Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial.

Abstract

IMPORTANCE:

Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy.

OBJECTIVE:

To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib.

DESIGN, SETTING, AND PARTICIPANTS:

CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C).

INTERVENTIONS:

Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C).

MAIN OUTCOMES AND MEASURES:

Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1).

RESULTS:

Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis).

CONCLUSIONS AND RELEVANCE:

In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT01658878.

• Authors: Thomas Yau, Yoon-Koo Kang, Tae-You Kim, Anthony B El-Khoueiry, Armando Santoro, Bruno Sangro, Ignacio Melero, Masatoshi Kudo, Ming-Mo Hou, Ana Matilla, Francesco Tovoli, Jennifer J Knox, Aiwu Ruth He, Bassel F El-Rayes, Mirelis Acosta-Rivera, Ho-Yeong Lim, Jaclyn Neely, Yun Shen, Tami Wisniewski, Jeffrey Anderson, Chiun Hsu
• Journal: JAMA oncology (JAMA Oncol) Vol. 6 Issue 11 Pg. e204564 (Nov 01 2020) ISSN: 2374-2445 [Electronic] United States
• PMID: 33001135 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Ipilimumab
• Nivolumab
• Sorafenib

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Carcinoma, Hepatocellular (drug therapy, etiology)
• Humans
• Ipilimumab (therapeutic use)
• Liver Neoplasms (drug therapy, etiology)
• Male
• Nivolumab (therapeutic use)
• Sorafenib (therapeutic use)