Nivolumab Plus Ipilimumab Receives EC Approval for First-Line Unresectable HCC

The European Commission (EC) has approved nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the frontline treatment of adult patients with unresectable or advanced hepatocellular carcinoma (HCC).1

The regulatory decision was supported by findings from the phase 3 CheckMate 9DW trial (NCT04039607), which compared nivolumab plus ipilimumab vs lenvatinib (Lenvima) or sorafenib (Nexavar) monotherapy in patients with treatment-naive unresectable HCC. Updated data from the study presented during the 2025 Gastrointestinal Cancers Symposium demonstrated that at a median follow-up of 35.2 months (range, 26.8-48.9), patients who received the combination (n = 335) achieved a median overall survival (OS) of 23.7 months (95% CI, 18.8-29.4) compared with 20.6 months (95% CI, 17.5-22.5) for those treated in the control arm (n = 333; HR, 0.79; 95% CI, 0.65-0.96; P = .018).2 The 24-month OS rates were 49% (95% CI, 44%-55%) vs 39% (95% CI, 34%-45%), respectively, and the 36-month rates were 38% (95% CI, 32%-43%) vs 24% (95% CI, 19%-30%), respectively.

“The EC’s approval for [nivolumab] plus [ipilimumab] adds to the growing body of evidence demonstrating the value of dual immunotherapy and represents an important new treatment option that may extend survival for patients with HCC,” Dana Walker, MD, MSCE, vice president and Opdivo global program lead at Bristol Myers Squibb, stated in a news release.1 “This approval marks a critical milestone in our commitment to improving outcomes for patients with liver cancer. We look forward to bringing this new first-line treatment option to patients in the European Union.”

In August 2024, the FDA accepted a supplemental biologics license application (sBLA)seeking the approval of nivolumab plus ipilimumab for the first-line treatment of adult patients with unresectable HCC.3 The sBLA was also supported by data from CheckMate 9DW; the Prescription Drug User Fee Act goal date is April 21, 2025.

Details of CheckMate 9DW

CheckMate 9DW was a global, open-label study that enrolled patients with unresectable HCC who were naive to systemic therapy and had at least 1 measurable lesion per RECIST 1.1 criteria.2 Eligible patients also needed to have a Child-Pugh score of 5 or 6; an ECOG performance status of 0 or 1; and no main portal invasion.

Eligible patients were randomly assigned 1:1 to receive nivolumab plus ipilimumab or investigator’s choice of lenvatinib or sorafenib. Nivolumab was administered intravenously (IV) at a dose of 1 mg/kg in combination with IV ipilimumab at a dose of 3 mg/kg every 3 weeks for up to 4 cycles, followed by 480 mg of nivolumab every 4 weeks. In the control arm, patients received oral lenvatinib at a dose of 8 mg or 12 mg once daily or 400 mg of oral sorafenib twice daily.

The primary end point was OS; secondary end points included overall response rate (ORR) and duration of response (DOR) by blinded independent central review (BICR) per RECIST 1.1 criteria. Progression-free survival by BICR per RECIST 1.1 criteria and safety represented key exploratory end points.

Additional efficacy data from CheckMate 9DW revealed the ORR in the combination arm was 36% (95% CI, 31%-42%), including a complete response (CR) rate of 7%, compared with an ORR of 13% (95% CI, 10%-17%) and a 2% CR rate in the control arm (P < .0001). The median DOR was 30.4 months (95% CI, 21.2-not evaluable) compared with 12.9 months (95% CI, 10.2-31.2), respectively.

Any-grade treatment-related adverse effects (TRAEs) occurred in 84% of patients in the combination arm (n = 332) compared with 91% of patients in the control arm (n = 325). Grade 3 or 4 TRAEs (41% vs 42%, respectively), any-grade serious TRAEs (28% vs 14%), and grade 3 or 4 serious TRAEs (25% vs 13%) were reported in both arms. Treatment-related deaths occurred in 12 patients in the combination arm compared with 3 in the control arm.

The EC’s approval of the combination of nivolumab plus ipilimumab is valid in all 27 member states of the European Union, as well as Iceland, Liechtenstein, and Norway.1

References

1. Bristol Myers Squibb receives European Commission approval for Opdivo (nivolumab) plus Yervoy (ipilimumab) for the first-line treatment of adult patients with unresectable or advanced hepatocellular carcinoma. News release. Bristol Myers Squibb. March 7, 2025. Accessed March 7, 2025. https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-Receives-European-Commission-Approval-for-Opdivo-nivolumab-plus-Yervoy-ipilimumab-for-the-First-Line-Treatment-of-Adult-Patients-with-Unresectable-or-Advanced-Hepatocellular-Carcinoma/default.aspx
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. Bristol Myers Squibb receives US Food and Drug Administration sBLA acceptance for first-line treatment of unresectable hepatocellular carcinoma. News release. Bristol Myers Squibb. August 21, 2024. Accessed March 7, 2025. https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Receives-U.S.-Food-and-Drug-Administration-sBLA-Acceptance-for-First-Line-Treatment-of-Unresectable-Hepatocellular-Carcinoma/default.aspx