Nivolumab Combo Earns Positive CHMP Opinion in Advanced Liver Cancer

The FDA accepted a supplemental biologic license application for first-line nivolumab/ipilimumab as a treatment for patients with unresectable HCC in August 2024.

The European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion in support of approving frontline nivolumab (Opdivo) plus ipilimumab (Yervoy) for adults with advanced or unresectable hepatocellular carcinoma (HCC) in the European Union, according to a press release from the developer, Bristol Myers Squibb.¹

The CHMP based its opinion on findings from the phase 3 CheckMate 9DW trial (NCT04039607), which assessed nivolumab/ipilimumab vs investigator’s choice of lenvatinib (Lenvima) or sorafenib (Nexavar) in patients who were previously untreated with advanced or unresectable HCC. The European Commission will now review the CHMP’s opinion on approving the nivolumab combination for this patient population.

Updated results from the 2025 ASCO Gastrointestinal Cancers Symposium showed that the median overall survival (OS) was 23.7 months with nivolumab/ipilimumab vs 20.6 months with investigator’s choice of chemotherapy (HR, 0.79; 95% CI, 0.65-0.96; P = .018).² Additionally, the objective response rate (ORR) was 36% vs 13% in each respective arm (P <.0001).

Data highlighted a median duration of response (DOR) of 30.4 months (95% CI, 21.2-not evaluable [NE]) in the nivolumab/ipilimumab arm and 12.9 months (95% CI, 10.2-31.2) in the comparator arm. Investigators noted that survival benefits with the nivolumab combination extended across subgroups based on factors such as HCC etiology and disease stage.

Safety data showed that adverse effects (AEs) were typically manageable in the study population; investigators observed no new safety signals. Immune-mediated hepatitis affected 2% of those in the nivolumab/ipilimumab arm, while hyperbilirubinemia occurred in 2% of the comparator arm. Hypertension was reported in 2% and 41% of patients in each respective arm.

“[HCC] is the predominant type of liver cancer globally, including in the [EU], and when diagnosed at the advanced or unresectable stage, prognosis and [OS] remain sub-optimal with conventional therapy,” Dana Walker, MD, MSCE, vice president and nivolumab global program lead at Bristol Myers Squibb, stated in the press release.¹ “The positive opinion received by the CHMP is a significant step forward in providing patients with additional treatment options, and we look forward to the upcoming European Commission review and the potential to expand the treatment landscape for adult patients with unresectable or advanced [HCC].”

In the open-label phase 3 CheckMate 9DW trial, approximately 668 patients were randomly assigned to receive nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg once every 3 weeks for a maximum of 4 doses followed by nivolumab monotherapy at 480 mg every 4 weeks or lenvatinib or sorafenib monotherapy.

The trial’s primary end point was OS. Secondary end points included ORR, DOR, and time to symptom deterioration.³

Patients 18 years and older with histologically confirmed advanced HCC and 1 or more measurable lesions per RECIST v1.1 criteria were eligible for enrollment on the trial. Other requirements for study entry included having a Child-Pugh score of 5 or 6 and an ECOG performance status of 0 or 1.

Those with fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC histology were ineligible for enrollment on the trial. Patients were also unable to enroll if they had prior liver transplant, grade 2 or higher hepatic encephalopathy within 12 months before randomization, and active brain metastases or leptomeningeal metastases.

The FDA accepted a supplemental biologic license application for first-line nivolumab/ipilimumab as a treatment for patients with unresectable HCC in August 2024.⁴ Supporting data for the application came from the phase 3 CheckMate 9DW trial.

References

1. Bristol Myers Squibb receives positive CHMP opinion for Opdivo® (nivolumab) plus Yervoy® (ipilimumab) as a first-line treatment option for adult patients with unresectable or advanced hepatocellular carcinoma. News release. Bristol Myers Squibb. January 31, 2025. Accessed January 31, 2025. https://tinyurl.com/5d37fpsf
2. Kudo M, Yau T, Decaens T, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) therapy for unresectable hepatocellular carcinoma (uHCC): CheckMate 9DW expanded analyses. J Clin Oncol. 2025;43(suppl 4):520. doi:10.1200/JCO.2025.43.4_suppl.520
3. A study of nivolumab in combination with ipilimumab in participants with advanced hepatocellular carcinoma (CheckMate 9DW). Clinicaltrials.gov. Updated May 2, 2024. Accessed January 31, 2025. https://tinyurl.com/mrskbku7
4. 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. August 21, 2024. Accessed January 31, 2025. https://tinyurl.com/hjwjrbbx