U.S. Food and Drug Administration Approves Opdivo® (nivolumab) plus Yervoy® (ipilimumab) as a First-Line Treatment for Unresectable or Metastatic Hepatocellular Carcinoma

Rhea-AI Summary

Bristol Myers Squibb (NYSE: BMY) received FDA approval for Opdivo plus Yervoy as a first-line treatment for unresectable or metastatic hepatocellular carcinoma (HCC). The approval is based on the Phase 3 CheckMate-9DW trial results, where the combination therapy showed superior overall survival of 23.7 months versus 20.6 months with lenvatinib or sorafenib, reducing death risk by 21%.

Key findings include:

• 38% three-year survival rate with Opdivo plus Yervoy versus 24% with comparator therapy
• 36.1% overall response rate compared to 13.2% for lenvatinib/sorafenib
• Median duration of response of 30.4 months versus 12.9 months

This approval converts the previous 2020 accelerated approval to full approval and expands the indication to first-line treatment. The safety profile remained consistent with previous findings, though serious adverse reactions occurred in 53% of patients receiving the combination therapy.

Positive

• FDA approval for first-line treatment expands market opportunity
• Superior survival rates with 38% 3-year survival vs 24% for competitors
• Significant 36.1% response rate vs 13.2% for competitor treatments
• Longer duration of response at 30.4 months vs 12.9 months for competitors

Negative

• Serious adverse reactions in 53% of patients
• Permanent treatment discontinuation in 27% of patients
• Fatal adverse reactions occurred in 3.6% of patients
• 17% experienced serious liver-related adverse reactions

Insights

Oncology Specialist

Bristol Myers Squibb's FDA approval for Opdivo plus Yervoy as a first-line treatment for hepatocellular carcinoma represents a significant therapeutic advancement. The CheckMate-9DW trial data shows 38% survival at 3 years versus 24% with standard therapy, demonstrating meaningful clinical benefit for patients with this aggressive cancer type.

The 21% reduction in death risk (HR=0.79) and nearly tripled response rate (36.1% vs 13.2%) highlight the superior efficacy of this immunotherapy combination compared to tyrosine kinase inhibitors. Particularly noteworthy is the improved duration of response of 30.4 months versus 12.9 months with comparators, indicating more durable disease control.

While the safety profile shows serious immune-mediated adverse events including hepatitis (which is particularly concerning in HCC patients who often have underlying liver disease), the risk-benefit profile supports this approval. This represents a paradigm shift for HCC treatment, moving powerful immunotherapy combinations to the frontline setting where they can benefit more patients before disease progression limits therapeutic options.

Pharmaceutical Analyst

This approval significantly strengthens Bristol Myers Squibb's position in the liver cancer market by expanding Opdivo+Yervoy from second-line to first-line treatment for hepatocellular carcinoma. The conversion from accelerated to full approval, backed by robust Phase 3 data, provides greater competitive stability for these established immunotherapy assets.

Strategically, this approval increases the addressable patient population substantially, as first-line therapies capture the entire treatment-eligible market versus the smaller subset of patients who progress to second-line therapy. With liver cancer incidence tripling over four decades and approximately 42,240 new diagnoses expected in 2025, this represents a growing commercial opportunity.

The clinical differentiation is compelling - triple the response rate and substantially improved duration of response versus standard therapies provide strong arguments for adoption. This approval builds momentum for BMS's immuno-oncology franchise, marked by the company's note that this is their "second approval for Opdivo plus Yervoy in the gastrointestinal space this week alone," demonstrating execution on their strategy to expand these cornerstone products across multiple indications.

Based on the Phase 3 CheckMate-9DW trial, Opdivo plus Yervoy demonstrated a statistically significant overall survival benefit compared to investigator’s choice of lenvatinib or sorafenib¹

In the trial, 38% of patients were still alive at 3 years with this dual immunotherapy vs. 24% with the comparator arm¹

PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) approved Opdivo^® (nivolumab) plus Yervoy^® (ipilimumab) as a first-line treatment for adult patients with unresectable or metastatic hepatocellular carcinoma (HCC), the most common primary liver cancer.^1,2 This approval is based on the results from the global Phase 3 randomized, open-label CheckMate-9DW trial evaluating the combination of Opdivo plus Yervoy compared to investigator’s choice of tyrosine kinase inhibitor monotherapy (lenvatinib or sorafenib) in patients with unresectable or metastatic HCC who have not received prior systemic therapy.¹ In the trial, Opdivo plus Yervoy demonstrated statistically significant overall survival (OS) and overall response rate (ORR) vs the comparator arm.¹ It is the only trial supporting an FDA approval to show superior results against this comparator arm.¹

“The CheckMate-9DW approval is an important advancement for patients, considering the incidence of liver cancer has tripled in the last four decades, yet prognosis for HCC patients remains poor,” said Aiwu Ruth He, MD, PhD, a CheckMate-9DW study investigator while at MedStar Georgetown University Hospital.^3,4 “The availability of a new first-line treatment option that demonstrated a deep response can offer adults with this form of liver cancer long-term overall survival and may help address an unmet need.^1,5,6 Given the strength of evidence from the trial, especially considering the selection and performance of a strong comparator arm, I believe that Opdivo plus Yervoy has the potential to become a standard of care for the first-line treatment of patients with unresectable or metastatic HCC.”¹

In the CheckMate-9DW trial, in which 85% of patients in the comparator arm were treated with lenvatinib and 15% were treated with sorafenib, mOS with Opdivo plus Yervoy (n=335) was 23.7 months (95% CI: 18.8-29.4) vs. 20.6 months (95% CI: 17.5-22.5) with lenvatinib or sorafenib (n=333; HR=0.79; 95% CI: 0.65-0.96 P=0.0180), reducing the risk of death by 21%.¹ Opdivo plus Yervoy showed an OS rate of 38% at three years vs. 24% with lenvatinib or sorafenib monotherapy.¹ The trial also showed a deeper response with Opdivo plus Yervoy, demonstrating an ORR of 36.1% (95% CI: 31-41.5) compared to 13.2% (95% CI: 9.8-17.3; P<0.0001) of patients treated with lenvatinib or sorafenib (complete response 6.9% vs 1.8%; partial response 29.3% vs 11.4%).¹ Longer responses were seen with Opdivo plus Yervoy with a median duration of response (mDOR) of 30.4 months (95% CI: 21.2-NR) and 12.9 months (95% CI: 10.2-31.2) with lenvatinib or sorafenib.¹ DOR is not included in the statistical hierarchical testing and therefore is not a powered endpoint.¹ The safety profile with Opdivo plus Yervoy is well-established and there were no new safety signals identified.⁵

Opdivo plus Yervoy is 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.¹ Please see the Important Safety Information section below.

“Bringing Opdivo plus Yervoy to patients with HCC in the first-line setting is a testament to our ongoing commitment to research and delivering important progress for people living with cancer,” said Wendy Short Bartie, senior vice president of Oncology Commercialization at Bristol Myers Squibb. “Today’s approval builds on the legacy of our dual immunotherapy and the value it has brought to patients for years.¹ We are thrilled to add this indication for this important therapy – our second approval for Opdivo plus Yervoy in the gastrointestinal space this week alone – and look forward to providing a new first-line treatment option to patients in need.^”1

The combination of Opdivo plus Yervoy was previously granted accelerated approval by the U.S. FDA in 2020 based on results from the Phase 1/2 CheckMate-040 trial and has been an established second-line treatment for patients with advanced HCC who were previously treated with sorafenib.¹ Today’s FDA decision converts this existing indication to full approval and expands the indication into the first-line setting based on the results from the CheckMate-9DW trial.¹

About CheckMate-9DW
CheckMate-9DW is a Phase 3 randomized, open-label trial evaluating the combination of Opdivo^® (nivolumab) plus Yervoy^® (ipilimumab) compared to investigator’s choice of lenvatinib or sorafenib monotherapy in patients with unresectable or advanced hepatocellular carcinoma (HCC) who have not received prior systemic therapy.⁷ In the trial, 668 patients were randomized to receive Opdivo plus Yervoy IV infusion (Opdivo 1mg/kg with Yervoy 3mg/kg every three weeks for up to four doses, followed by Opdivo monotherapy 480mg every four weeks until disease progression, unacceptable toxicity or for a maximum duration of two years), or single agent lenvatinib (8mg orally daily, if body weight <60kg, or 12mg orally daily, if body weight ≥60kg) or sorafenib (400mg orally twice daily) in the control arm.^1,5 The primary endpoint of the trial is overall survival and key secondary endpoints include objective response rate and time to symptom deterioration.¹ The study was not designed to independently compare Opdivo plus Yervoy vs. lenvatinib or Opdivo plus Yervoy vs. sorafenib.¹

Select Safety Profile from CheckMate-9DW
The safety analysis in CheckMate-9DW included 657 patients, of whom 332 received Opdivo plus Yervoy.¹ Serious adverse reactions occurred in 53% of patients treated with Opdivo plus Yervoy.¹ 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 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%).¹ The most common adverse reactions reported in >20% of patients treated with Opdivo plus Yervoy were rash, pruritus, fatigue, and diarrhea. Fatal adverse reactions occurred in 12 (3.6%) patients who received Opdivo plus 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.¹ Permanent discontinuation due to an adverse reaction occurred in 27% of patients treated 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%), and hepatic failure (1.2%).¹

About Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is a type of primary liver cancer and is the most common form of liver cancer in adults.² Liver cancer is the sixth leading cause of cancer deaths in the United States.⁸ HCC is often diagnosed at an advanced stage and is usually associated with poor prognosis with limited effective treatment options.^5,9,10 About 42,240 people in the United Stated will be diagnosed and about 30,090 people will die of liver cancer in 2025.³ The incidence rates of liver cancer have tripled in the U.S. since 1980 and deaths have doubled since then.³ HCC typically develops in patients with hepatitis virus infection or cirrhosis.¹¹ While most cases of HCC are caused by hepatitis B virus or hepatitis C virus infections, metabolic syndrome and metabolic dysfunction-associated steatohepatitis are rising in prevalence and expected to contribute to increased rates of HCC.¹¹

INDICATIONS

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

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

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 or YERVOY 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 and YERVOY 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%). 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), 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), 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 nonexfoliative 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 or YERVOY and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO or YERVOY 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 and YERVOY 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% or 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 hepatoxicity (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. In CheckMate-40, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in ≥4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis.

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%). In CheckMate-040, the most common adverse reactions (≥20%) in patients receiving OPDIVO with YERVOY (n=49) were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%).

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

Clinical Trials and Patient Populations

CheckMate-9DW – hepatocellular carcinoma, in combination with YERVOY; CheckMate-040 – hepatocellular carcinoma, in combination with YERVOY, after prior treatment with sorafenib.

Bristol Myers Squibb: Creating a Better Future for People with Cancer
Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle.

Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About Bristol Myers Squibb’s Patient Access Support
Bristol Myers Squibb remains committed to providing assistance so that cancer patients who need our medicines can access them and expedite time to therapy.

BMS Access Support^®, the Bristol Myers Squibb patient access and reimbursement program, is designed to help appropriate patients initiate and maintain access to BMS medicines during their treatment journey. BMS Access Support offers benefit investigation, prior authorization assistance, as well as co-pay assistance for eligible, commercially insured patients. More information about our access and reimbursement support can be obtained by calling BMS Access Support at 1-800-861-0048 or by visiting www.bmsaccesssupport.com.

About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

About Bristol Myers Squibb
Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, X, YouTube, Facebook and Instagram.

Cautionary Statement Regarding Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, whether Opdivo^® (nivolumab) plus Yervoy^® (ipilimumab) for the additional indications described in this release will be commercially successful, any marketing approvals, if granted, may have significant limitations on their use, and that continued approval of combination treatment for such indications may be contingent upon verification and description of clinical benefit in confirmatory trials. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2024, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

References

1. Opdivo Prescribing Information. Opdivo U.S. Product Information. Last updated: April 2025. Princeton, NJ: Bristol Myers Squibb Company.
2. American Cancer Society. What is Liver Cancer? Available at https://www.cancer.org/cancer/types/liver-cancer/about/what-is-liver-cancer.html. Accessed February 21, 2025.
3. American Cancer Society. Key Statistics About Liver Cancer. Available at https://www.cancer.org/cancer/types/liver-cancer/about/what-is-key-statistics.html. Accessed February 21, 2025.
4. American Cancer Society. Liver Cancer Survival Rates. Available at https://www.cancer.org/cancer/types/liver-cancer/detection-diagnosis-staging/survival-rates.html. Accessed February 21, 2025.
5. Galle et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW. Journal of Clinical Oncology. 42, LBA4008-LBA4008(2024).
6. Finn et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382:1894-1905.
7. ClinicalTrials.gov: NCT04039607. A Study of Nivolumab in Combination With Ipilimumab in Participants With Advanced Hepatocellular Carcinoma. Available at https://clinicaltrials.gov/study/NCT04039607. Accessed February 21, 2025.
8. American Cancer Society. Cancer Facts and Figures 2025. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2025/2025-cancer-facts-and-figures-acs.pdf. Accessed February 21, 2025.
9. Abou-Alfa et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. N Engl J Med Evid. 2022;1(8).
10. American Cancer Association. Can Liver Cancer Be Found Early? Available at https://www.cancer.org/cancer/types/liver-cancer/detection-diagnosis-staging/detection.html. Accessed February 21, 2025.

11. American Cancer Society. Liver Cancer Risk Factors. Available at https://www.cancer.org/content/dam/CRC/PDF/Public/8699.00.pdf. Accessed February 21, 2025.

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FAQ

What are the survival rates for BMY's Opdivo plus Yervoy in HCC treatment?

The 3-year survival rate is 38% for Opdivo plus Yervoy compared to 24% with lenvatinib or sorafenib, with median overall survival of 23.7 months versus 20.6 months.

What is the response rate for BMY's Opdivo plus Yervoy in liver cancer?

The overall response rate is 36.1% for Opdivo plus Yervoy compared to 13.2% for lenvatinib or sorafenib, with complete response rates of 6.9% vs 1.8%.

What are the main side effects of BMY's Opdivo plus Yervoy treatment?

Common side effects include rash, pruritus, fatigue, and diarrhea. Serious adverse reactions occurred in 53% of patients, with liver-related serious adverse reactions in 17%.

How does BMY's new FDA approval change Opdivo plus Yervoy's status?

The approval converts the 2020 accelerated approval to full approval and expands the indication to first-line treatment for unresectable or metastatic HCC.