Frontline Nivolumab Plus Ipilimumab Improves Overall Survival for Unresectable Hepatocellular Carcinoma

According to first results from the phase 3 CheckMate 9DW, nivolumab plus ipilimumab showed a statistically significant improvement to overall survival (OS) when compared to lenvatinib or sorafenib among patients with previously untreated unresectable hepatocellular carcinoma (HCC).

These data were first reported by Peter Robert Galle, MD, PhD, University Medical Center Mainz, Germany, at the 2024 ASCO Annual Meeting.

In his presentation at the meeting, Dr Galle noted that treatment for this patient population with tyrosine kinase inhibitors (TKI) had “modest efficacy and issues on tolerability” and, “major improvement” was seen with PD-L1 inhibitor-based regimens, “80% to 70% [of patients are] non-responders. He stated, therefore, “There is clearly an unmet medical need for further…systemic treatment in the frontline setting of hepatocellular carcinoma.”

In this phase 3, open-label, randomized trial, 668 patients with previously untreated HCC who were not eligible for curative surgical or locoregional therapies were enrolled. Patients were randomized on a 1-to-1 basis to receive either 1 mg/kg of nivolumab plus 3 mg/kg ipilimumab once every 3 weeks for up to 4 cycles followed by 480 mg of nivolumab once every 4 weeks (nivolumab-ipilimumab arm, n = 335), or investigator’s choice of 8 mg or 12 mg lenvatinib once daily or 400 mg sorafenib twice daily (TKI arm, n = 333). Novlumab was given for a maximum of 2 years. The primary end point of this study is OS, with secondary end points including objective response rate (ORR) and duration of response (DOR) as evaluated by blinded independent central review (BICR).

This prespecified interim analysis occurred with a median follow-up duration of 35.2 months. The median OS was 23.7 months in the nivolumab-ipilimumab arm vs 20.6 months in the TKI arm (hazard ratio [HR], 0.79; P = .0180). The 24-month OS rates were 49% and 39%, respectively. The ORR was 36% in the nivolumab-ipilimumab arm vs 13% in the TKI arm (P < .0001), with 7% and 2% achieving a complete response, respectively. The median DOR was 30.4 months in the nivolumab-ipilimumab arm vs 12.9 months in the TKI arm.

Additionally, at the 24-month landmark timepoint the survival benefit seen with nivolumab plus ipilumab was consistent across all best overall response subgroups. The ORR was higher across different subgroups, including all HCC etiologies and among patients with Barcelona Clinic Liver Cancer stage ≤B  or stage C.

There were 657 patients included in the safety analysis (ipilimumab-nivolumab arm, n = 332; TKI arm, n = 325). Any grade treatment-related adverse events occurred in 84% of patients in the ipilimumab arm and 91% of patients in the TKI arm, while grade 3/4 treatment-related adverse events occurred in 41% and 42% respectively. There were 18% of patients in the ipilimumab-nivolumab arm who discontinued treatment due to a treatment-related adverse event vs 10% in the TKI arm.

In his presentation, Dr Galle concluded that nivolumab plus ipilimumab demonstrated a “statistically significant and clinically meaningful OS benefit [and] ORR benefit” compared to lenvatinib or sorafenib in this patient population, as well as “higher [complete response] rate and durable responses.” The PFS rates were numerically higher in the ipilimumab-nivolumab arm and there was a significantly reduced risk of symptom deterioration with a trend toward improvement of health-related quality of life.

In an interview with Oncology Learning Network during the 2024 ASCO Annual Meeting, Dr Galle remarked, “We believe that this trial and this combination, ipilimumab and nivolumab, in front-line for advanced stage hepatocellular carcinoma patients will be a new option added to what we already have.”

Sources:

Galle PR, Decaens T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW. J Clin Oncol. 2024;42(17_suppl). doi:10.1200/JCOP.2024.42.17_suppl.LBA4008

Galle PR. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW. Presented at 2024 ASCO Annual Meeting. May 31-June 4, 2024; Chicago, IL. Abstract LBA 4008.

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(4_suppl). doi: 10.1200/JCO.2025.43.4_suppl.520.

Galle PR. Nivolumab Plus Ipilimumab as Potential New Frontline Option for Patients With Unresectable Hepatocellular Carcinoma. Oncology Learning Network; 2024. https://www.hmpgloballearningnetwork.com/site/onc/conference-coverage/nivolumab-plus-ipilimumab-potential-new-frontline-option-patients