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BACKGROUND: Patients with advanced biliary tract cancer have a poor prognosis, and first-line standard of care (gemcitabine plus cisplatin) has remained unchanged for more than 10 years. The TOPAZ-1 trial evaluated durvalumab plus chemotherapy for patients with advanced biliary tract cancer. METHODS: In this double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease 1:1 to receive durvalumab or placebo in combination with gemcitabine plus cisplatin for up to eight cycles, followed by durvalumab or placebo monotherapy until disease progression or unacceptable toxicity. The primary objective was to assess overall survival. Secondary end points included progression-free survival, objective response rate, and safety. RESULTS: Overall, 685 patients were randomly assigned to durvalumab (n=341) or placebo (n=344) with chemotherapy. As of data cutoff, 198 patients (58.1%) in the durvalumab group and 226 patients (65.7%) in the placebo group had died. The hazard ratio for overall survival was 0.80 (95% confidence interval [CI], 0.66 to 0.97; P=0.021). The estimated 24-month overall survival rate was 24.9% (95% CI, 17.9 to 32.5) for durvalumab and 10.4% (95% CI, 4.7 to 18.8) for placebo. The hazard ratio for progression-free survival was 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates were 26.7% with durvalumab and 18.7% with placebo. The incidences of grade 3 or 4 adverse events were 75.7% and 77.8% with durvalumab and placebo, respectively. CONCLUSIONS: Durvalumab plus chemotherapy significantly improved overall survival versus placebo plus chemotherapy and showed improvements versus placebo plus chemotherapy in prespecified secondary end points including progression-free survival and objective response rate. The safety profiles of the two treatment groups were similar. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03875235.)
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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.