemolytic anemia (including fatal cases)