Trastuzumab plus nivolumab with gemcitabine and cisplatin as first-line therapy for HER2-positive unresectable biliary tract cancer: a phase 1b/2 trial
Mené sur 40 patients atteints d'un cancer non résécable des voies biliaires HER2+ (durée médiane de suivi : 17 mois), cet essai de phase IB/II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité d'un traitement de première ligne combinant trastuzumab, nivolumab, gemcitabine et cisplatine
Biliary tract cancers (BTCs) are associated with poor outcomes despite recent incorporation of immune checkpoint inhibitors into first-line chemotherapy. Human epidermal growth factor receptor 2 (HER2) overexpression or amplification defines a therapeutically targetable subset of BTC but its integration into first-line chemoimmunotherapy has not been prospectively evaluated. This multi-institutional, open-label, phase 1b/2 HERBOT study (KCSG-HB23-05) aimed to evaluate first-line HER2-targeted quadruplet regimen consisting of trastuzumab, nivolumab, gemcitabine and cisplatin in participants with HER2-positive advanced BTC. Here the primary endpoint was met with an objective response rate of 55% (95% confidence interval (CI) 38.5–70.7; one complete response and 21 partial responses among 40 participants) and a disease control rate of 95% (95% CI 83.5–99.4); the median duration of response was 12.6 months (95% CI 5.7–not reached). With a median follow-up of 17.0 months, the median progression-free survival was 10.6 months (95% CI 7.8–17.4) and median overall survival was not reached. Two participants (5.0%) underwent curative-intent conversion surgery. Common grade ≥3 treatment-related adverse events included neutropenia (57.5%), anemia (30.0%) and thrombocytopenia (22.5%). Preplanned artificial-intelligence-powered whole-slide image analyses suggested that tumors with higher proportions of HER2 3+ cells were associated with greater clinical benefit. These findings suggest that upfront HER2-targeted therapeutic intensification in BTC may represent a promising direction for future first-line treatment strategies, with relevance to ongoing phase 3 studies. ClinicalTrials.gov identifier: NCT05749900.
Nature Medicine , article en libre accès, 2026