@article{3972, keywords = {Humans, Male, Carcinoma, Hepatocellular, Liver Neoplasms, Nivolumab, Sorafenib, Antineoplastic Combined Chemotherapy Protocols, Ipilimumab}, author = {Thomas Yau and Yoon-Koo Kang and Tae-You Kim and Anthony El-Khoueiry and Armando Santoro and Bruno Sangro and Ignacio Melero and Masatoshi Kudo and Ming-Mo Hou and Ana Matilla and Francesco Tovoli and Jennifer Knox and Aiwu He and Bassel El-Rayes and Mirelis Acosta-Rivera and Ho-Yeong Lim and Jaclyn Neely and Yun Shen and Tami Wisniewski and Jeffrey Anderson and Chiun Hsu}, title = {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.

}, year = {2020}, journal = {JAMA Oncol}, volume = {6}, pages = {e204564}, month = {2020 Nov 01}, issn = {2374-2445}, doi = {10.1001/jamaoncol.2020.4564}, language = {eng}, }