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Nivolumab Plus Ipilimumab Demonstrates Long-Term Survival Benefit in Patients with Advanced HCC Who Were Sorafenib Intolerant or Refractory

5-year results from the CheckMate 040 study
28 May 2024
Hepatobiliary Cancers

At a minimum follow-up of 60 months in the CheckMate 040 study, longest duration of follow-up reported for an immunotherapy combination in previously treated patients with advanced hepatocellular carcinoma (HCC), the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit in patients who were sorafenib intolerant or refractory.

Responses were deep and durable across treatment arms, with a median duration of response (DoR) of 51.2 months in arm A. Among the three dosing regimens, arm A continued to demonstrate the highest survival benefit with a median overall survival (OS) of 22.2 months and a landmark 5-year OS rate of 29%. No new safety signals were identified. The findings are reported by Prof. Ignacio Melero of the Clinica Universidad de Navarra and CIBERONC in Pamplona, Spain and colleagues who published the findings on 22 May 2024 in the Annals of Oncology.

The first-line standard of care in advanced HCC includes immunotherapy-based regimens and tyrosine kinase inhibitors such as sorafenib. In patients whose cancer progresses following first-line treatment with sorafenib, subsequent-line systemic treatment options for Child–Pugh class A disease are regorafenib, cabozantinib, and ramucirumab (in patients with AFP ≥400 ng/ml only); however, OS following these therapies is poor. In the US, the combination of nivolumab with ipilimumab, and pembrolizumab monotherapy are also approved as subsequent-line treatment options for Child–Pugh A disease.

The authors wrote in the background that different doses and schedules of nivolumab plus ipilimumab were evaluated in patients with advanced HCC who were intolerant to or progressed on sorafenib in CheckMate 040 study. With a median follow-up of 30.7 months, the arm A regimen of nivolumab plus ipilimumab followed by nivolumab until intolerance or disease progression demonstrated durable clinical benefit with an objective response rate (ORR) of 32% (95% confidence interval [CI] 20%-47%] and median OS of 22.8 months (95% CI 9.4-not reached).

Based on these results, the arm A regimen of nivolumab plus ipilimumab has been approved in the US for patients with advanced HCC previously treated with sorafenib. At a minimum follow-up of 44 months, nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefits in advanced HCC. In the latest article published in the Annals of Oncology, the study team presents the 5-year results of efficacy, safety, and exploratory biomarker analyses from this cohort of the CheckMate 040 study.

Patients were randomised 1:1:1 to arm A (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses) or arm B (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses), each followed by nivolumab 240 mg every 2 weeks, or arm C (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks). The primary objectives were safety, tolerability, investigator-assessed ORR and DoR per RECIST v1.1.

A total of 148 patients were randomised across treatment arms. At 60-month minimum follow-up with 62.6-month of median follow-up, the ORR was 34%, 27%, and 29% in arms A, B, and C. The median DoR was 51.2 months (95% CI 12.6-not estimable [NE]), 15.2 months (95% CI 7.1-NE), and 21.7 months (95% CI 4.2-NE).

The median OS was 22.2 months (95% CI 9.4-54.8) in arm A, 12.5 months (95% CI 7.6-16.4) in arm B, and 12.7 months (95% CI 7.4-30.5) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus non-responders for all arms.

No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis.

The authors emphasized that a separation of the OS curve of arm A from those of arms B and C that was observed in the primary analysis continued with long-term follow-up. The observed long-term clinical benefit of nivolumab plus ipilimumab reported in this analysis is consistent with reports in other solid tumours. A randomised phase III CheckMate 9DW study comparing first-line nivolumab plus ipilimumab versus lenvatinib or sorafenib in advanced HCC is in progress.

The study was supported by Bristol Myers Squibb, Princeton, NJ, US. Dako (an Agilent Technologies, Inc. Company, Santa Clara, CA, US) was acknowledged for the collaborative development of the PD-L1 IHC 28-8 pharmDx assay.


Melero I, Yau T, Kang Y-K, et al. Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040. Annals of Oncology; Published online 22 May 2024. DOI: https://doi.org/10.1016/j.annonc.2024.03.005

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