Nivolumab and Ipilimumab Combination Treatment in Patients with Advanced Intrahepatic Cholangiocarcinoma and Gallbladder Cancer: Results from the Phase II MoST-CIRCUIT Trial.

Anti-PD-1/PD-L1 blockade combined with chemotherapy has become the first-line treatment for advanced biliary tract cancers. 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 and SWOG1609). MoST-CIRCUIT further evaluated combined checkpoint blockade using nivolumab/ipilimumab in patients with advanced iCCA and GBC. Patients with a maximum of 1 line of prior systemic therapy were enrolled as cohort B into MoST-CIRCUIT, a single-arm, nonrandomized phase 2 trial. Patients received nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks for 96 weeks. Response (RECIST 1.1) was assessed every 12 weeks. Coprimary endpoints were objective response rate (ORR) and 6-month progression-free survival (6-PFS), with the secondary endpoints being median overall survival (mOS), PFS, and treatment-related toxicity. Sixty patients (37 iCCA and 23 GBC) were enrolled; 85% were pretreated, including 13 patients with durvalumab. The ORR was 12% (2% complete response, 10% partial response): 3% and 26% in the iCCA and GBC subgroups, respectively. The 6-PFS was 27% (iCCA 19%; GBC 39%), and mOS was 7 months. In the immunotherapy-naïve population, the ORR was 19% (iCCA 10%; GBC 38%). Severe immune-related adverse events were observed in 20% of patients. Efficacy was limited in what is the largest biliary tract cancer 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 biliary tract cancer should focus on patients with GBC.