*Fluoropyrimidine-and platinum-containing chemotherapy.1

CHECKMATE 649

OPDIVO® (nivolumab), 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.

CHECKMATE 648

OPDIVO® (nivolumab), 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).

Checkmate 649 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 CapeOX1,2

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

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

  • 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 24 months2

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 (both PD-L1 expressors and non-expressors) 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: 28% of patients alive at 2 years1,3 ||

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)**
  • 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)**

Secondary endpoint in the all comers
population

  • mOS: 13.8 mos (95% CI: 12.6–14.6) with
    OPDIVO + FOLFOX or CapeOX vs 11.6 mos
    (95% CI: 10.9–12.5) with chemotherapy# alone
    (HR=0.80; 95% CI:
    0.71–0.90); P=0.002

Overall survival: all comers1,2 ¶

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 exploratory 12-month and 24-month OS-rate analyses were pre-specified within the study protocol.1,2

All comers refers to all randomized patients in Checkmate 649.

FOLFOX or CapeOX.

Minimum follow-up: 24 mos.

mOS: 13.8 months with OPDIVO + FOLFOX or CapeOX vs 11.6 months with chemo†† alone1

FOLFOX or CapeOX.1


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 responders based on 24-month analysis1,3

Response rates at 24 months: All comers

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

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

Primary analysis (12.1-month follow-up in all comers1||||)

Duration of response‡‡§§##

  • ORR: 47% (370/789) with OPDIVO + FOLFOX or CapeOx (95% CI: 43–50) vs 37% (293/792) with chemotherapy alone (95% CI: 34–40)
  • CR: 10% (78/789) with OPDIVO + FOLFOX or CapeOx vs 7% (52/792) with chemotherapy
  • PR: 37% (292/789) with OPDIVO + FOLFOX or CapeOx vs 30% (241/792) with chemotherapy alone
  • 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¶¶ alone1,3

Based on confirmed response.1

Assessed using the blind independent central review (BICR).1

All comers refers to all randomized patients in Checkmate 649.1

FOLFOX or CapeOX.1

An exploratory endpoint.1

CI=confidence interval; CR=complete response; EAC=esophageal adenocarcinoma; GC=gastric cancer; GEJC=gastroesophageal junction cancer; HR=hazard ratio; mDOR=median duration of response; mos=months;
mOS=median overall survival; mPFS=median progression-free survival; PR=partial response.

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.

An HCP discusses the role of OPDIVO in the treatment of certain metastatic UGI cancers

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SPEAKER: Dr. Kelly
Hello, I’m Dr. Ronan Kelly, Oncologist, from Dallas, Texas. Today I’m here to share with you the approval of 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.

OPDIVO + Folfox or CapeOX is the only first line Immuno-oncology regimen approved in these three gastroesophageal tumor types regardless of PD-L1 status.

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SPEAKER: Dr. Kelly
Metastatic gastric cancer is often associated with poor prognosis with median overall survival at less than a year with chemotherapy alone.

There were approximately 26,200 new cases of stomach cancer in 2020 with approximately 13,400 being unresectable/metastatic HER2-drug treatable.

Up to 68% of those patients may not go on to greater than or equal to second line therapy.

Unfortunately, the relative 5-year survival rate of these patients is only 5.5%.

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SPEAKER: Dr. Kelly
Let’s review the indication for OPDIVO. OPDIVO, in combination with fluoropyrimidine and platinum containing chemotherapy, is indicated for treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

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SPEAKER: Dr. Kelly
It's important to highlight some of the safety information before we get into the trial design and the study results. OPDIVO is associated with the following warnings and precautions, many of which will be very familiar to the audience. We do need to watch out for the severe and fatal immune-mediated adverse reactions that can occur, including infusion related reactions. Also people should be aware that there may be complications in a population of patients that have received the hematopoietic stem cell transplantation. It is also very important to highlight the risk of embryo-fetal toxicity and then in patients who have multiple myeloma to know that there's an increased mortality risk. When OPDIVO is added to a thalidomide analogue and dexamethasone in patients with multiple myeloma, mortality is increased.

Immune-mediated adverse reactions may be severe or fatal and can occur in any organ system or tissue. Reactions may include immune-mediated pneumonitis and colitis. You also need to be on the lookout for liver dysfunction with hepatitis and hepatotoxicity and endocrinopathies, including thyroid function, but other endocrinopathies can happen, as well as skin reactions and some kidney dysfunction. We do, of course, always monitor liver enzymes, creatine and thyroid function at baseline and throughout a patient’s treatment journey. Withhold or permanently discontinue based on severity and type of reaction.

Please interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions and if we have a more severe reaction to discontinue the infusion.

The hematopoietic stem cell transplantation patient group, there can be some fatal and other serious complications, as I've mentioned, so please be aware of that. We've already talked about the embryo-fetal toxicity, and we mentioned briefly the risk in patients with multiple myeloma when you give a thalidomide analogue and dexamethasone.

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SPEAKER: Dr. Kelly
Let’s review the study design of Checkmate 649; the only randomized, global phase 3 study of PD-1 inhibitor-based therapies in the first line setting for patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

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SPEAKER: Dr. Kelly
Key eligibility criteria included previously untreated, unresectable, advanced or metastatic gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma. If patients were subsequently identified to be HER2 positive, they were allowed to remain in the study. It was only patients who had known HER2 positive status at the time of enrollment who were ineligible. The ECOG performance status was zero to one.

You can see the stratification factors here, tumor cell PD-L1 expression, region of the world, ECOG performance status and chemotherapy.

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SPEAKER: Dr. Kelly
In this study, over 1,500 patients were randomized in a 1:1 manner to either OPDIVO plus chemotherapy versus chemotherapy alone. The chemotherapy backbone could either be FOLFOX or CapeOX. If you're giving FOLFOX every two weeks, you give a slightly lower dose of OPDIVO at 240 milligrams, if you chose to give CapeOX, which is every three weeks, you would use a slightly higher dose of OPDIVO, at 360 milligrams versus chemotherapy alone at the same scheduling. Treatment was for two years or until disease progression or unacceptable toxicity.

The dual primary endpoint of the study was Overall Survival and Progression Free Survival in a PD-L1 population that had a combined positive score of greater than or equal to 5.

Secondary endpoints, such as overall survival in patients who had a combined positive score of greater than or equal to one and then in all randomized patients were also assessed.

As a reminder, the FDA approved this combination regardless of PD-L1 expression status.

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SPEAKER: Dr. Kelly
The indication and formal FDA approval for OPDIVO is in combination with fluoropyrimidine- and platinum-containing chemotherapy.

Patients were treated until disease progression, unacceptable toxicity, or up to two years. In patients who received OPDIVO in combination with chemotherapy and in whom chemotherapy was discontinued, OPDIVO monotherapy was allowed to be given as a single agent.

As I mentioned, the trial excluded those that were known to be HER2 positive at baseline and then those patients that had untreated CNS metastases. Tumor specimens were evaluated prospectively using the PD-L1, IHC 28-8 pharma DX assay at a central laboratory.

The efficacy analysis included patients with a combined positive score greater than or equal to five, so that turned out to be 473 patients in the OPDIVO plus chemotherapy arm and 482 patients in the chemotherapy alone arm. It's approximately 60 percent of the patients in this particular study at a combined positive score of greater than or equal to five. The minimum follow-up time at primary analysis was 12.1 months and the minimum follow-up time at extended analysis was 24 months.

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SPEAKER: Dr. Kelly
Let’s see what happens when these patients were randomly assigned to receive OPDIVO + chemotherapy or chemotherapy alone. Here we see the overall survival in all randomized patients. The median overall survival is 13.8 months versus 11.6 months.

The hazard ratio is 0.80 p value of 0.0002.

In fact if you look at the Kaplan Meier curves, you can see that there is an exploratory 12 month and 24 month overall survival rate analysis. You can see at 12 months, it's 55 percent of the patients with OPDIVO plus chemotherapy versus 48 percent on chemotherapy alone, and at 24 months, it's 28 percent of the patients with OPDIVO plus chemotherapy versus 19 percent on chemotherapy alone.

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SPEAKER: Dr. Kelly
In terms of other efficacy endpoints, the study also looked at response rate and median duration of response.

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SPEAKER: Dr. Kelly
Now we look at the safety profile of the study, divided this into three categories serious adverse reactions, common adverse reactions, and fatal adverse reactions. If we start on the left hand side in Checkmate 649 serious adverse reactions occurred in 52 percent of the patients treated with OPDIVO in combination with chemotherapy. The most frequent of those reported in greater or equal to two percent of the patients were vomiting at 3.7 percent, pneumonia at 3.6 percent, anemia at 3.6 percent, pyrexia at 2.8 percent, diarrhea at 2.7 percent, febrile neutropenia at 2.6 percent, and pneumonitis at 2.4 percent.

If we move to the common adverse reactions in the study, those most common adverse reactions reported in greater or equal to 20 percent of patients treated with OPDIVO In combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation and musculoskeletal pain.

And finally, fatal adverse reactions occurred in 16 patients, or two percent of patients who were treated with OPDIVO in combination with chemotherapy, and that included four patients that had pneumonitis. Two patients who had febrile neutropenia. Two patients who had stroke. The rest were single patients with gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia infection. gastrointestinal bleeding, mesenteric vessel thrombosis and disseminated intravascular coagulation.

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SPEAKER: Dr. Kelly
Here you can see breakdown of adverse reactions that occurred in greater than or equal to 10 percent of the patients who received OPDIVO plus chemotherapy.

In blue are the patients on OPDIVO plus chemotherapy; in gray are the patients who received chemotherapy alone.

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SPEAKER: Dr. Kelly
This is a continuation of the adverse events.

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.

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SPEAKER: Dr. Kelly
OPDIVO is the only PD-1 inhibitor that offers every two or three week dosing designed to match your chemotherapy preferences.

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SPEAKER: Dr. Kelly
So, if you would prefer to give every two weeks, you give OPDIVO at a dose of 240 milligrams, if you prefer to give the OPDIVO every three weeks, you would give a slightly higher dose of 360 milligrams.

And you continue treatment until disease progression, unacceptable toxicity or for up to two years.

In the 649 Study, patients were permitted to keep going with single agent OPDIVO at either two weeks, three weeks or four weeks at those doses of 240 milligrams, 360 milligrams or 480 milligrams, respectively.

Please refer to the prescribing information for each of the other therapeutic agents that will be administered in combination with OPDIVO for the recommended dose and administration information. Always remember to administer the OPDIVO first, followed by fluoropyrimidine and platinum containing chemotherapy on the same day.

Also, please remember as we discussed previously that OPDIVO is associated with severe infusion related reactions.

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SPEAKER: Dr. Kelly
In summary, OPDIVO plus chemotherapy, offers a chance to extend survival regardless of PD-L1 status. OPDIVO plus chemotherapy is the only first-line immuno-oncology regimen approved across 3 gastroesophageal tumor types of gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma.

And, it's approved regardless of PD-L1 status across those three types.

The chemotherapy backbone in the study was FOLFOX or CapeOX.

Remember, OPDIVO offers every two or three week dosing which is designed to match your chemotherapy preferences.

Please stay with me as I share some important safety information about OPDIVO.

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Read ISI verbatim.

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Read ISI verbatim.

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Read ISI verbatim.

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Read ISI verbatim.

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Read ISI verbatim.

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Read ISI verbatim.

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SPEAKER:
I’d like to thank you for spending time with me today and I hope you found the presentation educational and informative. If you have additional questions, your BMS sales representative will be there to help you.

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 648, serious adverse reactions occurred in 62% of patients receiving OPDIVO in combination with chemotherapy (n=310). 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%). 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. 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 648, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=310) were nausea (65%), decreased appetite (51%), fatigue (47%), constipation (44%), stomatitis (44%), diarrhea (29%), and vomiting (23%). 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 US Full Prescribing Information for OPDIVO.

Clinical Trials and Patient Populations

  • Checkmate 577–adjuvant treatment of esophageal or gastroesophageal junction cancer; Checkmate 648–previously untreated, unresectable advanced, metastatic esophageal squamous cell carcinoma in combination with fluoropyrimidine- and platinum-containing chemotherapy; Checkmate 649–previously untreated advanced or metastatic gastric or gastroesophageal junction or esophageal adenocarcinoma

References:

  • 1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  • 2. Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386:449-462.
  • 2. Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386:449-462.
  • 2. Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386(5):449-462.
  • 2. 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.