These highlights do not include all the information needed to use OPDIVO safely and effectively. See full prescribing information for OPDIVO.OPDIVO® (nivolumab) injection, for intravenous useInitial U.S. Approval: 2014

1 INDICATIONS AND USAGE

1.1 Unresectable or Metastatic Melanoma

OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma.

1.2 Adjuvant Treatment of Melanoma

OPDIVO is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.

1.3 Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer

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

1.4 Metastatic Non-Small Cell Lung Cancer

• •OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations.
• •OPDIVO, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations.
• •OPDIVO is indicated for the treatment of adult patients with metastatic 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.

1.5 Malignant Pleural Mesothelioma

OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

1.6 Advanced Renal Cell Carcinoma

• •OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced RCC.
• •OPDIVO, in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced RCC.
• •OPDIVO as a single agent is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

1.7 Classical Hodgkin Lymphoma

OPDIVO is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after:

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.7)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

• •autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or
• •3 or more lines of systemic therapy that includes autologous HSCT.

1.8 Squamous Cell Carcinoma of the Head and Neck

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

1.9 Urothelial Carcinoma

OPDIVO 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 [see Clinical Studies (14.9)].

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

OPDIVO is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:

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

1.10 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

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 confirmatory trials.

1.11 Hepatocellular Carcinoma

OPDIVO, in combination with ipilimumab, is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.11)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

1.12 Esophageal Cancer

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

1.13 Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

OPDIVO, 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.

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Select patients with metastatic NSCLC for treatment with OPDIVO in combination with ipilimumab based on PD-L1 expression [see Clinical Studies (14.4)].

Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended dosages of OPDIVO as a single agent are presented in Table 1.

The recommended dosages of OPDIVO 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 for the recommended dosage information, as appropriate.

2.3 Dose Modifications

No dose reduction for OPDIVO is recommended. In general, withhold OPDIVO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue OPDIVO 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 or OPDIVO in combination for adverse reactions that require management different from these general guidelines are summarized in Table 3 and Table 4.

When OPDIVO is administered in combination with ipilimumab, withhold or permanently discontinue both ipilimumab and OPDIVO for an adverse reaction meeting these dose modification guidelines.

2.4 Preparation and Administration

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

Preparation

• •Withdraw the required volume of OPDIVO and transfer into an intravenous container.
• •Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 160 mL.•     For adult and pediatric patients with body weight 40 kg or greater, do not exceed a total volume of infusion of 160 mL.•     For adult and pediatric patients with body weight less than 40 kg, do not exceed a total volume of infusion of 4 mL/kg of body weight.
• •Mix diluted solution by gentle inversion. Do not shake.
• •Discard partially used vials or empty vials of OPDIVO.
• •The product does not contain a preservative.

Administration

• •Administer the infusion, after dilution, over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).
• •Administer OPDIVO in combination with other therapeutic agents as follows:•With ipilimumab: administer OPDIVO first followed by ipilimumab on the same day.•With platinum-doublet chemotherapy: administer OPDIVO first followed by platinum-doublet chemotherapy on the same day•With ipilimumab and platinum-doublet chemotherapy: administer OPDIVO first followed by ipilimumab and then platinum-doublet chemotherapy on the same day.•With fluoropyrimidine- and platinum-containing chemotherapy: administer OPDIVO first followed by fluoropyrimidine- and platinum-containing chemotherapy on the same day.
• •Use separate infusion bags and filters for each infusion.
• •Flush the intravenous line at end of infusion.
• •Do not co-administer other drugs through the same intravenous line.

3 DOSAGE FORMS AND STRENGTHS

Injection: 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), 120 mg/12 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL) clear to opalescent, colorless to pale-yellow solution in a single-dose vial.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

OPDIVO is 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. 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 depending on severity [see Dosage and Administration (2.3)]. In general, if OPDIVO 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.

Immune-Mediated Pneumonitis

OPDIVO 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.

OPDIVO as a Single Agent

Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDIVO in 1.1% and withholding of OPDIVO in 0.8% of patients.

Systemic corticosteroids were required in 100% (61/61) of patients with pneumonitis. Pneumonitis resolved in 84% of the 61 patients. Of the 15 patients in whom OPDIVO was withheld for pneumonitis, 14 reinitiated OPDIVO after symptom improvement; of these, 4 (29%) had recurrence of pneumonitis.

OPDIVO with Ipilimumab

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of OPDIVO with ipilimumab in 5% of patients and withholding of OPDIVO with ipilimumab in 3.6% of patients.

Systemic corticosteroids were required in 100% of patients with pneumonitis. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after reinitiation of OPDIVO with ipilimumab.

Immune-Mediated Colitis

OPDIVO 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.

OPDIVO as a Single Agent

Immune-mediated colitis occurred in 2.9% (58/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (1.7%) and Grade 2 (1%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.9% of patients.

Systemic corticosteroids were required in 100% (58/58) of patients with colitis. Four patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 86% of the 58 patients. Of the 18 patients in whom OPDIVO was withheld for colitis, 16 reinitiated OPDIVO after symptom improvement; of these, 12 (75%) had recurrence of colitis.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.4%), Grade 3 (14%), and Grade 2 (8%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 14% and withholding of OPDIVO with ipilimumab in 4.4% of patients.

Systemic corticosteroids were required in 100% (115/115) of patients with colitis. Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 93% of the 115 patients. Of the 20 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 9 (56%) had recurrence of colitis.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated colitis occurred in 9% (60/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (4.4%) and Grade 2 (3.7%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.2% and withholding of OPDIVO with ipilimumab in 2.7% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (60/60) of patients with colitis. Approximately 23% of patients with immune-mediated colitis required addition of infliximab to high-dose corticosteroids. Colitis resolved in 95% of the 60 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 10 (63%) had recurrence of colitis.

Immune-Mediated Hepatitis and Hepatotoxicity

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

OPDIVO as a Single Agent

Immune-mediated hepatitis occurred in 1.8% (35/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.6% of patients.

Systemic corticosteroids were required in 100% (35/35) of patients with hepatitis. Two patients required the addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 35 patients. Of the 12 patients in whom OPDIVO was withheld for hepatitis, 11 reinitiated OPDIVO after symptom improvement; of these, 9 (82%) had recurrence of hepatitis.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 8% or withholding of OPDIVO with ipilimumab in 3.5% of patients.

Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis. Approximately 9% of patients with immune-mediated hepatitis required the addition mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 70 patients. Of the 16 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 8 (57%) had recurrence of hepatitis.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated hepatitis occurred in 7% (48/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.6% and withholding of OPDIVO with ipilimumab in 2.6% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (48/48) of patients with hepatitis. Approximately 19% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 88% of the 48 patients. Of the 17 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 10 (71%) had recurrence of hepatitis.

OPDIVO with Cabozantinib

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO 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 OPDIVO and cabozantinib and consider administering corticosteroids [see Dosage and Administration (2.3)].

With the combination of OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients [see Adverse Reactions (6.1)]. 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 OPDIVO (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 OPDIVO, 2 patients receiving cabozantinib, and 7 patients receiving both OPDIVO and cabozantinib.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

OPDIVO 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 depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Adrenal insufficiency occurred in 1% (20/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.6%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.4% of patients.

Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 90% (18/20) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 35% of the 20 patients. Of the 8 patients in whom OPDIVO was withheld for adrenal insufficiency, 4 reinitiated OPDIVO after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 2.0% of patients.

Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Adrenal insufficiency occurred in 7% (48/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC.

Approximately 94% (45/48) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 29% of the 48 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 11 reinitiated treatment after symptom improvement; of these, all received hormone replacement therapy and 2 (18%) had recurrence of adrenal insufficiency.

OPDIVO with Cabozantinib

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received OPDIVO with cabozantinib, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO and cabozantinib in 0.9% and withholding of OPDIVO 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 OPDIVO 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 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 depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Hypophysitis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (0.3%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO in <0.1% and withholding of OPDIVO 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 OPDIVO was withheld for hypophysitis, 2 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hypophysitis.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (2.4%) and Grade 2 (6%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 4.2% of patients.

Approximately 86% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis. Hypophysitis resolved in 38% of the 42 patients. Of the 19 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement; of these, 1 (11%) had recurrence of hypophysitis.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hypophysitis occurred in 4.4% (29/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC.

Approximately 72% (21/29) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 59% of the 29 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 11 reinitiated treatment after symptom improvement; of these, 2 (18%) had recurrence of hypophysitis.

Thyroid Disorders

OPDIVO 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 depending on severity [see Dosage and Administration (2.3)].

Thyroiditis

OPDIVO as a Single Agent

Thyroiditis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 2 (0.2%) adverse reactions. Thyroiditis led to permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.2% of patients.

Systemic corticosteroids were required in 17% (2/12) of patients with thyroiditis. Thyroiditis resolved in 58% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for thyroiditis, 1 reinitiated OPDIVO after symptom improvement without recurrence of thyroiditis.

Hyperthyroidism

OPDIVO as a Single Agent

Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (<0.1%) and Grade 2 (1.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.4% of patients.

Approximately 19% of patients with hyperthyroidism received methimazole, 7% received carbimazole, and 4% received propylthiouracil. Systemic corticosteroids were required in 9% (5/54) of patients. Hyperthyroidism resolved in 76% of the 54 patients. Of the 7 patients in whom OPDIVO was withheld for hyperthyroidism, 4 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hyperthyroidism.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.9%) and Grade 2 (4.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.4% of patients.

Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole. Systemic corticosteroids were required in 17% (7/42) of patients. Hyperthyroidism resolved in 91% of the 42 patients. Of the 11 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement; of these, 1 (13%) had recurrence of hyperthyroidism.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hyperthyroidism occurred in 12% (80/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (4.5%) adverse reactions. Hyperthyroidism led to permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.3% of patients with RCC or CRC.

Of the 80 patients with RCC or CRC who developed hyperthyroidism, approximately 16% received methimazole and 3% received carbimazole. Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism. Hyperthyroidism resolved in 85% of the 80 patients. Of the 15 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 11 reinitiated treatment after symptom improvement; of these, 3 (27%) had recurrence of hyperthyroidism.

Hypothyroidism

OPDIVO as a Single Agent

Hypothyroidism occurred in 8% (163/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (4.8%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.5% of patients.

Approximately 79% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 3.1% (5/163) of patients with hypothyroidism. Hypothyroidism resolved in 35% of the 163 patients. Of the 9 patients in whom OPDIVO was withheld for hypothyroidism, 3 reinitiated OPDIVO after symptom improvement; of these, 1 (33%) had recurrence of hypothyroidism.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.4%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 0.9% of patients.

Approximately 89% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism. Hypothyroidism resolved in 41% of the 91 patients. Of the 4 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement; of these, none had recurrence of hypothyroidism.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hypothyroidism occurred in 18% (122/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to permanent discontinuation of OPDIVO with ipilimumab in 0.2% and withholding of OPDIVO with ipilimumab in 1.4% of patients with RCC or CRC.

Of the 122 patients with RCC or CRC who developed hypothyroidism, approximately 82% received levothyroxine. Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism. Hypothyroidism resolved in 27% of the 122 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 5 reinitiated treatment after symptom improvement; of these, 1 (20%) had recurrence of hypothyroidism.

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 depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Diabetes occurred in 0.9% (17/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.3%) adverse reactions, and two cases of diabetic ketoacidosis. Diabetes led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.1% of patients.

No patients (0/17) with diabetes required systemic corticosteroids. Diabetes resolved in 29% of the 17 patients. Of the 2 patients in whom OPDIVO was withheld for diabetes, both reinitiated OPDIVO after symptom improvement; of these, neither had recurrence of diabetes.

Immune-Mediated Nephritis with Renal Dysfunction

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

OPDIVO as a Single Agent

Immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.4% of patients.

Systemic corticosteroids were required in 100% (23/23) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 78% of the 23 patients. Of the 7 patients in whom OPDIVO was withheld for nephritis or renal dysfunction, 7 reinitiated OPDIVO after symptom improvement; of these, 1 (14%) had recurrence of nephritis or renal dysfunction.

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO 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 depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.5% of patients.

Systemic corticosteroids were required in 100% (171/171) of patients with immune-mediated rash. Rash resolved in 72% of the 171 patients. Of the 10 patients in whom OPDIVO was withheld for immune-mediated rash, 9 reinitiated OPDIVO after symptom improvement; of these, 3 (33%) had recurrence of immune-mediated rash.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (4.8%) and Grade 2 (10%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 3.9% of patients.

Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash. Rash resolved in 84% of the 127 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 15 reinitiated treatment after symptom improvement; of these, 8 (53%) had recurrence of immune-mediated rash.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated rash occurred in 16% (108/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (3.5%) and Grade 2 (4.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.5% of patients and withholding of OPDIVO with ipilimumab in 2.0% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (108/108) of patients with immune-mediated rash. Rash resolved in 75% of the 108 patients. Of the 13 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 11 reinitiated treatment after symptom improvement; of these, 5 (46%) 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 or OPDIVO in combination with ipilimumab, 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

5.2 Infusion-Related Reactions

OPDIVO can cause severe infusion-related reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

In patients who received OPDIVO as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.

In a trial assessing the pharmacokinetics and safety of a more rapid infusion, in which patients received OPDIVO as a 60-minute intravenous infusion or a 30-minute intravenous infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation, or withholding of OPDIVO.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg

Infusion-related reactions occurred in 2.5% (10/407) of patients with melanoma and in 8% (4/49) of patients with HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg

Infusion-related reactions occurred in 5.1% (28/547) of patients with RCC and 4.2% (5/119) of patients with CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, respectively. Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks.

5.3 Complications of Allogeneic Hematopoietic Stem Cell Transplantation

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.

5.4 Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, OPDIVO 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 and for 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

5.5 Increased Mortality in Patients with Multiple Myeloma when OPDIVO Is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including OPDIVO, 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.

6 ADVERSE REACTIONS

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)]
• •Infusion-Related Reactions [see Warnings and Precautions (5.2)]
• •Complications of Allogeneic HSCT [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

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

The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO as a single agent in 1994 patients enrolled in CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 or a single-arm trial in NSCLC (n=117); OPDIVO 1 mg/kg with ipilimumab 3 mg/kg in patients enrolled in CHECKMATE-067 (n=313), CHECKMATE-040 (n=49), or another randomized trial (n=94); OPDIVO 3 mg/kg administered with ipilimumab 1 mg/kg (n=666) in patients enrolled in CHECKMATE-214 or CHECKMATE-142; OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in patients enrolled in CHECKMATE-227 (n=576) or CHECKMATE-743 (n=300); OPDIVO 360 mg with ipilimumab 1 mg/kg and 2 cycles of platinum-doublet chemotherapy in CHECKMATE-9LA (n=361); and OPDIVO 240 mg with cabozantinib 40 mg in patients enrolled in CHECKMATE-9ER (n=320).

Unresectable or Metastatic Melanoma

Previously Treated Metastatic Melanoma

The safety of OPDIVO was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.1)]. 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 OPDIVO 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 OPDIVO-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 OPDIVO for >6 months and 3% of patients received OPDIVO for >1 year.

The population characteristics in the OPDIVO 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 OPDIVO group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%).

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

Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037.

Clinically important adverse reactions in <10% of patients who received OPDIVO 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

Previously Untreated Metastatic Melanoma

CHECKMATE-066

The safety of OPDIVO 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 (14.1)]. 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 OPDIVO 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 OPDIVO-treated patients. In this trial, 47% of patients received OPDIVO for >6 months and 12% of patients received OPDIVO for >1 year.

The trial population characteristics in the OPDIVO 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 OPDIVO group with ECOG performance status 0 (71% vs. 59%).

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

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO 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 7 and 8 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.

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

Nervous System Disorders: peripheral neuropathy

CHECKMATE-067

The safety of OPDIVO, 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 (14.1)]. 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:

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

The most frequent (≥10%) serious adverse reactions in the OPDIVO and ipilimumab arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). The most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO and ipilimumab arm and of OPDIVO in the OPDIVO arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1.0%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%).

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

Tables 9 and 10 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.

Clinically important adverse reactions in <10% of patients who received OPDIVO with ipilimumab or OPDIVO 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

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

Adjuvant Treatment of Melanoma

CHECKMATE-76K

The safety of OPDIVO 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 OPDIVO 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 (14.2)]. The median duration of exposure was 11 months in patients treated with OPDIVO and 11 months in patients treated with placebo.

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

Dosage interruptions of OPDIVO 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 11 and 12 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-76K.

CHECKMATE-238

The safety of OPDIVO 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 OPDIVO 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 (14.2)]. The median duration of exposure was 11.5 months in OPDIVO-treated patients and was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received OPDIVO for >6 months.

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

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-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 13 and 14 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

The safety of OPDIVO 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 (14.3)]. Patients received either OPDIVO 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 OPDIVO 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 OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy.

Study therapy with OPDIVO 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 OPDIVO 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 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-816.

Metastatic Non-Small Cell Lung Cancer

First-line Treatment of Metastatic NSCLC: In Combination with Ipilimumab

The safety of OPDIVO in combination with ipilimumab was evaluated in CHECKMATE-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.4)]. The trial excluded patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients received OPDIVO 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks and ipilimumab 1 mg/kg by intravenous infusion over 30 minutes every 6 weeks or platinum-doublet chemotherapy every 3 weeks for 4 cycles. The median duration of therapy in OPDIVO and ipilimumab-treated patients was 4.2 months (range: 1 day to 25.5 months): 39% of patients received OPDIVO and ipilimumab for >6 months and 23% of patients received OPDIVO and ipilimumab for >1 year. The population characteristics were: median age 64 years (range: 26 to 87); 48% were ≥65 years of age, 76% White, and 67% male. Baseline ECOG performance status was 0 (35%) or 1 (65%), 85% were former/current smokers, 11% had brain metastases, 28% had squamous histology and 72% had non-squamous histology.

Serious adverse reactions occurred in 58% of patients. OPDIVO and ipilimumab were discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.

The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. The most common (≥20%) adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus.

Tables 17 and 18 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.

Other clinically important adverse reactions in CHECKMATE-227 were:

Skin and Subcutaneous Tissue: urticaria, alopecia, erythema multiforme, vitiligo

Gastrointestinal: stomatitis, pancreatitis, gastritis

Musculoskeletal and Connective Tissue: arthritis, polymyalgia rheumatica, rhabdomyolysis

Nervous System: peripheral neuropathy, autoimmune encephalitis

Blood and Lymphatic System: eosinophilia

Eye Disorders: blurred vision, uveitis

Cardiac: atrial fibrillation, myocarditis

First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy

The safety of OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Clinical Studies (14.4)]. Patients received either OPDIVO 360 mg administered every 3 weeks in combination with ipilimumab 1 mg/kg administered every 6 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. The median duration of therapy in OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was 6 months (range: 1 day to 19 months): 50% of patients received OPDIVO and ipilimumab for >6 months and 13% of patients received OPDIVO and ipilimumab for >1 year.

Serious adverse reactions occurred in 57% of patients who were treated with OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy. The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

Study therapy with OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction. The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

Tables 19 and 20 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.

Second-line Treatment of Metastatic NSCLC

The safety of OPDIVO 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 (14.4)]. These trials excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received OPDIVO 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 OPDIVO-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 OPDIVO for at least 6 months and 18% of patients received OPDIVO for at least 1 year and in CHECKMATE-057, 30% of patients received OPDIVO for >6 months and 20% of patients received OPDIVO for >1 year.

Across both trials, the median age of OPDIVO-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 OPDIVO 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 OPDIVO. OPDIVO 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 OPDIVO 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 21 and 22 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057.

Other clinically important adverse reactions observed in OPDIVO-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).

Malignant Pleural Mesothelioma

The safety of OPDIVO in combination with ipilimumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see Clinical Studies (14.5)]. Patients received either OPDIVO 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years; or platinum-doublet chemotherapy for up to 6 cycles. The median duration of therapy in OPDIVO and ipilimumab-treated patients was 5.6 months (range: 0 to 26.2 months); 48% of patients received OPDIVO and ipilimumab for >6 months and 24% of patients received OPDIVO and ipilimumab for >1 year.

Serious adverse reactions occurred in 54% of patients who were treated with OPDIVO in combination with ipilimumab. The most frequent (≥2%) serious adverse reactions were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis and encephalitis.

Both OPDIVO and ipilimumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction.

The most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.

Tables 23 and 24 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.

Advanced Renal Cell Carcinoma

First-line Renal Cell Carcinoma

CHECKMATE-214

The safety of OPDIVO with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC received OPDIVO 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by OPDIVO 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 (14.6)]. The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in OPDIVO 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 OPDIVO 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 OPDIVO and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of OPDIVO and ipilimumab patients. Fifty-four percent (54%) of patients receiving OPDIVO and ipilimumab had a dose interruption for an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO 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 OPDIVO and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia.

Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of OPDIVO 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 OPDIVO and ipilimumab group compared to the sunitinib group (31% and 61%, respectively).

CHECKMATE-9ER

The safety of OPDIVO with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received OPDIVO 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 (14.6)]. 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 OPDIVO and cabozantinib-treated patients. In this trial, 82% of patients in the OPDIVO 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 OPDIVO 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 OPDIVO or cabozantinib occurred in 20% of patients: 7% OPDIVO 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 OPDIVO or cabozantinib occurred in 83% of patients: 3% OPDIVO 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 OPDIVO and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysaesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER.

Previously Treated Renal Cell Carcinoma

CHECKMATE-025

The safety of OPDIVO 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 OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.6)]. The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in OPDIVO-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 OPDIVO arm. Serious adverse reactions occurred in 47% of patients receiving OPDIVO. Study therapy was discontinued for adverse reactions in 16% of OPDIVO patients. Forty-four percent (44%) of patients receiving OPDIVO 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 OPDIVO group compared to the everolimus group (26% and 14%, respectively).

Tables 29 and 30 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

Classical Hodgkin Lymphoma

The safety of OPDIVO was evaluated in 266 adult patients with cHL (243 patients in the CHECKMATE-205 and 23 patients in the CHECKMATE-039 trials) [see Clinical Studies (14.7)]. Patients received OPDIVO 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity.

The median age was 34 years (range: 18 to 72), 98% of patients had received autologous HSCT, none had received allogeneic HSCT, and 74% had received brentuximab vedotin. The median number of prior systemic regimens was 4 (range: 2 to 15). Patients received a median of 23 doses (cycles) of OPDIVO (range: 1 to 48), with a median duration of therapy of 11 months (range: 0 to 23 months).

Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last nivolumab dose, 2 from infection 8 to 9 months after completing nivolumab, and 6 from complications of allogeneic HSCT. Serious adverse reactions occurred in 26% of patients. Dose delay for an adverse reaction occurred in 34% of patients. OPDIVO was discontinued due to adverse reactions in 7% of patients.

The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. The most common adverse reactions (≥20%) among all patients were upper respiratory tract infection, fatigue, cough, diarrhea, pyrexia, musculoskeletal pain, rash, nausea, and pruritus.

Tables 31 and 32 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-205 and CHECKMATE-039.

Additional information regarding clinically important adverse reactions:

Immune-mediated pneumonitis: In CHECKMATE-205 and CHECKMATE-039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO (one Grade 3 and 12 Grade 2). The median time to onset was 4.5 months (range: 5 days to 12 months). All 13 patients received systemic corticosteroids, with resolution in 12. Four patients permanently discontinued OPDIVO due to pneumonitis. Eight patients continued OPDIVO (three after dose delay), of whom two had recurrence of pneumonitis.

Peripheral neuropathy: Treatment-emergent peripheral neuropathy was reported in 12% (31/266) of all patients receiving OPDIVO. Twenty-eight patients (11%) had new-onset peripheral neuropathy and 3 patients had worsening of neuropathy from baseline. The median time to onset was 50 (range: 1 to 309) days.

Complications of allogeneic HSCT after OPDIVO: Of 17 patients with cHL from the CHECKMATE-205 and CHECKMATE-039 trials who underwent allogeneic HSCT after treatment with OPDIVO, 6 patients (35%) died from transplant-related complications. Five deaths occurred in the setting of severe (Grade 3 to 4) or refractory GVHD. Hyperacute GVHD occurred in 2 patients (12%) and Grade 3 or higher GVHD was reported in 5 patients (29%). Hepatic VOD occurred in 1 patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure.

Table 32 summarizes laboratory abnormalities in patients with cHL. The most common (≥20%) treatment-emergent laboratory abnormalities included cytopenias, liver function abnormalities, and increased lipase. Other common findings (≥10%) included increased creatinine, electrolyte abnormalities, and increased amylase.

Squamous Cell Carcinoma of the Head and Neck

The safety of OPDIVO 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 (14.8)]. 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 OPDIVO 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 OPDIVO-treated patients. In this trial, 18% of patients received OPDIVO for >6 months and 2.5% of patients received OPDIVO for >1 year.

The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the OPDIVO 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 OPDIVO. OPDIVO 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 OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in ≥10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea. The most common laboratory abnormalities occurring in ≥10% of OPDIVO-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)

The safety of OPDIVO was evaluated in CHECKMATE-274, a randomized, double-blind, multicenter trial of adjuvant OPDIVO 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 (14.9)]. Patients received OPDIVO 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 OPDIVO treatment was 8.8 months (range: 0 to 12.5).

Serious adverse reactions occurred in 30% of OPDIVO 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%). OPDIVO was discontinued for adverse reactions in 18% of patients. OPDIVO 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 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-274.

First-line Treatment of Unresectable or Metastatic UC

The safety of OPDIVO was evaluated in CHECKMATE-901, a randomized, open-label trial in cisplatin-eligible patients with unresectable or metastatic UC [see Clinical Studies (14.9)]. Patients received either OPDIVO 360 mg with cisplatin and gemcitabine every 3 weeks for up to 6 cycles followed by single-agent OPDIVO 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 OPDIVO with chemotherapy, the median duration of OPDIVO exposure was 7.4 months (range: 0.03 to 47.9 months). Serious adverse reactions occurred in 48% of patients receiving OPDIVO in combination with chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients who received OPDIVO 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 OPDIVO in combination with chemotherapy; these included sepsis (1%).

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

Tables 35 and 36 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-901.

Previously Treated Advanced or Metastatic UC

The safety of OPDIVO 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 (14.9)]. Patients received OPDIVO 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 OPDIVO. Serious adverse reactions occurred in 54% of patients. OPDIVO 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 37 and 38 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275.

MSI-H or dMMR Metastatic Colorectal Cancer

The safety of OPDIVO 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 (14.10)]. In CHECKMATE-142, 74 patients with mCRC received OPDIVO 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 OPDIVO 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses, then OPDIVO 3 mg/kg every 2 weeks until disease progression or until unacceptable toxicity.

In the OPDIVO 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 39 and 40 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 OPDIVO with ipilimumab were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%).

Hepatocellular Carcinoma

The safety of OPDIVO 1 mg/kg in combination with ipilimumab 3 mg/kg was evaluated in a subgroup comprising 49 patients with HCC and Child-Pugh Class A cirrhosis enrolled in Cohort 4 of CHECKMATE-040, a multicenter, multiple-cohort, open-label trial [see Clinical Studies (14.11)] who progressed on or were intolerant to sorafenib. OPDIVO and ipilimumab were administered every 3 weeks for 4 doses, followed by single-agent OPDIVO 240 mg every 2 weeks until disease progression or unacceptable toxicity. During the OPDIVO and ipilimumab combination period, 33 of 49 (67%) patients received all 4 planned doses of OPDIVO and ipilimumab. During the entire treatment period, the median duration of exposure to OPDIVO was 5.1 months (range: 0 to 35+ months) and to ipilimumab was 2.1 months (range: 0 to 4.5 months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction.

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

Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-040.

Clinically important adverse reactions reported in <10% of patients who received OPDIVO with ipilimumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%).

In patients who received OPDIVO with ipilimumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined as a 1 log increase in HCV RNA from baseline.

Esophageal Cancer

Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer

The safety of OPDIVO was evaluated in CHECKMATE-577, a randomized, placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following chemoradiotherapy (CRT) [see Clinical Studies (14.12)]. The trial excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Patients received either OPDIVO 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Patients were treated until disease recurrence, unacceptable toxicity, or for up to 1-year total duration. The median duration of exposure was 10.1 months (range: <0.1 to 14 months) in OPDIVO-treated patients and 9 months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received OPDIVO, 61% were exposed for >6 months and 54% were exposed for >9 months.

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

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

Tables 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-577.

First-line Treatment of Unresectable Advanced or Metastatic ESCC

The safety of OPDIVO in combination with chemotherapy or in combination with ipilimumab was evaluated in CHECKMATE-648, a randomized, active-controlled, multicenter, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC [see Clinical Studies (14.12)]. Patients received one of the following treatments:

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

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

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

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

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

Tables 45 and 46 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648.

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

The safety of OPDIVO was evaluated in ATTRACTION-3, a randomized, active-controlled, open-label, multicenter trial in 209 patients with unresectable advanced, recurrent or metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum-based chemotherapy [see Clinical Studies (14.12)]. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients received OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m2 intravenously every 3 weeks (n=65) or paclitaxel 100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off (n=143). Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 2.6 months (range: 0 to 29.2 months) in OPDIVO-treated patients and 2.6 months (range: 0 to 21.4 months) in docetaxel- or paclitaxel-treated patients. Among patients who received OPDIVO, 26% were exposed for >6 months and 10% were exposed for >1 year.

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

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

Tables 47 and 48 summarize the adverse reactions and laboratory abnormalities, respectively, in ATTRACTION-3.

Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

The safety of OPDIVO in combination with chemotherapy was evaluated in CHECKMATE-649, a randomized, multicenter, open-label trial in patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma [see Clinical Studies (14.13)]. The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive or had untreated central nervous system (CNS) metastases. Patients were randomized to receive OPDIVO in combination with chemotherapy or chemotherapy. Patients received one of the following treatments:

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

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

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

Tables 49 and 50 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-649.

a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and mFOLFOX6 or CapeOX group (407 to 767 patients) or mFOLFOX6 or CapeOX group (range: 405 to 735 patients).

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

6.2 Postmarketing Experience

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

Eye: Vogt-Koyanagi-Harada (VKH) syndrome

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

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], OPDIVO 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 (see Data). Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available data on OPDIVO use in pregnant women to evaluate a drug-associated risk. Advise pregnant women of the potential risk to a fetus.

The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period.

8.2 Lactation

Risk Summary

There are no data on the presence of nivolumab in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for 5 months after the last dose of OPDIVO.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating OPDIVO [see Use in Specific Populations (8.1)].

Contraception

OPDIVO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for 5 months following the last dose.

8.4 Pediatric Use

The safety and effectiveness of OPDIVO have been established in pediatric patients aged 12 years and older for the following indications: as a single agent and in combination with ipilimumab for the treatment of unresectable or metastatic melanoma, as a single agent for the adjuvant treatment of completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma and, as a single agent or in combination with ipilimumab for the treatment of MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of OPDIVO for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma or MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients. Nivolumab exposure in pediatric patients 12 years and older is comparable to that of adults and the courses of melanoma and MSI-H or dMMR mCRC are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1, 14.10)].

The safety and effectiveness of OPDIVO have not been established for pediatric patients younger than 12 years old with melanoma or MSI-H or dMMR mCRC.

The safety and effectiveness of OPDIVO have not been established in pediatric patients with non-small cell lung cancer, malignant pleural mesothelioma, advanced renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastroesophageal cancer and esophageal adenocarcinoma.

8.5 Geriatric Use

Single Agent

Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and esophageal or gastroesophageal junction cancer who were randomized to single agent OPDIVO in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients [see Clinical Studies (14.1, 14.2, 14.4, 14.6, 14.9, 14.12)].

In patients with cHL, recurrent head and neck SCC, or dMMR or MSI-H metastatic CRC (mCRC) who were treated with single agent OPDIVO in clinical studies did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients [see Clinical Studies (14.7, 14.8, 14.10)].

In Combination with Ipilimumab

Of the 314 patients with melanoma who were randomized to OPDIVO in combination with ipilimumab, 41% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients [see Clinical Studies (14.1)].

Of the 576 patients with NSCLC who were randomized to OPDIVO in combination with ipilimumab, 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received OPDIVO with ipilimumab (18%). Of the 396 patients in the primary efficacy population (PD-L1 ≥1%) randomized to OPDIVO in combination with ipilimumab, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Clinical Studies (14.3)].

Of the 303 patients with malignant pleural mesothelioma who were randomized to OPDIVO in combination with ipilimumab, 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received OPDIVO with ipilimumab (54% and 28%, respectively). For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and the discontinuation rate due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to OPDIVO in combination with ipilimumab [see Clinical Studies (14.5)].

Of the 550 patients with renal cell carcinoma who were randomized to OPDIVO in combination with ipilimumab, 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients. In elderly patients with intermediate or poor risk, no overall difference in effectiveness was reported [see Clinical Studies (14.6)].

Of the 49 patients with hepatocellular carcinoma who were treated with OPDIVO in combination with ipilimumab, 29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical studies of OPDIVO in combination with ipilimumab did not include sufficient numbers of patients with hepatocellular carcinoma aged 65 and over to determine whether they respond differently from younger patients [see Clinical Studies (14.11)].

Of the 325 patients with ESCC who were randomized to OPDIVO in combination with ipilimumab, 43% were 65 years old or older and 7% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (38%) relative to all patients who received OPDIVO with ipilimumab (23%). For patients aged 75 years or older who received chemotherapy, the discontinuation rate due to adverse reactions was 33% relative to 23% for all patients [see Clinical Studies (14.12)].

In Combination with Platinum-Containing Chemotherapy

Of the 179 patients with NSCLC who were randomized to OPDIVO in combination with platinum-doublet chemotherapy, 48% were 65 years old or older and 6% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years [see Clinical Studies (14.3)].

Of the 1,110 patients with ESCC, GC, GEJC, or EAC who were randomized to OPDIVO in combination with fluoropyrimidine- and platinum-containing chemotherapy), 42% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14.12, 14.13)].

Of the 304 patients with UC who were treated with OPDIVO in combination with gemcitabine and platinum-doublet chemotherapy, 40% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age and over and younger patients. Clinical studies of OPDIVO with platinum-doublet chemotherapy did not include sufficient numbers of patients aged 75 years and over to determine whether safety and effectiveness differs compared to younger patients. [see Clinical Studies (14.9)].

In Combination with Ipilimumab and Platinum-Doublet Chemotherapy

Of the 361 patients with NSCLC who were randomized to OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy, 51% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (43%) relative to all patients who received OPDIVO with ipilimumab and chemotherapy (24%). For patients aged 75 years or older who received chemotherapy only, the discontinuation rate due to adverse reactions was 16% relative to all patients who had a discontinuation rate of 13%. Based on an updated analysis for overall survival, of the 361 patients randomized to OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy, the hazard ratio for overall survival was 0.61 (95% CI: 0.47, 0.80) in the 176 patients younger than 65 years compared to 0.73 (95% CI: 0.56, 0.95) in the 185 patients 65 years or older [see Clinical Studies (14.4)].

In Combination with Cabozantinib

Of the 320 patients with renal cell carcinoma who were treated with OPDIVO in combination with cabozantinib, 41% were 65 years or older and 9% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14.6)].

11 DESCRIPTION

Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. It is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line.

OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles.

OPDIVO (nivolumab) injection for intravenous use is supplied in single-dose vials. Each mL of OPDIVO solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved anti-tumor responses in metastatic melanoma and advanced RCC. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity.

12.2 Pharmacodynamics

There are no clinically significant exposure-response relationships for efficacy or safety for nivolumab monotherapy across the approved dosing regimens, regardless of cancer type.

12.3 Pharmacokinetics

Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single agent OPDIVO and OPDIVO with ipilimumab. The PK of nivolumab was studied in patients over a dose range of 0.1 mg/kg to 20 mg/kg administered as a single dose or as multiple doses of OPDIVO as a 60-minute intravenous infusion every 2 or 3 weeks. The exposure to nivolumab increases dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The predicted exposure of nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion. Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 3.7-fold.

Distribution

The geometric mean volume of distribution at steady state (Vss) and coefficient of variation (CV%) is 6.8 L (27.3%).

Elimination

Nivolumab clearance (CL) decreases over time, with a mean maximal reduction from baseline values (CV%) of 24.5% (47.6%) resulting in a geometric mean steady-state clearance (CLss) (CV%) of 8.2 mL/h (53.9%) in patients with metastatic tumors; the decrease in CLss is not considered clinically relevant. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady state.

The geometric mean elimination half-life (t1/2) is 25 days (77.5%).

Specific Populations

The following factors had no clinically important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 160 kg), sex, race, baseline LDH, PD-L1 expression, solid tumor type, tumor size, renal impairment (eGFR ≥ 15 mL/min/1.73 m2), and mild (total bilirubin [TB] less than or equal to the ULN and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST) or moderate hepatic impairment (TB greater than 1.5 to 3 times ULN and any AST). Nivolumab has not been studied in patients with severe hepatic impairment (TB greater than 3 times ULN and any AST).

Pediatric Patients

The exposures of nivolumab in pediatric patients 12 years of age or older are comparable to those in adults at the recommended dosage [see Dosage and Administration (2.2)].

Drug Interaction Studies

When OPDIVO 3 mg/kg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 3 weeks, the CL of nivolumab and ipilimumab were unchanged compared to nivolumab or ipilimumab administered alone.

When OPDIVO 1 mg/kg every 3 weeks was administered in combination with ipilimumab 3 mg/kg every 3 weeks, the CL of nivolumab was increased by 29% compared to OPDIVO administered alone and the CL of ipilimumab was unchanged compared to ipilimumab administered alone.

When OPDIVO 3 mg/kg every 2 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks, the CL of nivolumab was unchanged compared to OPDIVO administered alone and the CL of ipilimumab was increased by 30% compared to ipilimumab administered alone.

When OPDIVO 360 mg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy, the CL of nivolumab was unchanged compared to OPDIVO administered alone and the CL of ipilimumab increased by 22% compared to ipilimumab administered alone.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of OPDIVO or of other nivolumab products.

Anti-drug antibody and neutralizing antibody responses were monitored throughout the treatment period where the benefit to risk ratio was assessed. Incidence of anti-drug antibodies and neutralizing antibodies are presented in Table 51.

Effects of Anti-Drug Antibodies

Presence of treatment-emergent anti-nivolumab antibodies increased nivolumab clearance by up to 20% after administration of nivolumab as monotherapy or in combination with ipilimumab. These anti-drug antibody-associated pharmacokinetic changes were not considered to be clinically significant. There was no identified clinically significant effect of anti-drug antibodies on incidence of infusion-related reactions. The effects of anti-drug antibodies on effectiveness have not been fully characterized.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.

13.2 Animal Toxicology and/or Pharmacology

In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis–infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

14 CLINICAL STUDIES

14.1 Unresectable or Metastatic Melanoma

Previously Treated Metastatic Melanoma

CHECKMATE-037 (NCT01721746) was a multicenter, open-label trial that randomized (2:1) patients with unresectable or metastatic melanoma to receive OPDIVO 3 mg/kg intravenously every 2 weeks or investigator’s choice of chemotherapy, either single-agent dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 intravenously every 3 weeks and paclitaxel 175 mg/m2 intravenously every 3 weeks. Patients were required to have progression of disease on or following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of Grade 4 ipilimumab-related 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. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter.

Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received OPDIVO in CHECKMATE-037 and in whom the minimum duration of follow-up was 6 months. The major efficacy outcome measures in this population were confirmed overall response rate (ORR) as measured by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response.

Among the 120 patients treated with OPDIVO, the median age was 58 years (range: 25 to 88), 65% of patients were male, 98% were White, and the ECOG performance score was 0 (58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V600 mutation positive (22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic therapies for metastatic disease (68%).

The ORR was 32% (95% confidence interval [CI]: 23, 41), consisting of 4 complete responses and 34 partial responses in OPDIVO-treated patients. Of 38 patients with responses, 87% had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer.

There were responses in patients with and without BRAF V600 mutation-positive melanoma. A total of 405 patients were randomized and the median duration of OS was 15.7 months (95% CI: 12.9, 19.9) in OPDIVO-treated patients compared to 14.4 months (95% CI: 11.7, 18.2) (HR 0.95; 95.54% CI: 0.73, 1.24) in patients assigned to investigator’s choice of treatment. Figure 1 summarizes the OS results.

Figure 1: Overall Survival - CHECKMATE-037*

*   The primary OS analysis was not adjusted to account for subsequent therapies, with 54 (40.6%) patients in the chemotherapy arm subsequently receiving an anti-PD1 treatment. OS may be confounded by dropout, imbalance of subsequent therapies, and differences in baseline factors.

Previously Untreated Metastatic Melanoma

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 OPDIVO 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 OPDIVO arm had an ECOG performance status of 0 (71% vs. 58%).

CHECKMATE-066 demonstrated a statistically significant improvement in OS for the OPDIVO 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 OPDIVO-treated patients had ongoing responses, which included 43 patients with ongoing response of 6 months or longer. Efficacy results are shown in Table 52 and Figure 2.

Figure 2: Overall Survival - CHECKMATE-066

CHECKMATE-067

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

Patients were randomized to receive:

Randomization was stratified by PD-L1 expression (≥5% vs. <5% tumor cell membrane expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M stage per the AJCC staging system (M0, M1a, M1b vs. 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 OPDIVO-containing arm as compared with the ipilimumab arm. The trial was not designed to assess whether adding ipilimumab to OPDIVO improves PFS or OS compared to OPDIVO as a single agent. Efficacy results are shown in Table 53 and Figure 3.

Figure 3: Overall Survival - CHECKMATE-067

Based on a minimum follow-up of 48 months, the median OS was not reached (95% CI: 38.2, NR) in the OPDIVO and ipilimumab arm. The median OS was 36.9 months (95% CI: 28.3, NR) in the OPDIVO 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 OPDIVO and ipilimumab arm, 6.9 months (95% CI: 4.3, 9.5) in the OPDIVO 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 OPDIVO and ipilimumab arm, 56% in the OPDIVO arm, and 39% in the ipilimumab arm.

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

14.2 Adjuvant Treatment of Melanoma

CHECKMATE-76K

CHECKMATE-76K (NCT04099251) was a randomized, double-blind trial in 790 patients with completely resected Stage IIB/C melanoma. Patients were randomized (2:1) to receive OPDIVO 480 mg or placebo by intravenous infusion every 4 weeks for up to 1 year or until disease recurrence or unacceptable toxicity. Enrollment required complete resection of the primary melanoma with negative margins and a negative sentinel lymph node within 12 weeks prior to randomization, and ECOG performance status of 0 or 1. The trial excluded patients with ocular/uveal or mucosal melanoma, autoimmune disease, any condition requiring systemic treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery. Randomization was stratified by AJCC 8th staging system edition (T3b vs. T4a vs. T4b). The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause, whichever occurred first and as assessed by the investigator. Tumor assessments were conducted every 26 weeks during years 1-3 and every 52 weeks thereafter until year 5.

The trial population characteristics were: median age 62 years (range: 19 to 92), 61% were male, 98% were White, 0.4% Black or African American, 0.1% Asian, and 1.1% race unknown, 2.2% Hispanic or Latino, 58% Not Hispanic or Latino, 40% ethnicity unknown, and 94% had an ECOG performance status of 0. Sixty one percent had stage IIB and 39% had stage IIC melanoma.

CHECKMATE-76K demonstrated a statistically significant improvement in RFS for patients randomized to the OPDIVO arm compared with the placebo arm. Efficacy results are shown in Table 54 and Figure 4.

Figure 4: Recurrence-free Survival - CHECKMATE-76K

CHECKMATE-238

CHECKMATE-238 (NCT02388906) was a randomized, double-blind trial in 906 patients with completely resected Stage IIIB/C or Stage IV melanoma. Patients were randomized (1:1) to receive OPDIVO 3 mg/kg by intravenous infusion every 2 weeks or ipilimumab 10 mg/kg intravenously every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year. Enrollment required complete resection of melanoma with margins negative for disease within 12 weeks prior to randomization. The trial excluded patients with a history of ocular/uveal melanoma, autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥6 months prior to randomization. Randomization was stratified by PD-L1 status (positive [based on 5% level] vs. negative/indeterminate) and AJCC stage (Stage IIIB/C vs. Stage IV M1a-M1b vs. Stage IV M1c). The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause, whichever occurs first and as assessed by the investigator. Patients underwent imaging for tumor recurrence every 12 weeks for the first 2 years then every 6 months thereafter.

The trial population characteristics were: median age was 55 years (range: 18 to 86), 58% were male, 95% were White, and 90% had an ECOG performance status of 0. Disease characteristics were AJCC Stage IIIB (34%), Stage IIIC (47%), Stage IV (19%), M1a-b (14%), BRAF V600 mutation positive (42%), BRAF wild-type (45%), elevated LDH (8%), PD-L1 ≥5% tumor cell membrane expression determined by clinical trial assay (34%), macroscopic lymph nodes (48%), and tumor ulceration (32%).

CHECKMATE-238 demonstrated a statistically significant improvement in RFS for patients randomized to the OPDIVO arm compared with the ipilimumab 10 mg/kg arm. Efficacy results are shown in Table 55 and Figure 5.

Figure 5: Recurrence-free Survival - CHECKMATE-238

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

CHECKMATE-816 (NCT02998528) was a randomized, open label trial in patients with resectable NSCLC. The trial included patients with resectable, histologically confirmed Stage IB (≥4 cm), II, or IIIA NSCLC (per the 7th edition American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging criteria), ECOG performance status 0 or 1, and measurable disease (per RECIST version 1.1). Patients with unresectable or metastatic NSCLC, known EGFR mutations or ALK translocations, Grade 2 or greater peripheral neuropathy, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study.

Patients were randomized to receive either:

Platinum-doublet chemotherapy consisted of paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC 5 or AUC 6 (any histology); pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 (non-squamous histology); or gemcitabine 1000 mg/m2 or 1250 mg/m2 and cisplatin 75 mg/m2 (squamous histology). In the platinum-doublet chemotherapy arm, two additional treatment regimen options included vinorelbine 25 mg/m2 or 30 mg/m2 and cisplatin 75 mg/m2; or docetaxel 60 mg/m2 or 75 mg/m2 and cisplatin 75 mg/m2 (any histology).

Stratification factors for randomization were tumor PD-L1 expression level (≥1% versus <1% or non-quantifiable), disease stage (IB/II versus IIIA), and sex (male versus female). Tumor assessments were performed at baseline, within 14 days of surgery, every 12 weeks after surgery for 2 years, then every 6 months for 3 years, and every year for 5 years until disease recurrence or progression. The major efficacy outcome measures were event-free survival (EFS) based on blinded independent central review (BICR) assessment and pathologic complete response (pCR) as evaluated by blinded independent pathology review (BIPR). Additional efficacy outcome measures included OS.

A total of 358 patients were randomized to receive either OPDIVO in combination with platinum-doublet chemotherapy (n=179) or platinum-doublet chemotherapy (n=179). The median age was 65 years (range: 34 to 84) with 51% of patients ≥65 years and 7% of patients ≥75 years, 50% were Asian, 47% were White, 2% were Black, and 71% were male. Baseline ECOG performance status was 0 (67%) or 1 (33%); 50% had tumors with PD-L1 expression ≥1%; 35% had stage IB/II and 64% had stage IIIA disease; 51% had tumors with squamous histology and 49% had tumors with non-squamous histology; and 89% were former/current smokers.

Eighty-three percent of patients in the OPDIVO in combination with platinum-doublet chemotherapy arm had definitive surgery compared to 75% of patients in the platinum-doublet chemotherapy arm.

The study demonstrated statistically significant improvements in EFS and pCR. Efficacy results are presented in Table 56 and Figure 6.

Figure 6: Event-Free Survival - CHECKMATE-816

At the time of the EFS analysis, 26% of the patients had died. A prespecified interim analysis for OS resulted in a HR of 0.57 (95% CI: 0.38, 0.87), which did not cross the boundary for statistical significance.

• •OPDIVO 360 mg administered intravenously over 30 minutes and platinum-doublet chemotherapy administered intravenously every 3 weeks for up to 3 cycles, or
• •platinum-doublet chemotherapy administered every 3 weeks for up to 3 cycles.

14.4 Metastatic Non-Small Cell Lung Cancer

First-line Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC) Expressing PD-L1 (≥1%): In Combination with Ipilimumab

CHECKMATE-227 (NCT02477826) was a randomized, open-label, multi-part trial in patients with metastatic or recurrent NSCLC. The study included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer [IASLC] classification), ECOG performance status 0 or 1, and no prior anticancer therapy. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents.

Primary efficacy results were based on Part 1a of the study, which was limited to patients with PD-L1 tumor expression ≥1%. Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. Randomization was stratified by tumor histology (non-squamous versus squamous). The evaluation of efficacy relied on the comparison between:

Chemotherapy regimens consisted of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) or pemetrexed (500 mg/m2) and carboplatin (AUC 5 or 6) for non-squamous NSCLC or gemcitabine (1000 or 1250 mg/m2) and cisplatin (75 mg/m2) or gemcitabine (1000 mg/m2) and carboplatin (AUC 5) (gemcitabine was administered on Days 1 and 8 of each cycle) for squamous NSCLC.

Study treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Treatment continued beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse event attributed to ipilimumab were permitted to continue OPDIVO as a single agent. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.

In Part 1a, a total of 793 patients were randomized to receive either OPDIVO in combination with ipilimumab (n=396) or platinum-doublet chemotherapy (n=397). The median age was 64 years (range: 26 to 87) with 49% of patients ≥65 years and 10% of patients ≥75 years, 76% White, and 65% male. Baseline ECOG performance status was 0 (34%) or 1 (65%), 50% with PD-L1 ≥50%, 29% with squamous and 71% with non-squamous histology, 10% had brain metastases, and 85% were former/current smokers.

The study demonstrated a statistically significant improvement in OS for PD-L1 ≥1% patients randomized to the OPDIVO and ipilimumab arm compared with the platinum-doublet chemotherapy arm. The OS results are presented in Table 57 and Figure 7.

Figure 7: Overall Survival (PD-L1 ≥1%) - CHECKMATE-227

BICR-assessed PFS showed a HR of 0.82 (95% CI: 0.69, 0.97), with a median PFS of 5.1 months (95% CI: 4.1, 6.3) in the OPDIVO and ipilimumab arm and 5.6 months (95% CI: 4.6, 5.8) in the platinum-doublet chemotherapy arm. The BICR-assessed confirmed ORR was 36% (95% CI: 31, 41) in the OPDIVO and ipilimumab arm and 30% (95% CI: 26, 35) in the platinum-doublet chemotherapy arm. Median duration of response observed in the OPDIVO and ipilimumab arm was 23.2 months and 6.2 months in the platinum-doublet chemotherapy arm.

• •OPDIVO 3 mg/kg administered intravenously over 30 minutes every 2 weeks in combination with ipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks; or
• •Platinum-doublet chemotherapy

First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy

CHECKMATE-9LA (NCT03215706) was a randomized, open-label trial in patients with metastatic or recurrent NSCLC. The trial included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification [IASLC]), ECOG performance status 0 or 1, and no prior anticancer therapy (including EGFR and ALK inhibitors) for metastatic disease. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with stable brain metastases were eligible for enrollment.

Patients were randomized 1:1 to receive either:

Platinum-doublet chemotherapy consisted of either carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m2, or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC. Patients with non-squamous NSCLC in the control arm could receive optional pemetrexed maintenance therapy. Stratification factors for randomization were tumor PD-L1 expression level (≥1% versus <1% or non-quantifiable), histology (squamous versus non-squamous), and sex (male versus female). Study treatment continued until disease progression, unacceptable toxicity, or for up to 2 years. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue OPDIVO as a single agent as part of the study. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.

A total of 719 patients were randomized to receive either OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy (n=358). The median age was 65 years (range: 26 to 86) with 51% of patients ≥65 years and 10% of patients ≥75 years. The majority of patients were White (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 1 (68%), 57% had tumors with PD-L1 expression ≥1% and 37% had tumors with PD-L1 expression that was <1%, 32% had tumors with squamous histology and 68% had tumors with non-squamous histology, 17% had CNS metastases, and 86% were former or current smokers.

The study demonstrated a statistically significant benefit in OS, PFS, and ORR. Efficacy results from the prespecified interim analysis when 351 events were observed (87% of the planned number of events for final analysis) are presented in Table 58.

With an additional 4.6 months of follow-up, the hazard ratio for overall survival was 0.66 (95% CI: 0.55, 0.80) and median survival was 15.6 months (95% CI: 13.9, 20.0) and 10.9 months (95% CI: 9.5, 12.5) for patients receiving OPDIVO and ipilimumab and platinum-doublet chemotherapy or platinum-doublet chemotherapy, respectively (Figure 8).

Figure 8: Overall Survival - CHECKMATE-9LA

• •OPDIVO 360 mg administered intravenously over 30 minutes every 3 weeks, ipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks, and platinum-doublet chemotherapy administered intravenously every 3 weeks for 2 cycles, or
• •platinum-doublet chemotherapy administered every 3 weeks for 4 cycles.

Second-line Treatment of Metastatic Squamous NSCLC

CHECKMATE-017 (NCT01642004) was a randomized (1:1), open-label trial in 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Patients received OPDIVO 3 mg/kg by intravenous infusion every 2 weeks (n=135) or docetaxel 75 mg/m2 intravenously every 3 weeks (n=137). Randomization was stratified by prior paclitaxel vs. other prior treatment and region (US/Canada vs. Europe vs. Rest of World). This trial included patients regardless of their PD-L1 status. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrollment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents. The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS.

The trial population characteristics were: median age was 63 years (range: 39 to 85) with 44% ≥65 years of age and 11% ≥75 years of age. The majority of patients were White (93%) and male (76%); the majority of patients were enrolled in Europe (57%) with the remainder in US/Canada (32%) and the rest of the world (11%). Baseline ECOG performance status was 0 (24%) or 1 (76%) and 92% were former/current smokers. Baseline disease characteristics of the population as reported by investigators were Stage IIIb (19%), Stage IV (80%), and brain metastases (6%). All patients received prior therapy with a platinum-doublet regimen and 99% of patients had tumors of squamous-cell histology.

The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with docetaxel at the prespecified interim analysis when 199 events were observed (86% of the planned number of events for final analysis). Efficacy results are shown in Table 59 and Figure 9.

Figure 9: Overall Survival - CHECKMATE-017

Archival tumor specimens were retrospectively evaluated for PD-L1 expression. Across the trial population, 17% of 272 patients had non-quantifiable results. Among the 225 patients with quantifiable results, 47% had PD-L1 negative squamous NSCLC, defined as <1% of tumor cells expressing PD-L1 and 53% had PD-L1 positive squamous NSCLC defined as ≥1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratios for survival were 0.58 (95% CI: 0.37, 0.92) in the PD-L1 negative subgroup and 0.69 (95% CI: 0.45, 1.05) in the PD-L1 positive subgroup.

Second-line Treatment of Metastatic Non-Squamous NSCLC

CHECKMATE-057 (NCT01673867) was a randomized (1:1), open-label trial in 582 patients with metastatic non-squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Appropriate prior targeted therapy in patients with known sensitizing EGFR mutation or ALK translocation was allowed. Patients received OPDIVO 3 mg/kg by intravenous infusion every 2 weeks (n=292) or docetaxel 75 mg/m2 intravenously every 3 weeks (n=290). Randomization was stratified by prior maintenance therapy (yes vs. no) and number of prior therapies (1 vs. 2). The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS. In addition, prespecified analyses were conducted in subgroups defined by PD-L1 expression.

The trial population characteristics: median age was 62 years (range: 21 to 85) with 42% of patients ≥65 years and 7% of patients ≥75 years. The majority of patients were White (92%) and male (55%); the majority of patients were enrolled in Europe (46%) followed by the US/Canada (37%) and the rest of the world (17%). Baseline ECOG performance status was 0 (31%) or 1 (69%), 79% were former/current smokers, 3.6% had NSCLC with ALK rearrangement, 14% had NSCLC with EGFR mutation, and 12% had previously treated brain metastases. Prior therapy included platinum-doublet regimen (100%) and 40% received maintenance therapy as part of the first-line regimen. Histologic subtypes included adenocarcinoma (93%), large cell (2.4%), and bronchoalveolar (0.9%).

CHECKMATE-057 demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with docetaxel at the prespecified interim analysis when 413 events were observed (93% of the planned number of events for final analysis). Efficacy results are shown in Table 60 and Figure 10.

Figure 10: Overall Survival - CHECKMATE-057

Archival tumor specimens were evaluated for PD-L1 expression following completion of the trial. Across the trial population, 22% of 582 patients had non-quantifiable results. Of the remaining 455 patients, the proportion of patients in retrospectively determined subgroups based on PD-L1 testing using the PD-L1 IHC 28-8 pharmDx assay were: 46% PD-L1 negative, defined as <1% of tumor cells expressing PD-L1 and 54% had PD-L1 expression, defined as ≥1% of tumor cells expressing PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% had ≥1% but <5% tumor cells with positive staining, 7% had ≥5% but <10% tumor cells with positive staining, and 67% had ≥10% tumor cells with positive staining. Figures 11 and 12 summarize the results of prespecified analyses of OS and PFS in subgroups determined by percentage of tumor cells expressing PD-L1.

Figure 11: Forest Plot: OS Based on PD-L1 Expression - CHECKMATE-057

Figure 12: Forest Plot: PFS Based on PD-L1 Expression - CHECKMATE-057

14.5 Malignant Pleural Mesothelioma

CHECKMATE-743 (NCT02899299) was a randomized, open-label trial in patients with unresectable malignant pleural mesothelioma. The trial included patients with histologically confirmed and previously untreated malignant pleural mesothelioma with no palliative radiotherapy within 14 days of initiation of therapy. Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial.

Patients were randomized 1:1 to receive either:

Stratification factors for randomization were tumor histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and sex (male vs. female). Study treatment continued for up to 2 years, or until disease progression or unacceptable toxicity. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue OPDIVO as a single agent. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR utilizing modified RECIST criteria.

A total of 605 patients were randomized to receive either OPDIVO in combination with ipilimumab (n=303) or chemotherapy (n=302). The median age was 69 years (range: 25 to 89), with 72% of patients ≥65 years and 26% ≥75 years; 85% were White, 11% were Asian, and 77% were male. Baseline ECOG performance status was 0 (40%) or 1 (60%), 35% had Stage III and 51% had Stage IV disease, 75% had epithelioid and 25% had non-epithelioid histology, 75% had tumors with PD-L1 expression ≥1%, and 22% had tumors with PD-L1 expression <1%.

The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO in combination with ipilimumab compared to chemotherapy. Efficacy results from the prespecified interim analysis are presented in Table 61 and Figure 13.

Figure 13: Overall Survival - CHECKMATE-743

In a prespecified exploratory analysis based on histology, in the subgroup of patients with epithelioid histology, the hazard ratio (HR) for OS was 0.85 (95% CI: 0.68, 1.06), with median OS of 18.7 months in the OPDIVO and ipilimumab arm and 16.2 months in the chemotherapy arm. In the subgroup of patients with non-epithelioid histology, the HR for OS was 0.46 (95% CI: 0.31, 0.70), with median OS of 16.9 months in the OPDIVO and ipilimumab arm and 8.8 months in the chemotherapy arm.

• •OPDIVO 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years, or
• •cisplatin 75 mg/m2 and pemetrexed 500 mg/m2, or carboplatin 5 AUC and pemetrexed 500 mg/m2 administered every 3 weeks for 6 cycles.

14.6 Advanced Renal Cell Carcinoma

First-line Renal Cell Carcinoma

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 OPDIVO 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by OPDIVO 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 OPDIVO and ipilimumab as compared with sunitinib (Table 62 and Figure 14). 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 62 and Figure 14.

Figure 14: Overall Survival (Intermediate/Poor Risk Population) - CHECKMATE-214

CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to OPDIVO 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 OPDIVO and ipilimumab compared to sunitinib has a hazard ratio of 1.45 (95% CI: 0.75, 2.81). The efficacy of OPDIVO 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 OPDIVO 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 OPDIVO 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 OPDIVO 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 63 and Figures 15 and 16.

Figure 15: Progression-free Survival - CHECKMATE-9ER

Figure 16: Updated Overall Survival - CHECKMATE-9ER

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

Previously Treated Renal Cell Carcinoma

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 OPDIVO 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 OPDIVO 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 64 and Figure 17.

Figure 17: Overall Survival - CHECKMATE-025

14.7 Classical Hodgkin Lymphoma

Two studies evaluated the efficacy of OPDIVO as a single agent in adult patients with cHL after failure of autologous HSCT.

CHECKMATE-205 (NCT02181738) was a single-arm, open-label, multicenter, multicohort trial in cHL. CHECKMATE-039 (NCT01592370) was an open-label, multicenter, dose escalation trial that included cHL. Both studies included patients regardless of their tumor PD-L1 status and excluded patients with ECOG performance status of 2 or greater, autoimmune disease, symptomatic interstitial lung disease, hepatic transaminases more than 3 times ULN, creatinine clearance <40 mL/min, prior allogeneic HSCT, or chest irradiation within 24 weeks. In addition, both studies required an adjusted diffusion capacity of the lungs for carbon monoxide (DLCO) of over 60% in patients with prior pulmonary toxicity.

Patients received OPDIVO 3 mg/kg by intravenous infusion every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity. A cycle consisted of one dose. Dose reduction was not permitted.

Efficacy was evaluated by ORR as determined by an IRRC. Additional outcome measures included duration of response (DOR).

Efficacy was evaluated in 95 patients in CHECKMATE-205 and CHECKMATE-039 combined who had failure of autologous HSCT and post-transplantation brentuximab vedotin. The median age was 37 years (range: 18 to 72). The majority were male (64%) and White (87%). Patients had received a median of 5 prior systemic regimens (range: 2 to 15). They received a median of 27 doses of OPDIVO (range: 3 to 48), with a median duration of therapy of 14 months (range: 1 to 23 months). Efficacy results are shown in Table 65.

Efficacy was also evaluated in 258 patients in CHECKMATE-205 and CHECKMATE-039 combined who had relapsed or progressive cHL after autologous HSCT. The analysis included the group described above. The median age was 34 years (range: 18 to 72). The majority were male (59%) and White (86%). Patients had a median of 4 prior systemic regimens (range: 2 to 15), with 85% having 3 or more prior systemic regimens and 76% having prior brentuximab vedotin. Of the 195 patients having prior brentuximab vedotin, 17% received it only before autologous HSCT, 78% received it only after HSCT, and 5% received it both before and after HSCT. Patients received a median of 21 doses of OPDIVO (range: 1 to 48), with a median duration of therapy of 10 months (range: 0 to 23 months). Efficacy results are shown in Table 66.

14.8 Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

CHECKMATE-141 (NCT02105636) was a randomized (2:1), active-controlled, open-label trial enrolling patients with metastatic or recurrent SCCHN who had experienced disease progression during or within 6 months of receiving platinum-based therapy administered in either the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. The trial excluded patients with autoimmune disease, medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma), or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. Patients were randomized to receive OPDIVO 3 mg/kg by intravenous infusion every 2 weeks or investigator’s choice of 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).

Randomization was stratified by prior cetuximab treatment (yes/no). The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and ORR.

A total of 361 patients were randomized; 240 patients to the OPDIVO arm and 121 patients to the investigator’s choice arm (docetaxel: 45%; methotrexate: 43%; and cetuximab: 12%). The trial population characteristics were: median age was 60 years (range: 28 to 83) with 31% ≥65 years of age, 83% were White, 12% Asian, and 4% were Black, and 83% male. Baseline ECOG performance status was 0 (20%) or 1 (78%), 76% were former/current smokers, 90% had Stage IV disease, 45% of patients received only one prior line of systemic therapy, the remaining 55% received two or more prior lines of systemic therapy, and 25% had HPVp16-positive tumors, 24% had HPV p16-negative tumors, and 51% had unknown status.

The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with investigator’s choice at a pre-specified interim analysis (78% of the planned number of events for final analysis). There were no statistically significant differences between the two arms for PFS (HR=0.89; 95% CI: 0.70, 1.13) or ORR (13.3% [95% CI: 9.3, 18.3] vs. 5.8% [95% CI: 2.4, 11.6] for nivolumab and investigator’s choice, respectively). Efficacy results are shown in Table 67 and Figure 18.

Figure 18: Overall Survival - CHECKMATE-141

Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1 IHC 28-8 pharmDx assay. Across the trial population, 28% (101/361) of patients had non-quantifiable results. Among the 260 patients with quantifiable results, 43% (111/260) had PD-L1 negative SCCHN, defined as <1% of tumor cells expressing PD-L1, and 57% (149/260) had PD-L1 positive SCCHN, defined as ≥1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratio for survival was 0.89 (95% CI: 0.54, 1.45) with median survivals of 5.7 and 5.8 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 negative subgroup. The HR for survival was 0.55 (95% CI: 0.36, 0.83) with median survivals of 8.7 and 4.6 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 positive SCCHN subgroup.

14.9 Urothelial Carcinoma

Adjuvant Treatment of UC at High Risk of Recurrence

CHECKMATE-274 (NCT02632409) was a randomized, double-blind, placebo-controlled study of adjuvant OPDIVO in patients who were within 120 days of radical resection (R0) of UC of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence. High risk of recurrence was defined as either 1) ypT2-ypT4a or ypN+ for patients who received neoadjuvant cisplatin or 2) pT3-pT4a or pN+ for patients who did not receive neoadjuvant cisplatin and who also either were ineligible for or refused adjuvant cisplatin. Patients were randomized 1:1 to receive OPDIVO 240 mg or placebo by intravenous infusion every 2 weeks until recurrence or until unacceptable toxicity for a maximum treatment duration of 1 year. Patients were stratified by pathologic nodal status (N+ vs. N0/x with <10 nodes removed vs. N0 with ≥10 nodes removed), tumor cells expressing PD-L1 (≥1% vs. <1%/indeterminate as determined by the central lab using the PD-L1 IHC 28-8 pharmDx assay), and use of neoadjuvant cisplatin (yes vs. no).

The trial population characteristics were: median age of 67 years (range: 30 to 92); 76% male; 76% White, 22% Asian, 0.7% Black, and 0.1% American Indian or Alaska Native. Of the 335 (47%) of patients with node-positive UC, 44 (6%) had non–muscle-invasive (

The major efficacy outcome measures were investigator-assessed DFS in all randomized patients and in patients with tumors expressing PD-L1 ≥1%. DFS was defined as time to first recurrence (local urothelial tract, local non-urothelial tract, or distant metastasis), or death. Additional efficacy outcome measures included OS.

At the pre-specified interim analysis, CHECKMATE-274 demonstrated a statistically significant improvement in DFS for patients randomized to OPDIVO vs. placebo in the all randomized patient population, as well as in the subpopulation of patients with PD-L1 ≥1%, as shown in Table 68 and Figure 19.

In exploratory subgroup analyses in patients with upper tract UC (n=149), no improvement in DFS was observed in the nivolumab arm compared to the placebo arm. The unstratified DFS hazard ratio estimate was 1.15 (95% CI: 0.74, 1.80).

In an exploratory subgroup analysis in patients with PD-L1 expression of <1% (n=414), the unstratified DFS hazard ratio estimate was 0.83 (95% CI: 0.64, 1.08).

OS data is immature with 33% of deaths in the overall randomized population. In the UTUC subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm).

Figure 19: Disease-free Survival in All Randomized Patients - CHECKMATE-274

First-line Treatment of Unresectable or Metastatic UC

CHECKMATE-901 (NCT 03036098) was a randomized, open-label study in patients with previously untreated unresectable or metastatic UC. Prior neoadjuvant or adjuvant chemotherapy were permitted as long as the disease recurrence took place ≥12 months from completion of therapy. Patients who were ineligible for cisplatin and those with active CNS metastases were excluded. Stratification factors for randomization were PD-L1 status (≥1% vs. <1% or indeterminate) and liver metastasis. Patients were randomized 1:1 to receive either:

The major efficacy outcome measures were OS and PFS as assessed by BICR using RECIST v1.1. Additional efficacy outcome measures included ORR as assessed by BICR.

The median age was 65 years of age (range: 32 to 86) with 51% of patients ≥65 years of age and 12% of patients ≥75 years of age, 23% were Asian, 72% were White, 0.3% were Black, 0.3% were American Indian or Alaska Native, 4.9% were Other, 12% were Hispanic or Latino, and 77% were male. Baseline ECOG performance status was 0 (53%) or 1 (46%). At baseline, 87% of patients had metastatic UC, including 20% with liver metastases, 11% had locally advanced UC, and 51% had UC histologic variants. Forty-nine (16%) in the OPDIVO in combination with cisplatin-based chemotherapy arm and 43 (14%) in the cisplatin-based chemotherapy arm switched from cisplatin to carboplatin after at least one cycle of cisplatin.

Efficacy results are presented in Table 69 and Figures 20 and 21.

Figure 20: Overall Survival - CHECKMATE-901

Figure 21: Progression-free Survival - CHECKMATE-901

Previously Treated Advanced or Metastatic UC

CHECKMATE-275 (NCT02387996) was a single-arm trial in 270 patients with locally advanced or metastatic UC who had disease progression during or following platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients were excluded for active brain or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, and ECOG performance status >1. Patients received OPDIVO 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 8 weeks for the first 48 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed ORR as assessed by IRRC using RECIST v1.1 and DOR.

The median age was 66 years (range: 38 to 90), 78% were male, 86% were White. Twenty-seven percent had non-bladder urothelial carcinoma and 84% had visceral metastases. Thirty-four percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy. Twenty-nine percent of patients had received ≥2 prior systemic regimens in the metastatic setting. Thirty-six percent of patients received prior cisplatin only, 23% received prior carboplatin only, and 7% were treated with both cisplatin and carboplatin in the metastatic setting. Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent of patients had a hemoglobin <10 g/dL, and twenty-eight percent of patients had liver metastases at baseline. Patients were included regardless of their PD-L1 status.

Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 270 patients, 46% were defined as having PD-L1 expression of ≥1% (defined as ≥1% of tumor cells expressing PD-L1). The remaining 54% of patients were classified as having PD-L1 expression of <1% (defined as <1% of tumor cells expressing PD-L1). Confirmed ORR in all patients and the two PD-L1 subgroups are shown in Table 70. Median time to response was 1.9 months (range: 1.6-7.2). In 77 patients who received prior systemic therapy only in the neoadjuvant or adjuvant setting, the ORR was 23.4% (95% CI: 14.5%, 34.4%).

• •OPDIVO 360 mg and cisplatin 70 mg/m2 on Day 1 and gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle of a 21-day cycle for up to 6 cycles followed by single-agent OPDIVO 480 mg every 4 weeks until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, OPDIVO was continued for up to 2 years from first dose.
• •Cisplatin 70 mg/m2 on Day 1 and gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle for up to 6 cycles, until disease progression or unacceptable toxicity.

14.10 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

CHECKMATE-142 (NCT02060188) was a multicenter, non-randomized, multiple parallel-cohort, open-label trial conducted in patients with locally determined dMMR or MSI-H metastatic CRC (mCRC) who had disease progression during or after prior treatment with fluoropyrimidine- , oxaliplatin- , or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line of treatment for metastatic disease, ECOG performance status 0 or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression.

Patients enrolled in the single agent OPDIVO MSI-H mCRC cohort received OPDIVO 3 mg/kg by intravenous infusion (IV) every 2 weeks. Patients enrolled in the OPDIVO and ipilimumab MSI-H mCRC cohort received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses, followed by OPDIVO as a single agent at a dose of 3 mg/kg as intravenous infusion every 2 weeks. Treatment in both cohorts continued until unacceptable toxicity or radiographic progression.

Tumor assessments were conducted every 6 weeks for the first 24 weeks and every 12 weeks thereafter. Efficacy outcome measures included ORR and DOR as assessed by BICR using RECIST v1.1.

A total of 74 patients were enrolled in the single-agent MSI-H mCRC OPDIVO cohort. The median age was 53 years (range: 26 to 79) with 23% ≥65 years of age and 5% ≥75 years of age, 59% were male and 88% were White. Baseline ECOG performance status was 0 (43%), 1 (55%), or 3 (1.4%) and 36% were reported to have Lynch Syndrome. Across the 74 patients, 72% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 7%, 30%, 28%, 19%, and 16% received 0, 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively, and 42% of patients had received an anti-EGFR antibody.

A total of 119 patients were enrolled in the OPDIVO and ipilimumab MSI-H mCRC cohort. The median age was 58 years (range: 21 to 88), with 32% ≥65 years of age and 9% ≥75 years of age; 59% were male and 92% were White. Baseline ECOG performance status was 0 (45%) and 1 (55%), and 29% were reported to have Lynch Syndrome. Across the 119 patients, 69% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%, 24%, and 15% received 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively, and 29% had received an anti-EGFR antibody.

Efficacy results for each of these single-arm cohorts are shown in Table 71.

14.11 Hepatocellular Carcinoma

CHECKMATE-040 (NCT01658878) was a multicenter, multiple cohort, open-label trial that evaluated the efficacy of OPDIVO as a single agent and in combination with ipilimumab in patients with hepatocellular carcinoma (HCC) who progressed on or were intolerant to sorafenib. Additional eligibility criteria included histologic confirmation of HCC and Child-Pugh Class A cirrhosis. The trial excluded patients with active autoimmune disease, brain metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible.

Tumor assessments were conducted every 6 weeks for 48 weeks and then every 12 weeks thereafter. The major efficacy outcome measure was confirmed overall response rate as assessed by BICR using RECIST v1.1 and modified RECIST (mRECIST) for HCC. Duration of response was also assessed.

The efficacy of OPDIVO in combination with ipilimumab was evaluated in 49 patients (Cohort 4) who received OPDIVO 1 mg/kg and ipilimumab 3 mg/kg administered every 3 weeks for 4 doses, followed by single-agent OPDIVO at 240 mg every 2 weeks until disease progression or unacceptable toxicity. The median age was 60 years (range: 18 to 80), 88% were male, 74% were Asian, and 25% were White. Baseline ECOG performance status was 0 (61%) or 1 (39%). Fifty-seven (57%) percent of patients had active HBV infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The etiology for HCC was alcoholic liver disease in 16% and non-alcoholic fatty liver disease in 6% of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had extrahepatic spread; 35% had vascular invasion; and 51% had AFP levels ≥400 µg/L. Prior cancer treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of patients had received 2 or more prior systemic therapies.

Efficacy results are shown in Table 72. The results for OPDIVO in combination with ipilimumab in Cohort 4 are based on a minimum follow-up of 28 months.

14.12 Esophageal Cancer

Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer

CHECKMATE-577 (NCT02743494) was a randomized, multicenter, double-blind trial in 794 patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following concurrent chemoradiotherapy (CRT). Patients were randomized (2:1) to receive either OPDIVO 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Treatment was until disease recurrence, unacceptable toxicity, or for up to 1 year in total duration. Enrollment required complete resection within 4 to 16 weeks prior to randomization. The trial excluded patients who did not receive CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Randomization was stratified by tumor PD-L1 status (≥1% vs. <1% or indeterminate or non-evaluable), pathologic lymph node status (positive ≥ypN1 vs. negative ypN0), and histology (squamous vs. adenocarcinoma). The major efficacy outcome measure was disease-free survival (DFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant from the primary resected site) or death, from any cause, whichever occurred first as assessed by the investigator prior to subsequent anti-cancer therapy. Patients on treatment underwent imaging for tumor recurrence every 12 weeks for 2 years, and a minimum of one scan every 6 to 12 months for years 3 to 5.

The trial population characteristics were: median age 62 years (range: 26 to 86), 36% were ≥65 years of age, 85% were male, 15% were Asian, 82% were White, and 1.1% were Black. Disease characteristics were AJCC Stage II (35%) or Stage III (65%) at initial diagnosis carcinoma, EC (60%) or GEJC (40%) at initial diagnosis, with pathologic positive lymph node status (58%) at study entry and histological confirmation of predominant adenocarcinoma (71%) or squamous cell carcinoma (29%). The baseline Tumor PD-L1 status ≥1% was positive for 16% of patients and negative for 72% of patients. Baseline ECOG performance status was 0 (58%) or 1 (42%).

CHECKMATE-577 demonstrated a statistically significant improvement in DFS for patients randomized to the OPDIVO arm as compared with the placebo arm. DFS benefit was observed regardless of tumor PD-L1 expression and histology.

Efficacy results are shown in Table 73 and Figure 22.

Figure 22: Disease-free Survival - CHECKMATE-577

First-line Treatment of Unresectable Advanced or Metastatic ESCC

CHECKMATE-648 (NCT03143153) was a randomized, active-controlled, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC (squamous or adenosquamous histology). The trial enrolled patients whose tumor was evaluable for tumor cell (TC) PD-L1 expression [also called PD-L1 tumor proportion score (TPS)], which was evaluated using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. A retrospective scoring of a patient’s tumor PD-L1 status using Combined Positive Score (CPS), was also conducted using the PD-L1-stained tumor specimens used for randomization. Patients were not amenable to chemoradiation or surgery with curative intent. Prior treatment with curative intent was allowed if completed more than six months prior to trial enrollment. The trial excluded patients with brain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to apparent invasion of tumor to organs adjacent to the esophageal tumor. Patients were randomized to receive one of the following treatments:

Patients received OPDIVO until disease progression, unacceptable toxicity, or up to 2 years. In patients who received OPDIVO in combination with chemotherapy and in whom either fluorouracil and/or cisplatin were discontinued, other components of the treatment regimen were allowed to be continued. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue OPDIVO as a single agent.

Randomization was stratified by TC PD-L1 expression (≥1% vs. <1% or indeterminate), region (East Asia vs. Rest of Asia vs. Rest of World), ECOG performance status (0 vs. 1), and number of organs with metastases (≤1 vs. ≥2). The major efficacy outcome measures were OS and BICR-assessed PFS in patients with TC PD-L1 expression ≥ 1%. Additional efficacy measures included OS in all randomized patients, BICR-assessed PFS in all randomized patients, and ORR assessed by BICR in TC PD-L1 expression ≥ 1% and in all randomized patients. The tumor assessments per RECIST v1.1 were conducted every 6 weeks up to and including week 48, then every 12 weeks thereafter.

A total of 970 patients were randomized in CHECKMATE-648 study among whom 965 and 906 patients had quantifiable TC PD-L1 expression and CPS at baseline, respectively. The trial population characteristics for all randomized patients were median age 64 years (range: 26 to 90), 47% were ≥65 years of age, 82.% were male, 71% were Asian, 26% were White, and 1.1% were Black. Patients had histological confirmation of squamous cell carcinoma (98%) or adenosquamous cell carcinoma (1.9%) in the esophagus. Baseline ECOG performance status was 0 (47.0%) or 1 (53%).

Efficacy results are shown in Table 74 and Figure 23 and 24.

Figure 23: Overall Survival – CHECKMATE-648

Figure 24: Progression-free Survival – CHECKMATE-648

Exploratory subgroup analyses of patients with TC PD-L1 expression <1% (n=492) were conducted. OS results for each OPDIVO containing arm compared to chemotherapy were:

Exploratory subgroup analyses were also conducted by PD-L1 status per CPS (≥1 and <1) for each OPDIVO containing arm compared to chemotherapy. Among the 906 patients with quantifiable PD-L1 CPS at baseline, 278 in the OPDIVO with chemotherapy arm, 266 in the OPDIVO with Ipilimumab arm, and 280 in the chemotherapy arm had PD-L1 CPS≥1. A total of 27 patients in the OPDIVO with chemotherapy arm, 31 patients in the OPDIVO with Ipilimumab arm, and 24 patients in the chemotherapy arm had PD-L1 CPS<1.

OS results for each comparison by PD-L1 CPS status were:

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

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

ATTRACTION-3 (NCT02569242) was a multicenter, randomized (1:1), active-controlled, open-label trial in patients with unresectable advanced, recurrent, or metastatic ESCC, who were refractory or intolerant to at least one fluoropyrimidine- and platinum-based regimen. The trial enrolled patients regardless of PD-L1 status, but tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, or had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients were randomized to receive OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks or investigator’s choice of taxane chemotherapy consisting of docetaxel (75 mg/m2 intravenously every 3 weeks) or paclitaxel (100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off).

Randomization was stratified by region (Japan vs. Rest of World), number of organs with metastases (≤1 vs. ≥2), and PD-L1 status (≥1% vs. <1% or indeterminate). Patients were treated until disease progression, assessed by the investigator per RECIST v1.1, or unacceptable toxicity. The tumor assessments were conducted every 6 weeks for 1 year, and every 12 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were ORR and PFS as assessed by the investigator using RECIST v1.1 and DOR.

A total of 419 patients were randomized; 210 to the OPDIVO arm and 209 to the investigator’s choice arm (docetaxel: 31%, paclitaxel: 69%). The trial population characteristics were: median age 65 years (range: 33 to 87), 53% were ≥65 years of age, 87% were male, 96% were Asian and 4% were White. Sixty-seven percent of patients had received one prior systemic therapy regimen and 26% had received two prior systemic therapy regimens prior to enrolling in ATTRACTION-3. Baseline ECOG performance status was 0 (50%) or 1 (50%).

ATTRACTION-3 demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with investigator’s choice of taxane chemotherapy. OS benefit was observed regardless of PD-L1 expression level. The minimum follow-up was 17.6 months. Efficacy results are shown in Table 75 and Figure 25.

Figure 25: Overall Survival - ATTRACTION-3

Of the 419 patients, 48% had PD-L1 positive ESCC, defined as ≥1% of tumor cells expressing PD-L1. The remaining 52% had PD-L1 negative ESCC defined as <1% of tumor cells expressing PD-L1.

In a pre-specified exploratory analysis by PD-L1 status, the hazard ratio (HR) for OS was 0.69 (95% CI: 0.51, 0.94) with median survivals of 10.9 and 8.1 months for the OPDIVO and investigator’s choice arms, respectively, in the PD-L1 positive subgroup. In the PD-L1 negative subgroup, the HR for OS was 0.84 (95% CI: 0.62, 1.14) with median survivals of 10.9 and 9.3 months for the OPDIVO and investigator’s choice arms, respectively.

14.13 Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

CHECKMATE-649 (NCT02872116) was a randomized, multicenter, open-label trial in patients (n=1581) with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. The trial enrolled patients regardless of PD-L1 status, and tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive, or had untreated CNS metastases. Patients were randomized to receive OPDIVO in combination with chemotherapy (n=789) or chemotherapy (n=792). Patients received one of the following treatments:

Patients were treated until disease progression, unacceptable toxicity, or up to 2 years. In patients who received OPDIVO in combination with chemotherapy and in whom chemotherapy was discontinued, OPDIVO monotherapy was allowed to be given at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks up to 2 years after treatment initiation.

Randomization was stratified by tumor cell PD-L1 status (≥1% vs. <1% or indeterminate), region (Asia vs. US vs. Rest of World), ECOG performance status (0 vs. 1), and chemotherapy regimen (mFOLFOX6 vs. CapeOX). The major efficacy outcome measures, assessed in patients with PD-L1 CPS ≥5, were PFS assessed by BICR and OS. Additional efficacy outcome measures included OS and PFS in patients with PD-L1 CPS ≥1 and in all randomized patients, and ORR and DOR as assessed by BICR in patients with PD-L1 CPS ≥1 and ≥5, and in all randomized patients. Tumor assessments were conducted per RECIST v1.1 every 6 weeks up to and including week 48, then every 12 weeks thereafter.

The trial population characteristics were: median age 61 years (range: 18 to 90), 39% were ≥65 years of age, 70% were male, 24% were Asian, and 69% were White, and 1% were Black. Baseline ECOG performance status was 0 (42%) or 1 (58%). Seventy percent of patients had adenocarcinoma tumors in the stomach, 16% in the gastroesophageal junction, and 13% in the esophagus.

CHECKMATE-649 demonstrated a statistically significant improvement in OS and PFS for patients with PD-L1 CPS ≥5. Statistically significant improvement in OS was also demonstrated for all randomized patients. The minimum follow-up was 12.1 months. Efficacy results are shown in Table 76 and Figures 26, 27, and 28.

In an exploratory analysis in patients with PD-L1 CPS<1 (n=265), the median OS was 13.1 months (95% CI: 9.8, 16.7) for the OPDIVO and chemotherapy arm and 12.5 months (95% CI: 10.1, 13.8) for the chemotherapy arm, with a stratified HR of 0.85 (95% CI: 0.63, 1.15).

In an exploratory analysis in patients with PD-L1 CPS<5 (n=606), the median OS was 12.4 months (95% CI: 10.6, 14.3) for the OPDIVO and chemotherapy arm and 12.3 months (95% CI: 11.0, 13.2) for the chemotherapy arm, with a stratified HR of 0.94 (95% CI: 0.78, 1.14).

Figure 26: Overall Survival (All Patients) - CHECKMATE-649

Figure 27: Overall Survival (PD-L1 CPS ≥1) - CHECKMATE-649

Figure 28: Overall Survival (PD-L1 CPS ≥5) - CHECKMATE-649

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

16 HOW SUPPLIED/STORAGE AND HANDLING

OPDIVO® (nivolumab) Injection is a clear to opalescent, colorless to pale-yellow solution in a single-dose vial available as follows:

Store under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light by storing in the original package until time of use. Do not freeze or shake.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of OPDIVO, including:

Infusion-Related Reactions

Complications of Allogeneic HSCT

Embryo-Fetal Toxicity

Lactation

• •Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].
• •Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)].
• •Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.1)].
• •Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.1)].
• •Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions (5.1)].
• •Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions (5.1)].

SPL UNCLASSIFIED SECTION

Manufactured by:Bristol-Myers Squibb CompanyPrinceton, NJ 08543 USAU.S. License No. 1713

SPL MEDGUIDE SECTION

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: March 2024

OPDIVO 40 mg/4 mL Representative Packaging

See How Supplied section for a complete list of available packages of OPDIVO.

NDC 0003-3772-11Rx only

Opdivo®(nivolumab)injection

40 mg/4 mL(10 mg/mL)

For intravenous Infusion OnlySingle-dose vial; Discard unused portion.Please provide enclosed Medication Guide to the patient.

Bristol Myers Squibb

OPDIVO 100 mg/10 mL Representative Packaging

NDC 0003-3774-12Rx only

Opdivo®(nivolumab)injection

100 mg/10 mL(10 mg/mL)

For Intravenous Infusion OnlySingle-dose vial; Discard unused portion.Please provide enclosed Medication Guide to the patient.

Bristol Myers Squibb

OPDIVO 120 mg/12 mL Representative Packaging

NDC 0003-3756-14Rx only

Opdivo®(nivolumab)injection

120 mg/12 mL(10 mg/mL)

For Intravenous Infusion OnlySingle-dose vial; Discard unused portion.Please provide enclosed Medication Guide to the patient.

Bristol Myers Squibb

OPDIVO 240 mg/24 mL Representative Packaging

NDC 0003-3734-13Rx only

Opdivo®(nivolumab)injection

240 mg/24 mL(10 mg/mL)

For Intravenous Infusion OnlySingle-dose vial; Discard unused portion.Please provide enclosed Medication Guide to the patient.

Bristol Myers Squibb