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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Yau reported receiving personal fees from Bristol Myers Squibb during the conduct of the study; and grants and personal fees from Bristol Myers Squibb, personal fees from Merck Sharp & Dohme Oncology, Exelixis, Ipsen, and AstraZeneca outside the submitted work. Dr Kang reported personal fees from Bristol Myers Squibb, ALX Oncology, Novartis, and Surface Oncology outside the submitted work. Dr El-Khoueiry reported grants and nonfinancial support from Bristol Myers Squibb during the conduct of the study; personal fees from Bristol Myers Squibb, Bayer, Eisai Co, Merck, Roche/Genentech, Exelixis, AstraZeneca, Agenus, EMD Serono, Zymeworks, Agios, QED Therapeutics, Cytomx, Pieris, and Target PharmaSolutions outside the submitted work. Dr Santoro reported other support from Bristol Myers Squibb, Laboratoires Servier, Gilead Sciences, Pfizer, Eisai Co, Bayer, Merck Sharp & Dohme, ArQule Inc, Sanofi, Takeda, Bristol Myers Squibb, Roche, AbbVie, Amgen, Celgene, Laboratoires Servier, Gilead Sciences, AstraZeneca, Pfizer, Eli Lilly, Sandoz, and Novartis outside the submitted work. Dr Sangro reported personal fees from AstraZeneca, Adaptimmune Limited, Bayer, H3 Biomedicine, Ipsen, Eli Lilly, Roche/Genentech, and BTG; and grants and personal fees from Bristol Myers Squibb and Sirtex Medical outside the submitted work. Dr Melero reported personal fees from Bayer, Servier, Numab, Pieris, and Merck Sharp & Dohme, and grants and personal fees from Bristol Myers Squibb, Roche, Bioncotech, Alligator, AstraZeneca, and Merck Serono during the conduct of the study. Dr Kudo reported grants and other support from Eisai; other support from Bayer, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, and Ono Pharmaceutical; grants from Gilead Sciences, Taiho Pharmaceutical, Sumitomo Dainippon Pharma, Takeda Pharmaceutical Company, Otsuka Pharmaceutical, EA Pharma Co, and AbbVie outside the submitted work. Dr Matilla reported personal fees from Bristol Myers Squibb during the conduct of the study, and personal fees from Bristol Myers Squibb, Bayer, Boston Scientific, Terumo, and Eisai outside the submitted work. Dr Tovoli reported personal fees and nonfinancial support from Bayer AG and personal fees from LaForce outside the submitted work. Dr Knox reported grants from Ipsen and grants and personal fees from AstraZeneca, Merck, and F. Hoffman-La Roche outside the submitted work. Dr El-Rayes reported grants and personal fees from Bristol Myers Squibb during the conduct of the study; grants and personal fees from Merck, grants from Boston Biomedical, Pfizer, Novartis, MedImmune, Xencor, EUSA Pharma, grants and other support from Exilixis, and other support from Erytech, Incyte, Bayer, and Adaptimmune outside the submitted work. Dr Neely reported personal fees from Bristol Myers Squibb outside the submitted work. Dr Shen reported being an employee of Bristol Myers Squibb. Dr Wisniewski reported other support from Bristol Myers Squibb during the conduct of the study; other suport from Bristol Myers Squibb outside the submitted work; and stock ownership in Bristol Myers Squibb as an employee of the company. Dr Anderson reported other support from Bristol Myers Squibb during the conduct of the study and other support from Bristol Myers Squibb outside the submitted work. Dr Hsu reported grants and personal fees from Bristol Myers Squibb and Ono Pharmaceutical during the conduct of the study; grants from Roche and Ipsen, and personal fees from AstraZeneca, Bayer, Eisai, Eli Lilly, Ipsen, Merck Serono, Merck Sharp & Dohme, Novartis, Roche, and TTY Biopharm outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Enrollment, Randomization, and Outcomes

aThe 2 patients who did not receive treatment were excluded from the safety analysis.

Figure 2.. Kaplan-Meier Analysis of Median Overall Survival

A, survival by treatment arm; B, overall population survival stratified by best overall response. CR indicates complete response; mOS, median overall survival; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease. aEleven patients overall did not have a scan; therefore, best overall response could not be determined. bStable disease was reported as noncomplete response/nonprogressive disease in 2 patients in arm A and 1 patient in arm B. These were patients who only had nontarget lesions at baseline and did not meet the definition of stable disease by blinded independent central review.