OPDIVO® (nivolumab) + YERVOY® (ipilimumab) in the first-line treatment of unresectable or metastatic HCC1-5

RR Hem/Onc Updates, Special Issues
Liver Cancer (Hepatocellular)

Treating 1L unresectable or metastatic HCC? 3-year data may help you reassess your approach
Explore this 1L dual immunotherapy option for eligible patients

Expert opinion: Aiwu Ruth He, MD, PhD*
*Dr Aiwu Ruth He, MD, PhD, is a paid consultant of Bristol Myers Squibb (BMS) who was compensated by BMS for her contributions to this article.
Content sponsored by Bristol Myers Squibb

Unmet need in unresectable or metastatic HCC
Hepatocellular carcinoma (HCC) accounts for 75–85% of primary liver cancer cases and unresectable or metastatic HCC (uHCC) is associated with poor prognosis4,6. Thus, additional 1L treatments that prolong survival are needed. Approved 1L options, e.g. I-O + VEGFi and a dual I-O option, were evaluated against sorafenib alone, while OPDIVO® + YERVOY® was evaluated against investigator’s choice of lenvatinib or sorafenib, offering an alternative 1L immunotherapy option for uHCC1-5.

OPDIVO + YERVOY are associated with the following Warnings and Precautions2: 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.

OPDIVO + YERVOY in 1L treatment of unresectable or metastatic HCC
OPDIVO + YERVOY, a dual immune-checkpoint inhibitor combination studied in the global, randomized, phase 3 Checkmate 9DW trial, is the only FDA-approved treatment to show positive results*† versus investigator’s choice of lenvatinib or sorafenib, in the 1L treatment of adult patients with uHCC1-5. Checkmate 9DW enrolled 668 patients with uHCC‡ who were systemic-therapy–naïve, with at least 1 measurable lesion, Child-Pugh score 5 or 6, ECOG PS 0 or 1, and no main portal vein invasion (Vp4)1-3. An esophagogastroduodenoscopy (EGD) was not required2. Patients were randomized 1:1 to receive either OPDIVO (1 mg/kg) + YERVOY (3 mg/kg) q3w for up to 4 cycles followed by OPDIVO (480 mg IV) q4w or investigator’s choice of lenvatinib or sorafenib in the comparator arm1,2,5. YERVOY 3 mg/kg dosing in Checkmate 9DW was supported by Checkmate 0407.

HCC-Only-FDA-Approved-Treatment-Positive_Results

Efficacy and safety data for OPDIVO + YERVOY
Median overall survival (mOS), the primary endpoint, was 23.7 months (95% CI: 18.8, 29.4) with OPDIVO + YERVOY versus 20.6 months (95% CI: 17.5, 22.5) with the comparator arm, with a hazard ratio of 0.79 (95% CI: 0.65, 0.96; P=0.018)1,2. Notably, 38% of patients were alive at 3 years with OPDIVO + YERVOY, compared to 24% with the comparator arm1-3,5. According to Dr. He, “The Checkmate 9DW design was unique because one of the comparator arm treatments was investigator’s choice of lenvatinib—a modern TKI, received by 85% of patients—making these results particularly meaningful.”

OPDIVO + YERVOY achieved a deeper overall response rate (ORR), a secondary endpoint, of 36%, versus 13% with the comparator arm (P<0.0001)1-3,5. “The ORR being higher than the comparator arm is great. When my patients are symptomatic with a high tumor burden, I choose treatments with a higher response rate than their comparator arms to ease their symptoms and potentially reduce liver stress. Furthermore, an exploratory analysis found median time to response was 2.2 months,” said Dr. He.

Responses lasted over twice as long with the median duration of response (mDOR) at 30.4 months (95% CI: 21.2, NR) versus 12.9 months (95% CI: 10.2, 31.2) with the comparator arm1-3,5. Dr. He shared, “The DOR is clinically meaningful. Some of my Checkmate 9DW patients are now off treatment after 2 years, with ongoing disease control.”

Durable-Survival-Durable-Responses-Longer-Responses

The safety profile of OPDIVO + YERVOY is well established2,5. Dr. He added, “No new IMARs were observed in Checkmate 9DW. I encourage patients to report side effects early, and I manage IMARs per established protocols including treatment holds and steroid use.”

Opdivo-Yervoy-Safety

Summary and conclusions
OPDIVO + YERVOY, a differentiated 1L option for treatment of uHCC, achieved durable survival, deeper and longer responses with a well-established safety profile. “For OPDIVO + YERVOY, I choose patients who are relatively robust, socially supported, and report side effects promptly. I’m excited about this 1L treatment and its demonstrated durable survival benefits,” noted Dr. He.

INDICATIONS

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

Clinical Trials and Patient Populations

  • Checkmate 9DW – hepatocellular carcinoma, in combination with YERVOY.


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References

  1. Kudo M et al. Oral presentation at ASCO-GI 2025. Abstract 520.
  2. OPDIVO [package insert]. Princeton, NJ; Bristol-Myers Squibb Company.
  3. Galle PR et al. Oral presentation at ASCO 2024. Abstract LBA4008.
  4. American Cancer Society. https://www.cancer.org/cancer/liver-cancer/detection-diagnosis-staging/survival-rates.html. Accessed July 2025.
  5. YERVOY [package insert]. Princeton, NJ; Bristol-Myers Squibb Company.
  6. Yau T et al. 2025;405(10492):1851–1864.
  7. El-Khoueiry AB et al. Lancet. 2017;389(10088):2492–2502.
  8. Data on file. BMS-REF-NIVO-0335. Princeton, NJ: Bristol-Myers Squibb Company; 2025.
  9. Data on file. BMS-REF-NIVO-0326. Princeton, NJ: Bristol-Myers Squibb Company; 2025.

© 2025 Bristol-Myers Squibb Company. OPDIVO® and YERVOY® are registered trademarks of Bristol-Myers Squibb Company.

7356-US-2500331   08/2025

 

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