Efficacy Data Support Nivolumab/Ipilimumab as First-Line HCC Treatment

Nivolumab plus ipilimumab elicited a median OS of 23.7 months vs 20.6 months with lenvatinib or sorafenib in patients with previously untreated, advanced HCC.

Nivolumab (Opdivo) plus ipilimumab (Yervoy) significantly improved overall survival (OS) when compared with lenvatinib (Lenvima) or sorafenib (Nexavar) in patients with previously untreated hepatocellular carcinoma (HCC), according to results from the phase 3 CheckMate 9DW trial (NCT04039607) published in The Lancet.¹

With a median follow-up of 35.2 months (IQR, 31.1-39.9), the median OS with nivolumab plus ipilimumab was 23.7 months (95% CI, 18.9-29.4) vs 20.6 months (95% CI, 17.5-22.5) with lenvatinib or sorafenib (HR, 0.79; 95% CI, 0.65-0.96; P = .018). The respective 24-month OS rates were 49% (95% CI, 44%-55%) and 39% (95% CI, 34%-45%), and the respective 36-month OS rates were 38% (95% CI, 32%-43%) and 24% (95% CI, 19%-30%).

Across all relevant subgroups, nivolumab plus ipilimumab was superior to lenvatinib or sorafenib regarding OS, according to exploratory subgroup analyses.

In a prespecified analysis of piecewise HRs, there was an increased risk of death with nivolumab plus ipilimumab vs with lenvatinib or sorafenib within the first 6 months of randomization (HR, 1.65; 95% CI. 1.12-2.43). Thereafter, a reversed trend was observed (HR, 0.61; 95% CI, 0.48-0.77).

“In CheckMate 9DW, nivolumab plus ipilimumab showed a significant OS benefit over lenvatinib or sorafenib in patients with unresectable HCC who had not received previous systemic treatment for advanced disease,” lead study author Masatoshi Kudo, MD, PhD, a professor and chairman in the Department of Gastroenterology and Hepatology at Kindai University Faculty of Medicine, as well as an executive board member of Kindai University, wrote with fellow authors in the paper.¹ “These results support nivolumab plus

ipilimumab as a first-line treatment option for patients with unresectable HCC.”

The trial randomly assigned a total of 668 patients, in a 1:1 ratio, to receive nivolumab plus ipilimumab (n = 335) or lenvatinib or sorafenib (n = 333). Treatment was administered as follows: 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab intravenously every 3 weeks for up to 4 doses, then 480 mg of nivolumab monotherapy every 4 weeks, or 8 mg or 12 mg of lenvatinib daily (8 mg if bodyweight <60 kg and 12 mg otherwise) or 400 mg of oral sorafenib twice daily.

Eligible patients were 19 years or older with histologically confirmed HCC that was ineligible for curative surgical or locoregional therapy or that progressed after surgical or locoregional therapy. Additionally, patients had not received prior systemic therapy for advanced HCC, had 1 or more measurable untreated lesion per RECIST v1.1, a Child-Pugh score of 5 or 6, and an ECOG performance status of 0 or 1.

Exclusion criteria include prior liver transplant; episodes of hepatic encephalopathy within 12 months of randomization; clinically significant ascites; and known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.

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

The ORR was 36% (95% CI, 31%-42%) in the nivolumab plus ipilimumab group and 13% (95% CI, 10%-17%) in the lenvatinib or sorafenib group (P <.0001); 7% and 2% of patients, respectively, achieved complete responses, 29% and 11% achieved partial responses, 32% and 62% achieved stable disease; 20% and 14% had progressive disease, and 12% and 11% could not be evaluated.

The median DOR was 30.4 months (95% CI, 21.2-not estimable) with nivolumab plus ipilimumab and 12.9 months (95% CI, 10.2-31.2) with lenvatinib or sorafenib; DOR was 24 months or greater in 55% (95% CI, 44%-64%) and 35% of patients (95% CI, 17%-53%), respectively, and was 36 months or greater in 47% (95% CI, 34%-59%) and not applicable.

The median time to first symptom deterioration measured by hepatobiliary cancer subscale score was 2.6 months (95% CI, 2.0-3.9) with nivolumab plus ipilimumab and 2.1 months (95% CI, 1.6-2.8) with lenvatinib or sorafenib; there was a significantly reduced risk of symptom deterioration with nivolumab plus ipilimumab (HR, 0.76; 95% CI, 0.62-0.93; P = .0059).

Treatment-related adverse events (TRAEs) of any grade occurred in 84% of the nivolumab plus ipilimumab arm and 91% of the lenvatinib or sorafenib arm; TRAEs of grade 3 or 4 occurred in 41% and 42%, respectively. Any grade TRAEs led to treatment discontinuation in 18% and 10%, and death in 12 patients and 3 patients. The most common TRAEs of grade 3 or 4 in the nivolumab plus ipilimumab group were aspartate aminotransferase increased (6%), alanine aminotransferase increased (5%), and lipase increased (5%).

Previously, based on results from this trial, the FDA approved nivolumab plus ipilimumab in the first-line treatment of unresectable or metastatic HCC.²

References

1. Yau T, Galle PR, Decaens T, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet. Published online May 7, 2025. doi:10.1016/S0140-6736(25)00403-9
2. FDA approves nivolumab with ipilimumab for unresectable or metastatic hepatocellular carcinoma. News release. FDA. April 11, 2025. Accessed April 11, 2025. https://tinyurl.com/zhu43eyb