Multicenter phase 1b-2 trial of first-line trastuzumab plus nivolumab and chemotherapy for HER2-positive unresectable biliary tract cancer

Biliary tract cancers (BTCs) are associated with poor outcomes despite recent incorporation of immune checkpoint inhibitors into first-line chemotherapy. HER2 overexpression or amplification defines a therapeutically targetable subset of BTC, but its integration into first-line chemoimmunotherapy has not been prospectively evaluated. The multicenter phase 1b-2 HERBOT study in South Korea evaluated a first-line HER2-targeted quadruplet regimen consisting of trastuzumab, nivolumab, gemcitabine and cisplatin in participants with HER2- positive advanced BTC. The primary endpoint was objective response rate. This endpoint was met with an objective response rate of 55% (95% CI 38.5-70.7; 21 partial responses among 40 participants), a disease control rate of 95% (83.5-99.4); the median duration of response was 12.6 months (5.7-NR), the median progression-free survival was 10.6 months (7.8-17.4), and the median overall survival was not reached. Two participants (5%) underwent curative-intent conversion surgery. Common grade ≥ 3 treatment-related adverse events included neutropenia (57.5%), anemia (30.0%), and thrombocytopenia (22.5%). The authors conclude that these findings suggest that upfront HER2-targeted therapeutic intensification in BTC may be a promising strategy.