In a phase 3 trial with advanced, non-HER2+ gastric, GEJ, and esophageal adenocarcinomas

OPDIVO® is the only I-O therapy studied in combination with FOLFOX* or CapeOX1

OPDIVO® (nivolumab) + FOLFOX or CapeOX Combination Therapy: Checkmate 649 Study Design

OPDIVO® (nivolumab) + FOLFOX or CapeOX Combination Therapy: Checkmate 649 Study Design

INDICATION

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

  • In Checkmate 649, in the OPDIVO + chemotherapy arm, patients who discontinued chemotherapy were permitted to receive OPDIVO monotherapy at 240 mg q2w, 360 mg q3w, or 480 mg q4w up to 2 years after treatment initiation1
  • The trial excluded patients who were known HER2+ or had untreated CNS metastases1
  • Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory1
  • The efficacy analysis in patients with PD-L1 CPS ≥5 included 473 patients in the OPDIVO + FOLFOX or CapeOx arm and 482 patients in the FOLFOX or CapeOX arm1
  • Minimum follow-up time was 12.1 months1

mFOLFOX6 (leucovorin, fluorouracil, and oxaliplatin) regimen was given in Checkmate 649.1

Assessed using blinded independent central review (BICR).1

All comers refers to all randomized patients in Checkmate 649.

Based on confirmed response.1

1L=first-line; CapeOX=capecitabine and oxaliplatin; CM=Checkmate; CNS=central nervous system; CPS=combined positive score; ECOG PS=Eastern Cooperative Oncology Group Performance Status; FOLFOX=leucovorin, fluorouracil, and oxaliplatin; GEJ=gastroesophageal junction; HER2=human epidermal growth factor receptor 2; IHC=immunohistochemistry; I-O=immuno-oncology; IV=intravenous; ORR=overall response rate; OS=overall survival; PD-L1=programmed death-ligand 1; PFS=progression-free survival; q2w=every 2 weeks; q3w=every 3 weeks; q4w=every 4 weeks; ROW=rest of world.


In 1L patients with metastatic GC, GEJC, and EAC

OPDIVO + FOLFOX or CapeOX: the only I-O regimen with 55% of patients
alive at 1 year1,3

Dual primary endpoints in the PD-L1 CPS ≥5 population (n=955)1

  • mOS: 14.4 mos (95% CI: 13.1–16.2) with OPDIVO + FOLFOX or CapeOX vs 11.1 mos (95% CI: 10.0–12.1) with chemotherapy|| alone (HR=0.71; 95% CI: 0.61–0.83; P<0.0001)
  • mPFS: 7.7 mos (95% CI: 7.0–9.2) with OPDIVO + FOLFOX or CapeOX vs 6.0 mos (95% CI: 5.6–6.9) with chemotherapy|| alone (HR=0.68; 95% CI: 0.58–0.79 P<0.0001)

Overall survival: all comers1,3

OPDIVO® (nivolumab) + FOLFOX or CapeOX Combination Therapy - Overall Survival Data in All Comers

OPDIVO® (nivolumab) + FOLFOX or CapeOX Combination Therapy - Overall Survival Data in All Comers

  • The 12-month OS-rate analysis was exploratory and not pre-specified within the study protocol
mOS: 13.8 mos with ODPIVO + FOLFOX or CapeOX vs 11.6 months with chemo|| alone1

FOLFOX or CapeOX.1

In 1L patients with metastatic GC, GEJC, and EAC

Superior overall survival was achieved vs chemotherapy in all comers, PD-L1 CPS ≥1, and PD-L1 CPS ≥51,3

OPDIVO® (nivolumab) + FOLFOX or CapeOX Combination Therapy: Median Overall Survival in All-Comers, Patients with PD-L1 CPS ≥1 and Patients with PD-L1 CPS ≥5

    • All OS measures were part of the hierarchical OS testing in the trial and achieved statistical significance.1
      The individual results were not meant to be compared
    • The 12-month OS-rate analysis was exploratory and not pre-specified within the study protocol

FOLFOX or CapeOX.1

OPDIVO + FOLFOX or CapeOX vs FOLFOX or CapeOX alone.1

Secondary endpoint.

Primary endpoint.

CI=confidence interval; EAC=esophageal adenocarcinoma; GC=gastric cancer; GEJC=gastroesophageal junction cancer; HR=hazard ratio; I-O=immuno-oncology; mo=month; mOS=median overall survival; mPFS=median progression-free survival.


SELECT IMPORTANT SAFETY INFORMATION

Serious Adverse Reactions

In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). 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%). 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.

Please see additional Important Safety Information below.

In 1L patients with metastatic GC, GEJC, and EAC

47% of patients receiving OPDIVO + FOLFOX or CapeOX responded, and 10% were complete responders1

ORR in Patients Receiving OPDIVO® (nivolumab) + FOLFOX or CapeOX Combination Therapy

ORR in Patients Receiving OPDIVO® (nivolumab) + FOLFOX or CapeOX Combination Therapy

Duration of response†§††

  • mDOR in all comers: 8.5 mos (95% CI: 7.2–9.9; range 1.0+, 29.6+ mos) with OPDIVO + FOLFOX or CapeOX vs
    6.9 mos (95% CI: 5.8–7.2; range 1.2+, 30.8+ mos) with chemotherapy|| alone1

Assessed using blinded independent central review (BICR).1

Based on confirmed response.

FOLFOX or CapeOX.1

Secondary endpoint.

An exploratory endpoint.

SELECT IMPORTANT SAFETY INFORMATION

Common Adverse Reactions

In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

Please see additional Important Safety Information below.

SELECT IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

  • Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.
  • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. 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 (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO interruption or discontinuation is required, 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. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).

Immune-Mediated Colitis

  • OPDIVO can cause immune-mediated colitis. 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. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).

Immune-Mediated Hepatitis and Hepatotoxicity

  • OPDIVO can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%).

Immune-Mediated Endocrinopathies

  • OPDIVO can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. 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. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.
  • In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).
  • In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).
  • In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).
  • In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%).
  • In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).
  • In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction

  • OPDIVO can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

Immune-Mediated Dermatologic Adverse Reactions

  • OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.
  • Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).
  • In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%).

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 monotherapy 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-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; 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 rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.
  • Some ocular IMAR 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, which has been observed in patients receiving OPDIVO, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

  • OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute 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.

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 OPDIVO. 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). These complications may occur despite intervening therapy between OPDIVO and allogeneic HSCT.
  • Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

  • Based on its mechanism of action and findings from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. 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 at least 5 months after the last dose.

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 OPDIVO to a thalidomide analogue plus dexamethasone 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.

Lactation

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

Serious Adverse Reactions

  • In Checkmate 577, serious adverse reactions occurred in 33% of patients receiving OPDIVO (n=532). A serious adverse reaction reported in ≥2% of patients who received OPDIVO was pneumonitis. A fatal reaction of myocardial infarction occurred in one patient who received OPDIVO.
  • In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). 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%). 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.

Common Adverse Reactions

  • In Checkmate 577, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=532) were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%).
  • In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

Please see U.S. Full Prescribing Information for OPDIVO.

Clinical Trials and Patient Populations

  • Checkmate 577–adjuvant treatment of esophageal or gastroesophageal junction cancer; Checkmate 649–previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

References:

  • 1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
  • 2. Kelly RJ, Ajani JA, Kuzdzal J, Zander T, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384(13):1191-1203.
  • 3. Moehler M, Shitara K, Garrido M, et al. Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: first results of the CheckMate 649 study. Presentation at ESMO 2020. Presentation LBA6.
  • 4. Data on file. NIVO 612. Princeton, NJ: Bristol-Myers Squibb Company; 2020.
  • 5. Data on file. NIVO 609. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
  • 6. Data on file. NIVO 314. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
  • 7. Data on file. NIVO 649. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
  • 8. Long GV, Tykodi SS, Schneider JG, et al. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol 2018;29(11):2208-2213.