Opdivo Qvantig Injection, Solution
FDA Label NDC 0003-6120

OPDIVO QVANTIG™, as monotherapy, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC) following treatment with intravenous nivolumab and ipilimumab combination therapy.

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma.

OPDIVO QVANTIG, in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced RCC.

OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with advanced RCC who have received prior anti-angiogenic therapy.

OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic melanoma.

OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic melanoma following treatment with intravenous nivolumab and ipilimumab combination therapy.

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic melanoma.

OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult patients with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.

OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).

OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated for the neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by OPDIVO QVANTIG as monotherapy in the adjuvant setting after surgical resection.

OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO QVANTIG.

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC.

OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

OPDIVO QVANTIG, in combination with cisplatin and gemcitabine, is indicated for the first-line treatment of adult patients with unresectable or metastatic UC.

OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with locally advanced or metastatic UC who:

• have disease progression during or following platinum-containing chemotherapy.
• have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

OPDIVO QVANTIG, as monotherapy or as monotherapy following treatment with intravenous nivolumab and ipilimumab combination therapy, is indicated for the treatment of adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of MSI-H or dMMR metastatic CRC.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.9)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib and following treatment with intravenous nivolumab and ipilimumab.

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with HCC.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.10)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO QVANTIG as monotherapy, is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).

OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC.

OPDIVO QVANTIG as monotherapy, is indicated for the treatment of adult patients with unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

OPDIVO QVANTIG has different dosage and administration instructions than intravenously administered nivolumab products [see Dosage and Administration (2.4)].

OPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. Do not administer intravenously.

OPDIVO QVANTIG is to be administered by a healthcare professional only.

Adult patients currently receiving intravenous nivolumab as a single agent, or in combination with chemotherapy or cabozantinib, may switch to subcutaneous OPDIVO QVANTIG at their next scheduled dose.

The recommended dosages of OPDIVO QVANTIG as monotherapy agent are presented in Table 1.

The recommended dosages of OPDIVO QVANTIG in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with OPDIVO QVANTIG for the recommended dosage information, as appropriate.

No dose reduction for OPDIVO QVANTIG is recommended. In general, withhold OPDIVO QVANTIG for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue OPDIVO QVANTIG for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for OPDIVO QVANTIG or OPDIVO QVANTIG in combination with other anti-cancer agents for adverse reactions that require management different from these general guidelines are summarized in Table 3 and Table 4.

To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is OPDIVO QVANTIG for subcutaneous use and NOT intravenous nivolumab. Do NOT administer OPDIVO QVANTIG intravenously. OPDIVO QVANTIG should be administered by a healthcare professional.

Each OPDIVO QVANTIG vial is for one-time use only. It is a ready-to-use solution for injection. It should not be diluted.

Visually inspect for particulate matter and discoloration prior to administration. OPDIVO QVANTIG is a clear to opalescent, colorless to yellow solution. Discard if the solution is discolored or contains extraneous particulate matter other than a few translucent-to-white particles. Do not shake.

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

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

• 600 mg nivolumab and 10,000 units hyaluronidase
  • ∘Allow 1 OPDIVO QVANTIG vial to reach room temperature, then withdraw 5 mL of OPDIVO QVANTIG into the syringe.
  • 900 mg nivolumab and 15,000 units hyaluronidase
    • ∘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.
    • 1,200 mg nivolumab and 20,000 units hyaluronidase
      • ∘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.

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

• In the refrigerator at 2°C to 8°C (36°F to 46°F), protected from light for up to 48 hours; do not freeze, or
• At room temperature 20°C to 25°C (68°F to 77°F) for up to 8 hours. Storage at room temperature for this duration does not require protection from light.
• Discard if storage time exceeds these limits.
• If stored in the refrigerator, allow the solution to come to room temperature before administration.

• Administer the full contents of the syringe into the subcutaneous tissue of 1 of the 4 quadrants of the abdomen, or thigh over a period of 3 to 5 minutes.
• Alternate injection sites across the 4 quadrants of the abdomen or thighs for successive injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If the administration of OPDIVO QVANTIG is interrupted, continue administering at the same site, or at an alternate site.
• During treatment with OPDIVO QVANTIG, do not administer other subcutaneous medications at the same site used for OPDIVO QVANTIG.

Injection: 600 mg nivolumab and 10,000 units hyaluronidase per 5 mL (120 mg/2,000 units per mL), as a clear to opalescent, colorless to yellow solution in a single-dose vial.

None.

OPDIVO QVANTIG is a combination of a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance, and inducing immune-mediated adverse reactions, and an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD‑1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.3)]. In general, if OPDIVO QVANTIG requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

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.

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.

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.

Nivolumab in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to nivolumab alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt nivolumab and cabozantinib and consider administering corticosteroids [see Dosage and Administration (2.3)].

With the combination of intravenous nivolumab and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% (35/320) of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either intravenous nivolumab (n=11) or cabozantinib (n=9) administered as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving intravenous nivolumab, 2 patients receiving cabozantinib, and 7 patients receiving both intravenous nivolumab and cabozantinib.

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.

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.

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.

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.

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause) [see Adverse Reactions (6.1)]. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.

Based on its mechanism of action and data from animal studies, OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG and for 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including intravenous nivolumab, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

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)]

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.

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

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.

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.

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.

CHECKMATE-214

CHECKMATE-214 (NCT02231749) was a randomized (1:1), open-label trial in patients with previously untreated advanced RCC. Patients were included regardless of their PD-L1 status. CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and region.

Efficacy was evaluated in intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the IMDC criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status <80%, hemoglobin less than the lower limit of normal, corrected calcium of >10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal).

Patients were randomized to nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by nivolumab 3 mg/kg intravenously every two weeks (n=425), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=422). Treatment continued until disease progression or unacceptable toxicity.

The trial population characteristics were: median age was 61 years (range: 21 to 85) with 38% ≥65 years of age and 8% ≥75 years of age. The majority of patients were male (73%) and White (87%) and 26% and 74% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively.

The major efficacy outcome measures were OS, PFS (independent radiographic review committee [IRRC]-assessed) and confirmed ORR (IRRC-assessed) in intermediate/poor risk patients. In this population, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to intravenous nivolumab and ipilimumab as compared with sunitinib (Table 46 and Figure 1). OS benefit was observed regardless of PD-L1 expression level. The trial did not demonstrate a statistically significant improvement in PFS. Efficacy results are shown in Table 46 and Figure 1.

Figure 1: Overall Survival (Intermediate/Poor Risk Population) - CHECKMATE-214

Oq-os-checkmate-214 (Oq Os Checkmate 214)

CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to intravenous nivolumab and ipilimumab (n=125) or to sunitinib (n=124). These patients were not evaluated as part of the efficacy analysis population. OS in favorable risk patients receiving intravenous nivolumab and ipilimumab compared to sunitinib has a hazard ratio of 1.45 (95% CI: 0.75, 2.81). The efficacy of intravenous nivolumab and ipilimumab in previously untreated renal cell carcinoma with favorable-risk disease has not been established.

CHECKMATE-9ER

CHECKMATE-9ER (NCT03141177) was a randomized, open-label study of intravenous nivolumab combined with cabozantinib versus sunitinib in patients with previously untreated advanced RCC. CHECKMATE-9ER excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression. Patients were stratified by IMDC prognostic score (favorable vs. intermediate vs. poor), PD-L1 tumor expression (≥1% vs. <1% or indeterminate), and region (US/Canada/Western Europe/Northern Europe vs. Rest of World).

Patients were randomized to nivolumab 240 mg intravenously every 2 weeks and cabozantinib 40 mg orally daily (n=323), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (4 weeks on treatment followed by 2 weeks off) (n=328). Treatment continued until disease progression per RECIST v1.1 or unacceptable toxicity. Treatment beyond RECIST‑defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every 12 weeks thereafter.

The trial population characteristics were: median age 61 years (range: 28 to 90) with 38% ≥65 years of age and 10% ≥75 years of age. The majority of patients were male (74%) and White (82%) and 23% and 77% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. Patient distribution by IMDC risk categories was 22% favorable, 58% intermediate, and 20% poor.

The major efficacy outcome measure was PFS (BICR assessed). Additional efficacy outcome measures were OS and ORR (BICR assessed). The trial demonstrated a statistically significant improvement in PFS, OS, and ORR for patients randomized to intravenous nivolumab and cabozantinib compared with sunitinib. Consistent results for PFS were observed across pre-specified subgroups of IMDC risk categories and PD-L1 tumor expression status. An updated OS analysis was conducted when 271 deaths were observed based on the pre-specified number of deaths for the pre-planned final analysis of OS. Efficacy results are shown in Table 47 and Figures 2 and 3.

Figure 2: Progression-free Survival - CHECKMATE-9ER

Oq-pfs-checkmate-9er (Oq Pfs Checkmate 9er)

Figure 3: Updated Overall Survival - CHECKMATE-9ER

Oq-updated-os-checkmate-9er (Oq Updated Os Checkmate 9er)

In an exploratory analysis, the updated analysis of OS in patients with IMDC favorable, intermediate, intermediate/poor, and poor risk demonstrated a HR (95% CI) of 1.03 (0.55, 1.92), 0.74 (0.54, 1.01), 0.65 (0.50, 0.85), and 0.49 (0.31, 0.79), respectively.

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.

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

CHECKMATE-025

CHECKMATE-025 (NCT01668784) was a randomized (1:1), open-label trial in patients with advanced RCC who had experienced disease progression during or after one or two prior anti-angiogenic therapy regimens. Patients had to have a Karnofsky Performance Score (KPS) ≥70% and patients were included regardless of their PD-L1 status. The trial excluded patients with any history of or concurrent brain metastases, prior treatment with an mTOR inhibitor, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by region, Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group and the number of prior anti-angiogenic therapies. Patients were randomized to nivolumab 3 mg/kg by intravenous infusion every 2 weeks (n=410) or everolimus 10 mg orally daily (n=411). The first tumor assessments were conducted 8 weeks after randomization and continued every 8 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. The major efficacy outcome measure was overall survival (OS).

The trial population characteristics were: median age was 62 years (range: 18 to 88) with 40% ≥65 years of age and 9% ≥75 years of age. The majority of patients were male (75%) and White (88%) and 34% and 66% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. The majority of patients (77%) were treated with one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 34% favorable, 47% intermediate, and 19% poor.

The trial demonstrated a statistically significant improvement in OS for patients randomized to intravenous nivolumab as compared with everolimus at the prespecified interim analysis when 398 events were observed (70% of the planned number of events for final analysis). OS benefit was observed regardless of PD-L1 expression level. Efficacy results are shown in Table 48 and Figure 4.

Figure 4: Overall Survival - CHECKMATE-025

Oq-os-checkmate-025 (Oq Os Checkmate 025)

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

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.

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

Nervous System Disorders: peripheral neuropathy

CHECKMATE-067

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

Patients were randomized to receive:

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

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

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

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

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

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

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

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

Toxicity was graded per NCI CTCAE v4.
a   Includes asthenia and fatigue.
b   Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash.
c   Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
d   Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
e   Includes hypertension and blood pressure increased.
Adverse Reaction	Intravenous Nivolumab and Ipilimumab (n=313)		Intravenous Nivolumab (n=313)		Ipilimumab (n=311)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
General
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 and Ipilimumab		Intravenous Nivolumab		Ipilimumab
	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Chemistry
Increased ALT	55	16	25	3	29	2.7
Hyperglycemia	53	5.3	46	7	26	0
Increased AST	52	13	29	3.7	29	1.7
Hyponatremia	45	10	22	3.3	26	7
Increased lipase	43	22	32	12	24	7
Increased alkaline phosphatase	41	6	27	2	23	2
Hypocalcemia	31	1.1	15	0.7	20	0.7
Increased amylase	27	10	19	2.7	15	1.6
Increased creatinine	26	2.7	19	0.7	17	1.3
Hematology
Anemia	52	2.7	41	2.6	41	6
Lymphopenia	39	5	41	4.9	29	4

The effectiveness of OPDIVO QVANTIG has been established for the treatment of previously untreated unresectable or metastatic melanoma. Use of OPDIVO QVANTIG for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of these adequate and well-controlled studies of intravenous nivolumab in this melanoma population.

OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.

CHECKMATE-066

CHECKMATE-066 (NCT01721772) was a multicenter, double-blind, randomized (1:1) trial in 418 patients with BRAF V600 wild-type unresectable or metastatic melanoma. Patients were randomized to receive either nivolumab 3 mg/kg by intravenous infusion every 2 weeks or dacarbazine 1000 mg/m² intravenously every 3 weeks until disease progression or unacceptable toxicity. Randomization was stratified by PD-L1 status (≥5% of tumor cell membrane staining by immunohistochemistry vs. <5% or indeterminate result) and M stage (M0/M1a/M1b versus M1c). Key eligibility criteria included histologically confirmed, unresectable or metastatic, cutaneous, mucosal, or acral melanoma; no prior therapy for metastatic disease; completion of prior adjuvant or neoadjuvant therapy at least 6 weeks prior to randomization; ECOG performance status 0 or 1; absence of autoimmune disease; and absence of active brain or leptomeningeal metastases. The trial excluded patients with ocular melanoma. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year and then every 12 weeks thereafter. The major efficacy outcome measure was overall survival (OS). Additional outcome measures included investigator-assessed progression-free survival (PFS) and ORR per RECIST v1.1.

The trial population characteristics were: median age was 65 years (range: 18 to 87), 59% were male, and 99.5% were White. Disease characteristics were M1c stage disease (61%), cutaneous melanoma (74%), mucosal melanoma (11%), elevated LDH level (37%), PD-L1 ≥5% tumor cell membrane expression (35%), and history of brain metastasis (4%). More patients in the intravenous nivolumab arm had an ECOG performance status of 0 (71% vs. 58%).

CHECKMATE-066 demonstrated a statistically significant improvement in OS for the intravenous nivolumab arm compared with the dacarbazine arm in an interim analysis based on 47% of the total planned events for OS. At the time of analysis, 88% (63/72) of intravenous nivolumab-treated patients had ongoing responses, which included 43 patients with ongoing response of 6 months or longer. Efficacy results are shown in Table 49 and Figure 6.

Table 49: Efficacy Results - CHECKMATE-066

a   Not Reached
b   Based on a stratified proportional hazards model.
c   Based on stratified log-rank test.
d   p-value is compared with the allocated alpha of 0.0021 for this interim analysis.
	Intravenous Nivolumab (n=210)	Dacarbazine (n=208)
Overall Survival
Deaths (%)	50 (24)	96 (46)
Median (months) (95% CI)	NRa	10.8 (9.3, 12.1)
Hazard ratio (95% CI)b	0.42 (0.30, 0.60)
p-valuec,d	<0.0001
Progression-free Survival
Disease progression or death (%)	108 (51)	163 (78)
Median (months) (95% CI)	5.1 (3.5, 10.8)	2.2 (2.1, 2.4)
Hazard ratio (95% CI)b	0.43 (0.34, 0.56)
p-valuec,d	<0.0001
Overall Response Rate	34%	9%
(95% CI)	(28, 41)	(5, 13)
Complete response rate	4%	1%
Partial response rate	30%	8%

Figure 6: Overall Survival - CHECKMATE-066



Oq-os-checkmate-066 (Oq Os Checkmate 066)

CHECKMATE-067

CHECKMATE-067 (NCT01844505) was a multicenter, randomized (1:1:1), double-blind trial in 945 patients with previously untreated, unresectable or metastatic melanoma to one of the following arms: intravenous nivolumab and ipilimumab, intravenous nivolumab, or ipilimumab. Patients were required to have completed adjuvant or neoadjuvant treatment at least 6 weeks prior to randomization and have no prior treatment with anti-CTLA-4 antibody and no evidence of active brain metastasis, ocular melanoma, autoimmune disease, or medical conditions requiring systemic immunosuppression.

Patients were randomized to receive:

• Nivolumab 1 mg/kg with ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses, followed by nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (nivolumab and ipilimumab arm),
• Nivolumab 3 mg/kg by intravenous infusion every 2 weeks (nivolumab arm), or
• Ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses, followed by placebo every 2 weeks (ipilimumab arm).

Randomization was stratified by PD-L1 expression (≥5% vs. <5% tumor cell membrane expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M stage per the AJCC staging system (M0, M1a, M1b vs. M1c). Tumor assessments were conducted 12 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. The major efficacy outcome measures were investigator-assessed PFS per RECIST v1.1 and OS. Additional efficacy outcome measures were confirmed ORR and duration of response.

The trial population characteristics were: median age 61 years (range: 18 to 90); 65% male; 97% White; ECOG performance score 0 (73%) or 1 (27%). Disease characteristics were: AJCC Stage IV disease (93%); M1c disease (58%); elevated LDH (36%); history of brain metastases (4%); BRAF V600 mutation-positive melanoma (32%); PD-L1 ≥5% tumor cell membrane expression as determined by the clinical trials assay (46%); and prior adjuvant therapy (22%).

CHECKMATE-067 demonstrated statistically significant improvements in OS and PFS for patients randomized to either intravenous nivolumab-containing arm as compared with the ipilimumab arm. The trial was not designed to assess whether adding ipilimumab to intravenous nivolumab improves PFS or OS compared to intravenous nivolumab as a single agent. Efficacy results are shown in Table 50 and Figure 7.

Table 50: Efficacy Results - CHECKMATE-067

a   OS results are based on final OS analysis with 28 months of minimum follow-up; PFS (co-primary endpoint) and ORR (secondary endpoint) results were based on primary analysis with 9 months of minimum follow-up.
b   Based on a stratified proportional hazards model.
c   Based on stratified log-rank test.
d   If the maximum of the two OS p-values is less than 0.04 (a significance level assigned by the Hochberg procedure), then both p-values are considered significant.
e   p-value is compared with .005 of the allocated alpha for final PFS treatment comparisons.
f   Based on the stratified Cochran-Mantel-Haenszel test.
+   Censored observation
	Intravenous Nivolumab and Ipilimumab (n=314)	Intravenous Nivolumab (n=316)	Ipilimumab (n=315)
Overall Survivala
Deaths (%)	128 (41)	142 (45)	197 (63)
Hazard ratiob (vs. ipilimumab) (95% CI)	0.55 (0.44, 0.69)	0.63 (0.50, 0.78)
p-valuec, d	<0.0001	<0.0001
Progression-free Survivala
Disease progression or death	151 (48%)	174 (55%)	234 (74%)
Median (months) (95% CI)	11.5 (8.9, 16.7)	6.9 (4.3, 9.5)	2.9 (2.8, 3.4)
Hazard ratiob (vs. ipilimumab) (95% CI)	0.42 (0.34, 0.51)	0.57 (0.47, 0.69)
p-valuec, e	<0.0001	<0.0001
Confirmed Overall Response Ratea	50%	40%	14%
(95% CI)	(44, 55)	(34, 46)	(10, 18)
p-valuef	<0.0001	<0.0001
Complete response	8.9%	8.5%	1.9%
Partial response	41%	31%	12%
Duration of Response
Proportion ≥6 months in duration	76%	74%	63%
Range (months)	1.2+ to 15.8+	1.3+ to 14.6+	1.0+ to 13.8+

Figure 7: Overall Survival - CHECKMATE-067



Oq-os-checkmate-067 (Oq Os Checkmate 067)

Based on a minimum follow-up of 48 months, the median OS was not reached (95% CI: 38.2, NR) in the intravenous nivolumab and ipilimumab arm. The median OS was 36.9 months (95% CI: 28.3, NR) in the intravenous nivolumab arm and 19.9 months (95% CI: 16.9, 24.6) in the ipilimumab arm.

Based on a minimum follow-up of 28 months, the median PFS was 11.7 months (95% CI: 8.9, 21.9) in the intravenous nivolumab and ipilimumab arm, 6.9 months (95% CI: 4.3, 9.5) in the intravenous nivolumab arm, and 2.9 months (95% CI: 2.8, 3.2) in the ipilimumab arm. Based on a minimum follow-up of 28 months, the proportion of responses lasting ≥24 months was 55% in the intravenous nivolumab and ipilimumab arm, 56% in the intravenous nivolumab arm, and 39% in the ipilimumab arm.

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.

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.

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.

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

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.

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.

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.