Phase 2 trial of domvanalimab plus zimberelimab in unresectable and immunotherapy refractory biliary tract cancers

TIGIT is an inhibitory receptor that promotes immune evasion, and dual blockade of TIGIT and PD-1 may restore antitumor immunity. A phase 2 trial at the University of Texas Southwestern Medical Center (Dallas, TX) evaluated the Fc-silent anti-TIGIT antibody domvanalimab plus the anti-PD-1 antibody zimberelimab in patients with biliary tract cancers (BTCs) refractory to prior anti-PD-(L)1 therapy. The primary endpoint was confirmed objective response rate (ORR). Among 29 evaluable patients, the ORR was 10.3% (95% CI 2.2-27.4), not meeting the prespecified target, with a disease control rate of 44.8%. The median duration of response was 13.6 months, and the 6-month progression-free survival rate was 17.2% (95% CI 6.0-35.8). Treatment-related adverse events occurred in 36.4% of patients and were primarily limited to low-grade pruritus and rash. Emergent circulating tumor DNA alteration in RAS signaling, receptor tyrosine kinases, and DNA damage response were identified as putative mechanisms of anti-TIGIT resistance. The authors conclude that, although the primary endpoint was not met, the durability of responses, favorable safety profile, and translational findings support further evaluation of anti-TIGIT-based combination strategies in BTCs.