Nivolumab and ipilimumab combination treatment in patients with advanced intrahepatic cholangiocarcinoma and gallbladder cancer: Results from the phase II MoST-CIRCUIT trial

PURPOSE: Anti-PD-1/PD-L1 blockade combined with chemotherapy has become first line treatment for advanced biliary tract cancers (BTC). Combined anti-PD-1/CTLA-4 blockade using nivolumab and ipilimumab has shown encouraging activity in patients with intrahepatic cholangiocarcinoma (iCCA) and gallbladder carcinoma (GBC) in two trials (CA209-538, SWOG1609). MoST-CIRCUIT further evaluated combined checkpoint blockade using nivo/ipi in patients with advanced iCCA and GBC. PATIENTS AND METHODS: Patients with a maximum of 1 line of prior systemic therapy were enrolled as cohort B into MoST-CIRCUIT, a single arm, non-randomised phase 2 trial. Patients received nivolumab 3mg/kg and ipilimumab 1mg/kg q3 weekly for four doses, followed by nivolumab 480mg q4 weekly for 96 weeks. Response (RECIST 1.1) was assessed every 12 weeks. Co-primary endpoints were objective response rate (ORR) and 6 month-progression free-survival (6-PFS) with the secondary endpoints being median overall survival (mOS), progression-free survival (PFS) and treatment related toxicity. RESULTS: 60 patients (37 iCCA and 23 GBC) were enrolled with 85% being pre-treated, including 13 patients with durvalumab. ORR was 12% (2% CR, 10% PR): 3% and 26% in iCCA and GBC subgroups respectively. The 6-month-PFS was 27% (iCCA 19%; GBC 39%) and mOS 7 months. In the immunotherapy-naïve population ORR was 19% (iCCA 10%; GBC 38%). Severe immune-related adverse events were observed in 20% of patients. CONCLUSIONS: Efficacy was limited in what is the largest BTC cohort treated to date with combined anti-CTLA-4/PD-1 blockade. Encouraging activity was observed in the GBC subgroup. Further evaluation of checkpoint inhibition in BTC should focus on GBC patients.