Frontline Nivolumab/Ipilimumab Prolongs OS in Unresectable HCC

Treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) produced a statistically significant and clinically meaningful overall survival (OS) benefit compared with lenvatinib (Lenvima) or sorafenib (Nexavar) in patients with unresectable hepatocellular carcinoma (HCC) who were naive to systemic therapy, according to data from the phase 3 CheckMate 9DW study (NCT04039607) that were presented at the 2025 Gastrointestinal Cancers Symposium.1

The combination of nivolumab plus ipilimumab generated a median OS of 23.7 months vs 20.6 months with lenvatinib or sorafenib (HR, 0.79; 95% CI, 0.65-0.96; P = .018). Nivolumab plus ipilimumab also induced a a significantly higher overall response rate (ORR) of 36% compared with 13% in the lenvatinib/sorafenib arm (P < .0001).

At the 24-week landmark analysis, the median OS for patients in the nivolumab plus ipilimumab arm with complete response (CR) or partial response (PR; n = 101) was not reached, indicating superior survival outcomes vs in those with stable disease (SD; n = 105) or progressive disease (PD; n = 47). In the nivolumab/ipilimumab arm, the hazard ratio (HR) for CR or PR vs PD was 0.14 (95% CI, 0.08-0.24), and for SD vs PD, the HR was 0.40 (95% CI, 0.26-0.60).

In both treatment arms, the ORR, assessed by blinded independent central review (BICR), was associated with improved OS outcomes. In the lenvatinib/sorafenib arm, the HR for CR or PR vs PD was 0.45 (95% CI, 0.23-0.86), and for SD vs PD, the HR was 0.69 (95% CI, 0.45-1.08).

The median duration of response (DOR) was significantly longer for nivolumab plus ipilimumab vs lenvatinib or sorafenib at 30.4 months (95% CI, 21.2-not evaluable) compared with 12.9 months (95% CI, 10.2-31.2). The survival benefit seen with the nivolumab/ipilimumab combination was consistent across various subgroups, including different HCC etiologies and disease stages.

“In CheckMate 9DW, nivolumab/ipilimumab demonstrated clinical benefit in terms of [improved] OS, higher ORR, and higher CR rate, and also an acceptable safety profile,” Masatoshi Kudo, MD, PhD, professor and chairman in the Department of Gastroenterology and Hepatology at Kindai University in Osaka, Japan, stated in the presentation.

In August 2024, the FDA accepted the supplemental biologics license application seeking the approval of nivolumab plus ipilimumab for the first-line treatment of adult patients with unresectable HCC, and a Prescription Drug User Fee Act target action date of April 21, 2025, was set.2

CheckMate 9DW is a phase 3, randomized, controlled trial evaluating the combination of nivolumab, a PD-1 inhibitor, and ipilimumab, a CTLA-4 inhibitor, in patients with unresectable HCC.1 The trial assessed the clinical benefit of nivolumab plus ipilimumab compared with the standard of care (SOC) TKIs lenvatinib and sorafenib.

Eligible patients were adults with untreated, unresectable HCC, a Child-Pugh score of 5 or 6, and an ECOG performance status of 0 or 1. Key exclusion criteria included prior systemic therapy for HCC and any prior locoregional or surgical therapy with curative intent.

Patients were randomly assigned in a 1:1 ratio to receive nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for up to 4 cycles followed by nivolumab at 480 mg every 4 weeks; or lenvatinib at 8 mg or 12 mg daily or sorafenib at 400 mg twice daily. Nivolumab was administered for a maximum of 2 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 assessed by BICR using RECIST 1.1 criteria. Key exploratory end points were progression-free survival and safety.

The safety profile of nivolumab plus ipilimumab was consistent with data from prior studies, with adverse effects (AEs) generally manageable and no new safety signals identified.

Most treatment-related AEs were grade 1 or 2 and did not lead to treatment discontinuation. Although 12 patients had treatment-related deaths, most deaths in the nivolumab plus ipilimumab group (n = 9) occurred in patients with severe and underlying liver disease. Disease progression per BICR was confirmed in 1 patient and was suspected in 3 additional patients.

Among AEs, immune-mediated hepatitis occurred in 2% of patients receiving nivolumab plus ipilimumab, whereas hyperbilirubinemia was observed in 2% of those receiving lenvatinib or sorafenib. Hypertension occurred in 2% of patients in the nivolumab plus ipilimumab arm and 41% of patients receiving lenvatinib or sorafenib. Hemorrhagic events were rare (< 1%) in the nivolumab plus ipilimumab arm, whereas epistaxis occurred in 4% of the lenvatinib or sorafenib group.

“These results support nivolumab [plus] ipilimumab as a new first-line SOC for patients with unresectable HCC,” said Kudo.

References

1. 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
2. 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 24, 2025. https://news.bms.com/news/corporate-financial/2024/Bristol-Myers-Squibb-Receives-U.S.-Food-and-Drug-Administration-sBLA-Acceptance-for-First-Line-Treatment-of-Unresectable-Hepatocellular-Carcinoma/default.aspx