EC Approves Nivolumab/Ipilimumab in Frontline Unresectable HCC

Nivolumab (Opdivo) plus ipilimumab (Yervoy) has been approved by the European Commission in the first-line treatment of adult patients with unresectable or advanced hepatocellular carcinoma (HCC), according to a press release from the developer, Bristol Myers Squibb.¹

When compared with investigators choice of lenvatinib (Lenvima) or sorafenib (Nexavar), nivolumab/ipilimumab demonstrated clinically meaningful and statistically significant improvements in overall survival (OS) with a median OS of 20.6 months vs 23.7 months, respectively, (HR, 0.79; 95% CI, 0.65-0.96; P = .018).²

Previously, in February 2025, the treatment combination was recommended for approval in this population by the Committee for Medicinal Products.³ In August 2024, the FDA accepted a supplemental biologics license application for the combination in HCC.⁴

Supporting results come from the randomized, multicenter phase 3 CheckMate 9DW trial (NCT04039607) that evaluated nivolumab plus ipilimumab vs standard of care in the first-line treatment of HCC. Updated results were shared at the 2025 Gastrointestinal Cancer Symposium.²

“The European Commission’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 nivolumab global program lead at Bristol Myers Squibb, stated in the press 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.”

The trial enrolled a total of 668 patients who were randomly assigned, in a 1:1 ratio, to receive either 1 mg/kg of intravenous nivolumab plus 3 mg/kg of intravenous ipilimumab once every 3 weeks for up to 4 cycles then 480 mg of nivolumab every 4 weeks or investigators choice of 8 mg or 12 mg of daily, oral lenvatinib or 400 mg of oral sorafenib every other day.

Eligible patients had unresectable HCC with at least 1 measurable lesion who were systemic therapy naïve. Additionally, patients had a Child-Pugh score of 5 or 6, an ECOG performance status of 0 or 1, and no main portal invasion.

The trial’s primary end point was OS. Key secondary end points were overall response rate (ORR), duration of response (DOR), and time to symptom deterioration.

The ORR was 36.1% (95% CI, 31.0%-41.5%) with the treatment combination and 13.2% (95% CI, 9.8%-17.3%) with standard of care (P <.0001); the median time to response was 2.2 months (95% CI, 1.1-11.6) and 3.7 months (95% CI, 0.6-11.2), respectively; and the median duration of response was 30.4 months (95% CI, 21.2-not evaluable [NE]) and 12.9 months (95% CI, 19.2-31.2).

In patients who experienced a complete or partial response, the median OS was not reached (95% CI, 44.4-NE) for the combination arm and 28.3 months (95% CI, 20.6-NE); in patients who had stable disease, median OS was 30.0 months (95% CI, 23.5-37.8) and 22.5 months (95% CI, 20.5-24.8); and in patients with progressive disease, the median OS was 16.0 months (95% CI, 12.0-18.7) and 13.5 months (95% CI, 8.7-23.5).

The 24-month and 36-month OS rates were 49% (95% CI, 44%-55%) and 38% (95% CI, 32%-43%) in the combination treatment arm compared with 39% (95% CI, 34%-45%) and 24% (95% CI, 19%-30%), respectively.

Regarding safety, treatment-related adverse events (TRAEs) of any grade and grade 3 or higher occurred in 84% and 41% of the combination arm and 91% and 42% in the standard of care arm; serious TRAEs occurred in 28% vs 14%, respectively. TRAEs led to discontinuation for 18% of patients and 10% of patients, respectively, and treatment related deaths occurred in 12 patients (4%) and 3 patients (< 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://tinyurl.com/23zrh4vz
2. 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 March 7, 2025. https://tinyurl.com/5d37fpsf
3. 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 March 7, 2025. https://tinyurl.com/hjwjrbbx
4. 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