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NOW APPROVED

For the treatment of 1L
unresectable or
metastatic HCC1,2

When your patients have
milestones in mind,

Extend the possibilities
of durable survival1,2*

38% of patients alive at 3 years†

In Checkmate 9DW, mOS with OPDIVO + YERVOY (n=335) was 23.7 mos (95% CI: 18.8, 29.4) vs 20.6 mos (95% CI: 17.5, 22.5) with investigator’s choice of lenvatinib/sorafenib (n=333); HR=0.79 (95% CI: 0.65, 0.96); P=0.0180.2 †vs 24% of patients alive at 3 years with investigator’s choice of lenvatinib/sorafenib.1

1L=first-line; CI=confidence interval; HCC=hepatocellular carcinoma; HR=hazard ratio; I‑O=immuno-oncology; mos=months; mHCC=metastatic hepatocellular carcinoma; mOS=median overall survival.

INDICATION

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC).

SELECT IMPORTANT SAFETY INFORMATION

Summary of Warnings and Precautions

OPDIVO and YERVOY are associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.

Please see additional Important Safety Information for OPDIVO and YERVOY below, and U.S. Full Prescribing Information for OPDIVO and YERVOY.

Durable survival with OPDIVO + YERVOY1,2*†

38% of patients alive at 3 years1‡

OVERALL SURVIVAL (OS)1,2

•

Median follow-up: 35.2 months (range: 26.8–48.9).1,2

mOS of 23.7 mos vs 20.6 mos with investigator’s choice of lenvatinib/sorafenib; HR=0.79 (95% CI: 0.65, 0.96); P=0.0180.2 †Study was not designed to independently compare OPDIVO + YERVOY vs lenvatinib or OPDIVO + YERVOY vs sorafenib. ‡vs investigator’s choice of lenvatinib/sorafenib.2 § Median OS is estimated using Kaplan-Meier methodology. HR and 95% CI from stratified Cox proportional hazard model. HR is OPDIVO + YERVOY vs lenvatinib/sorafenib.3 IIInvestigator’s choice.2 ¶Two-sided P value from stratified log-rank test. Boundary for statistical significance: P≤0.0257.3

DOR=duration of response; LEN=lenvatinib; mo=month; ORR=overall response rate; OS=overall survival; SOR=sorafenib.

Deeper response with OPDIVO + YERVOY2*†

36% of patients achieved a response vs 13% with lenvatinib or sorafenib‡

OVERALL RESPONSE RATE (ORR) (SECONDARY ENDPOINT)§

•

OPDIVO + YERVOY demonstrated a statistically significant improvement (P<‍0.0001) in ORR vs lenvatinib or sorafenib3‡

•

Median TTR (exploratory analysis) was 2.2 months for OPDIVO + YERVOY (range: 1.1–11.6) and 3.7 months (range: 0.6–11.2) for lenvatinib or sorafenib1‡¶

vs investigator’s choice of lenvatinib/sorafenib.2 †Study was not designed to independently compare OPDIVO + YERVOY vs lenvatinib or OPDIVO + YERVOY vs sorafenib. ‡Investigator’s choice.2 §ORR was a secondary endpoint in Checkmate 9DW; assessed by BICR based on RECIST v1.1. 1,2 ‖Two-sided P value from stratified Cochran-Mantel-Haenszel test. Boundary for statistical significance: P≤0.025.2 ¶Median TTR in confirmed responders (OPDIVO + YERVOY: n=121; lenvatinib/sorafenib: n=44).1

BICR=blinded independent central review; CR=complete response; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; TTR=time to response.

Longer responses with OPDIVO + YERVOY1-4*†

Responses lasting more than twice as long*

DURATION OF RESPONSE (DOR)

•

Median follow-up: 35.2 months (range: 26.8–48.9).1-3

vs investigator’s choice of lenvatinib/sorafenib.2 †Study was not designed to independently compare OPDIVO + YERVOY vs lenvatinib or OPDIVO + YERVOY vs sorafenib.‡DOR was a secondary endpoint in Checkmate 9DW; assessed by BICR per RECIST v1.1.1 Duration of response (DOR) is not included in the statistical hierarchical testing, and therefore is not a powered endpoint. §Investigator’s choice.2 ‖Number of confirmed responders.1,2

Well-established safety profile with OPDIVO + YERVOY2

ADVERSE REACTIONS IN ≥10% OF PATIENTS RECEIVING OPDIVO + YERVOY

•

Serious adverse reactions occurred in 53% of patients treated with OPDIVO in combination with YERVOY. The most frequent non-liver-related serious adverse reactions reported in ≥2% of patients who received OPDIVO with YERVOY were diarrhea/colitis (4.5%), gastrointestinal hemorrhage (3%), and rash (2.4%).2,5

•

Liver-related serious adverse reactions occurred in 17% of patients treated with OPDIVO in combination with YERVOY, including Grade 3-4 events in 16% of patients. The most frequently reported all grade liver-related serious adverse reactions occurring in ≥1% of patients who received OPDIVO in combination with YERVOY were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2.4%), ascites (2.4%), and hepatotoxicity (1.2%).2,5

•

Fatal adverse reactions occurred in 12 patients (3.6%), including 4 patients (1.2%) who died due to immune-mediated or autoimmune hepatitis and 4 (1.2%) patients who died of hepatic failure.2,5

•

Permanent discontinuations due to an adverse reaction occurred in 27% of patients with OPDIVO in combination with YERVOY. Adverse reactions leading to permanent discontinuation in >1% of patients included immune-mediated hepatitis (1.8%), diarrhea/colitis (1.8%), hepatic failure (1.2%).2,5 Dosage interruptions due to an adverse reaction occurred in 62% of patients treated with OPDIVO in combination with YERVOY. Adverse reactions which required dosage interruption in >5% of patients included increased AST (13%), increased ALT (11%), and diarrhea/colitis (8%).

•

Clinically important adverse reactions reported in <‍10% of patients who received OPDIVO with YERVOY were hyperglycemia (8%), adrenal insufficiency (4.2%), pneumonitis (2.7%), and pancreatitis (2.4%).2,5

Toxicity was graded per NCI CTCAE v5.

Represents a composite of multiple related terms.2

ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

Study Design1-4: Checkmate 9DW, a randomized (1:1), open-label, phase 3 trial, studied OPDIVO (nivolumab) 1 mg/kg IV plus YERVOY (ipilimumab) 3 mg/kg IV q3w for up to 4 cycles, followed by OPDIVO 480 mg IV q4w* in the first-line treatment of metastatic or unresectable HCC† compared with investigator’s choice‡ of lenvatinib 8 mg§ or 12 mg|| PO qd or sorafenib 400 mg PO BID.¶ The trial included patients with unresectable HCC, who had at least 1 measurable lesion, were systemic therapy–naïve, Child-Pugh score 5 or 6, ECOG PS 0 or 1, and no main portal vein invasion. Patients were stratified by etiology (HBV or HCV vs non-viral),# MVI/EHS (present vs absent), and AFP (<‍400 vs ≥400 ng/mL). Patients were not required to have an EGD. The primary endpoint was OS. Secondary endpoints were ORR and DOR by BICR per RECIST v1.1 and time to symptom deterioration.** Key exploratory endpoints were PFS and TTR by BICR per RECIST v1.1, safety, and HRQOL. Study treatment for OPDIVO in combination with ipilimumab continued until disease progression, unacceptable toxicity, withdrawal of consent (all arms), or a maximum treatment duration of 2 years (OPDIVO + YERVOY arm only). At the data cutoff (1/31/24), the median follow-up was 35.2 months (range: 26.8–48.9).††

Minimum of 1 dose of OPDIVO + YERVOY is required before proceeding to OPDIVO monotherapy.1 †Disease not eligible for, or progressive disease after, curative surgical and/or locoregional therapies.1 ‡Study was not designed to independently compare OPDIVO + YERVOY vs lenvatinib or OPDIVO + YERVOY vs sorafenib. §If body weight <‍60 kg.2 ||If body weight ≥60 kg.2 ¶Among 325 patients treated with lenvatinib/sorafenib: 275 (85%) received lenvatinib and 50 (15%) received sorafenib.1 #Based on central lab serology results for stratification purpose.3 **Based on HCS subscale score of the FACT-Hep.1 ††Time between randomization date and cutoff date.3

AFP=alpha-fetoprotein; BID=twice daily; DOR=duration of response; EGD=esophagogastroduodenoscopy; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EHS=extrahepatic spread; FACT-Hep=Functional Assessment of Cancer Therapy-Hepatic; HBV=hepatitis B virus; HCC=hepatocellular carcinoma; HCS=hepatobiliary cancer subscale; HCV=hepatitis C virus; IV=intravenous; MVI=macroscopic vascular invasion; ORR=overall response rate; OS=overall survival; PO=orally; qd=every day; q3w=every 3 weeks; q4w=every 4 weeks.

Explore the data to see if OPDIVO + YERVOY
could be right for your patients with
unresectable or metastatic HCC

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 or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. 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 and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY 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 and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. 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 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%).

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY 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 and YERVOY 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 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456) of patients, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%).

In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456) of patients, including Grade 3 (2.4%) and Grade 2 (6%).

In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%).

In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%).

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis.

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 non-exfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%).

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 OPDIVO in combination with YERVOY 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, other transplant (including corneal graft) rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <‍1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

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 and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY 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 HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients.

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 or YERVOY. 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 or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY 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 or YERVOY 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 9DW, serious adverse reactions occurred in 53% of patients receiving OPDIVO with YERVOY (n=332). The most frequent non liver-related serious adverse reactions reported in ≥2% of patients who received OPDIVO with YERVOY were diarrhea/colitis (4.5%), gastrointestinal hemorrhage (3%), and rash (2.4%). Liver-related serious adverse reactions occurred in 17% of patients receiving OPDIVO with YERVOY, including Grade 3-4 events in 16% of patients. The most frequently reported all grade liver-related serious adverse reactions occurring in ≥1% of patients who received OPDIVO with YERVOY were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2.4%), ascites (2.4%), and hepatotoxicity (1.2%). Fatal adverse reactions occurred in 12 (3.6%) patients who received OPDIVO with YERVOY; these included 4 (1.2%) patients who died due to immune-mediated or autoimmune hepatitis and 4 (1.2%) patients who died of hepatic failure.

Common Adverse Reactions

In Checkmate 9DW, the most common adverse reactions (≥20%) in patients receiving OPDIVO with YERVOY (n=332) were rash (36%), pruritus (34%), fatigue (33%), and diarrhea (25%).

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

References:

1.	Kudo M, Yau T, Decaens T, et al. Nivolumab plus ipilimumab vs lenvatinib or sorafenib as first-line therapy for unresectable hepatocellular carcinoma: CheckMate 9DW expanded analyses. Oral presentation at ASCO-GI 2025. Abstract 520.

2.	OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.

3.	Galle PR, Decaens T, Kudo M, et al. Nivolumab plus ipilimumab vs lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma: first results from CheckMate 9DW. Oral presentation at ASCO 2024. Abstract LBA4008.

4.	Data on file. BMS-REF-NIVO-0326. Princeton, NJ: Bristol-Myers Squibb Company; 2025.

5.	YERVOY [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.

Bristol Myers Squibb is committed to transparency. For information on the list price of OPDIVO and OPDIVO combinations indications as well as information regarding average out-of-pocket costs and assistance programs, please visit our pricing information page.

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1506-‍US-‍2500221 06/‍25

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