Among patients with unresectable hepatocellular carcinoma (uHCC), the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) significantly improves overall survival (OS) and offers manageable safety, according to findings from the CheckMate 9DW study, presented at the 2025 Gastrointestinal Cancers Symposium.
For overall survival (OS), the combination of Opdivo plus Yervoy showed a significant improvement in median OS compared with Lenvima (lenvatinib) or Nexavar (sorafenib) at 23.7 versus 20.6 months, respectively. Opdivo with Yervoy also demonstrated a significantly higher overall response rate (ORR) at 36% compared with the Lenvima plus Nexavar combination at 13%.
At the 24-week landmark, the median OS for patients with complete or partial responses (101 patients) was not reached, indicating superior survival outcomes versus those with stable disease (105 patients) or progressive disease (47 patients).
The risk of disease progression was 14% lower for patients with complete or partial response compared to those with progressive disease in the Opdivo plus Yervoy group. For patients with stable disease compared to those with progressive disease, the risk of disease progression was 40% lower.
Glossary:
Overall Survival (OS): the length of time from diagnosis or treatment initiation that a patient with cancer is still alive
Overall Response Rate (ORR): the percentage of patients whose cancer shrunk or disappeared after treatment.
Complete Response: there are no longer any detectable signs of cancer in the patient’s body.
Partial Response: treatment caused a significant decrease in tumor size, but the cancer has not completely disappeared.
Progressive Disease: the tumor is growing or spreading.
Stable Disease: the tumor is neither shrinking nor growing.
Immune-mediated hepatitis: liver inflammation caused by a dysregulation of the body’s immune system.
In both treatment groups, the ORR was associated with improved OS outcomes. The risk of disease progression was 55% lower for patients with complete or partial response compared to those with progressive disease in the Lenvima plus Nexavar group. For patients with stable disease compared to those with progressive disease, the risk of disease progression was 31% lower.
The median duration of response (DOR) for Opdivo plus Yervoy was significantly longer at 30.4 months compared with 12.9 months for Lenvima or Nexavar. The survival benefit of the Opdivo plus Yervoy combination was consistent across various subgroups, including different HCC etiologies and disease stages.
“In CheckMate 9DW, [Opdivo plus Yervoy] demonstrated clinical benefit in terms of improving OS, higher objective response rate, and higher CR rate, and also acceptable safety profile,” Dr. Masatoshi Kudo, professor and chairman, Department of Gastroenterology and Hepatology, Kindai University, Osaka, Japan, stated in the presentation.
The safety profile of Opdivo and Yervoy was consistent with prior studies, with side effects generally manageable and no new safety signals identified.
The majority of treatment-related side effects were grade 1 (mild) or 2 (moderate) and did not lead to treatment discontinuation. Though 12 patients had treatment-related deaths, most in the Opdivo and Yervoy group (9 patients) occurred in patients with severe and underlying liver disease. Disease progression was confirmed in one patient and was suspected in three additional patients.
Among side effects, immune-mediated hepatitis occurred in 2% of patients receiving Opdivo and Yervoy, while high levels of bilirubin in the blood were observed in 2% of those receiving Lenvima and Nexavar. Hypertension occurred in 2% of patients in the Opdivo plus Yervoy group and 41% of patients receiving Lenvima plus Nexavar. Bleeding events were rare (less than 1%) in the Opdivo plus Yervoy group, while nosebleeds occurred in 4% of the Lenvima plus Nexavar group.
In August 2024, the FDA accepted the supplemental biologics license application of Opdivo and Yervoy for the first-line treatment of uHCC, and a Prescription Drug User Fee Act target action date of April 21, 2025, was set.
CheckMate 9DW is a phase 3, randomized-controlled trial evaluating the combination of Opdivo, a PD-1 inhibitor, and Yervoy, a CTLA-4 inhibitor, in patients with uHCC. The trial aimed to assess the clinical benefit of Opdivo and Yervoy compared with the standard-of-care tyrosine kinase inhibitors Lenvima and Nexavar in this challenging population.
Patients were randomized to receive Opdivo plus Yervoy every three weeks for up to four cycles, followed by Opdivo every four weeks, or Lenvima daily, or Nexavar twice daily. Opdivo was administered for a maximum of two years. Treatment continued until disease progression or unacceptable toxicity.
The primary end point was OS and secondary end points were ORR, DOR, safety and time to symptom deterioration with response.
“These results support Opdivo and Yervoy as a new first-line standard of care for patients with unresectable HCC,” said Kudo.
References:
- “Nivolumab (NIVO) plus ipilimumab (IPI) versus Lenvima (LEN) or Nexavar (SOR) as first-line (1L) therapy for unresectable hepatocellular carcinoma (uHCC): CheckMate 9DW expanded analyses.” Kudo M, et al. J Clin Oncol. suppl.520
- “Bristol Myers Squibb receives U.S. Food and Drug Administration sBLA acceptance for first-line treatment of unresectable hepatocellular carcinoma.” News release. Bristol Myers Squibb.
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