Domvanalimab plus zimberelimab in unresectable and immunotherapy refractory biliary tract cancers: a phase 2 trial.

T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor that promotes immune evasion, and dual blockade of TIGIT and PD-1 may restore antitumor immunity. Here we report the primary analysis of the biliary tract cancer cohort from a phase 2 trial (ClinicalTrials.gov registration: NCT05724563) evaluating the Fc-silent anti-TIGIT antibody domvanalimab plus the anti-PD-1 antibody zimberelimab in patients with biliary tract cancers (BTCs) refractory to prior PD-1/L1 therapy. The primary endpoint was confirmed objective response rate (ORR); secondary endpoints included disease control rate (DCR), safety, 6-month progression-free survival (PFS), duration of response (DoR), and overall survival. Among 29 evaluable patients, the confirmed ORR was 10.3% (95% CI, 2.2-27.4%), with a DCR of 44.8%. The 6-month PFS rate was 17.2% (95% CI, 6.0-35.8%), and the median DoR was 13.6 months. Treatment-related adverse events occurred in 36.4% of patients and were primarily limited to low grade pruritus and rash. Emergent circulating tumor DNA alterations in RAS signaling, receptor tyrosine kinases, and DNA damage response were identified as putative mechanisms of anti-TIGIT resistance. Although the prespecified ORR threshold was not met, the durability of responses, favorable safety profile, and translational findings support further evaluation of anti-TIGIT-based combination strategies in BTCs.