Preparation

No incompatibilities were observed between OPDIVO QVANTIG and polypropylene and polycarbonate syringes, or between OPDIVO QVANTIG and polyethylene, polyurethane, polyvinyl chloride, and fluorinated ethylene propylene subcutaneous administration sets.

A syringe and a transfer needle are needed to withdraw OPDIVO QVANTIG solution from the vial. OPDIVO QVANTIG may be injected subcutaneously using a 23G-25G (3/8”-5/8”) hypodermic injection needle or subcutaneous administration set (eg., winged/butterfly).

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600 mg nivolumab and 10,000 units hyaluronidase

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Allow 1 OPDIVO QVANTIG vial to reach room temperature, then withdraw 5 mL of OPDIVO QVANTIG into the syringe.

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900 mg nivolumab and 15,000 units hyaluronidase

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Allow 2 OPDIVO QVANTIG vials to reach room temperature, then withdraw 5 mL from one vial and 2.5 mL from the other vial, for a total volume of 7.5 mL of OPDIVO QVANTIG into a single syringe.

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1,200 mg nivolumab and 20,000 units hyaluronidase

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Allow 2 OPDIVO QVANTIG vials to reach room temperature, then withdraw 10 mL of OPDIVO QVANTIG into a single syringe.

Select the appropriate syringe label provided in the carton that matches the prescribed dose and apply to the prepared syringe.

Discard partially used or empty vials of OPDIVO QVANTIG.

If the dose is not to be used immediately, attach a tip cap to the syringe prior to storage. To avoid clogging of the hypodermic injection needle, attach a 23G-25G (3/8”-5/8”) hypodermic injection needle to the syringe immediately prior to administration.

Storage in Syringe

Once withdrawn into the syringe, OPDIVO QVANTIG should be used immediately. If not used immediately, store the syringe:

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In the refrigerator at 2°C to 8°C (36°F to 46°F), protected from light for up to 48 hours; do not freeze, or

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At room temperature 20°C to 25°C (68°F to 77°F) for up to 8 hours. Storage at room temperature for this duration does not require protection from light.

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Discard if storage time exceeds these limits.

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If stored in the refrigerator, allow the solution to come to room temperature before administration.

Administration

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Administer the full contents of the syringe into the subcutaneous tissue of 1 of the 4 quadrants of the abdomen, or thigh over a period of 3 to 5 minutes.

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Alternate injection sites across the 4 quadrants of the abdomen or thighs for successive injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If the administration of OPDIVO QVANTIG is interrupted, continue administering at the same site, or at an alternate site.

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During treatment with OPDIVO QVANTIG, do not administer other subcutaneous medications at the same site used for OPDIVO QVANTIG.

Immune-Mediated Pneumonitis

OPDIVO QVANTIG can cause immune-mediated pneumonitis, which is defined as requiring use of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

Immune-mediated pneumonitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (2.0%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDIVO QVANTIG in 1.6% and withholding of OPDIVO QVANTIG in 1.6% of patients.

Systemic corticosteroids were required in 100% (7/7) of patients with pneumonitis. Pneumonitis resolved in 27% of the 7 patients. Of the 4 patients in whom OPDIVO QVANTIG was withheld for pneumonitis, 2 reinitiated OPDIVO QVANTIG after symptom improvement; of these, 1 (50%) had recurrence of pneumonitis.

Immune-Mediated Colitis

OPDIVO QVANTIG can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated colitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.4%) and Grade 2 (2.4%) adverse reactions. Colitis led to withholding of OPDIVO QVANTIG in 2.0% of patients.

Systemic corticosteroids were required in 100% (7/7) of patients with colitis. Colitis resolved in 71% of the 7 patients. Of the 5 patients in whom OPDIVO QVANTIG was withheld for colitis, 3 reinitiated OPDIVO QVANTIG after symptom improvement; of these, 2 (67%) had recurrence of colitis.

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO QVANTIG can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Immune-mediated hepatitis occurred in 2.4% (6/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (1.6%), and Grade 2 (0.8%) adverse reactions. Hepatitis led to permanent discontinuation of OPDIVO QVANTIG in 0.8% and withholding of OPDIVO QVANTIG in 1.6% of patients.

Systemic corticosteroids were required in 100% (6/6) of patients with hepatitis. Hepatitis resolved in 67% of the 6 patients. Of the 2 patients in whom OPDIVO QVANTIG was withheld for hepatitis, 2 reinitiated OPDIVO QVANTIG after symptom improvement; of these, 1 (50%) had recurrence of hepatitis.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

OPDIVO QVANTIG can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.3)].

Adrenal insufficiency occurred in 2% (5/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (1.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO QVANTIG in 0.4% of patients and withholding of OPDIVO QVANTIG in 0.4% of patients.

Systemic corticosteroids were required in 100% (5/5) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 20% of the 5 patients.

Intravenous Nivolumab with Cabozantinib

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received intravenous nivolumab with cabozantinib, including Grade 3 (2.2%) and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of intravenous nivolumab and cabozantinib in 0.9% and withholding of intravenous nivolumab and cabozantinib in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom intravenous nivolumab with cabozantinib was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Hypophysitis

OPDIVO QVANTIG can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.3)].

Intravenous Nivolumab

Hypophysitis occurred in 0.6% (12/1994) of patients treated with single agent intravenous nivolumab, including Grade 3 (0.2%) and Grade 2 (0.3%). Hypophysitis led to permanent discontinuation of intravenous nivolumab in 0.2% of patients. Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom intravenous nivolumab was withheld for hypophysitis, 2 reinitiated intravenous nivolumab after symptom improvement; of these, none had recurrence of hypophysitis.

Thyroid Disorders

OPDIVO QVANTIG can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.3)].

Thyroiditis

Thyroiditis occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG, including a Grade 1 (0.4%) adverse reaction.

Systemic corticosteroids were not required in the patient with thyroiditis. Thyroiditis did not resolve in this patient.

Hyperthyroidism

Hyperthyroidism occurred in 0.8% (2/247) of patients receiving OPDIVO QVANTIG, including Grade 2 (0.4%) adverse reactions.

Systemic corticosteroids were not required in patients with hyperthyroidism. Hyperthyroidism resolved in 50% of the 2 patients.

Hypothyroidism

Hypothyroidism occurred in 9% (23/247) of patients receiving OPDIVO QVANTIG, including Grade 2 (5.7%) adverse reactions. Hypothyroidism led to withholding of OPDIVO QVANTIG in 0.8% of patients.

Systemic corticosteroids were not required in patients with hypothyroidism. Hypothyroidism resolved in 4.3% of the 23 patients. Of the 1 patient in whom OPDIVO QVANTIG was withheld for hypothyroidism, OPDIVO QVANTIG was not reinitiated after symptom improvement.

Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.3)].

Grade 3 diabetes occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG.

No patients with diabetes required systemic corticosteroids. Diabetes did not resolve in this patient.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO QVANTIG can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology.

Grade 2 immune-mediated nephritis and renal dysfunction occurred in 1.2% (3/247) of patients receiving OPDIVO QVANTIG. Immune-mediated nephritis and renal dysfunction led to withholding of OPDIVO QVANTIG in 1.2% of patients.

Systemic corticosteroids were required in 100% (3/3) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 100% of the 3 patients. Of the 3 patients in whom OPDIVO QVANTIG was withheld for nephritis or renal dysfunction, 1 reinitiated OPDIVO QVANTIG after symptom improvement without recurrence of nephritis or renal dysfunction.

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO QVANTIG can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.3)].

Immune-mediated rash occurred in 7% (17/247) of patients, including Grade 3 (0.8%) and Grade 2 (2.8%) adverse reactions. Immune-mediated rash led to withholding of OPDIVO QVANTIG in 1.2% of patients.

Systemic corticosteroids were required in 47% (8/17) of patients with immune-mediated rash. Rash resolved in 77% of the 17 patients. Of the 3 patients in whom OPDIVO QVANTIG was withheld for immune-mediated rash, all reinitiated OPDIVO QVANTIG after symptom improvement; of these, all (100%) had recurrence of immune-mediated rash.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO QVANTIG or intravenous nivolumab as a single agent or in combination with chemotherapy or immunotherapy, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss

Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatic

Endocrine: Hypoparathyroidism

Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

Advanced Renal Cell Carcinoma

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

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

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

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

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

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

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

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.

Unresectable or Metastatic Melanoma

Previously Treated Metastatic Melanoma

CHECKMATE-037

The safety of intravenous nivolumab was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.2)]. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/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.

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

Adjuvant Treatment of Melanoma

CHECKMATE-76K

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

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

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

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

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

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.

Non-Small Cell Lung Cancer

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

CHECKMATE-816

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

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

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

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

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

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

Squamous Cell Carcinoma of the Head and Neck

CHECKMATE-141

The safety of intravenous nivolumab was evaluated in CHECKMATE-141, a randomized, active-controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with progression during or within 6 months of receiving prior platinum-based therapy [see Clinical Studies (14.7)]. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma). Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either cetuximab (400 mg/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.

Urothelial Carcinoma

Adjuvant Treatment of Urothelial Carcinoma (UC)

CHECKMATE-274

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

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

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

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

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.

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.

MSI-H or dMMR Metastatic Colorectal Cancer

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.

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%).