A phase Ib/II trial of first-line trastuzumab, nivolumab, gemcitabine, and cisplatin in HER2-positive biliary tract cancer (HERBOT): A multi-institutional study from the Korean Cancer Study Group.

4016 Background: Several phase II trials support HER2 as a promising actionable target in advanced biliary tract cancers (BTCs). However, the efficacy of adding anti-HER2 therapy to the current first-line standard-of-care (ICI plus gemcitabine/cisplatin [GemCis]) remains unknown. We report the results of the HERBOT trial evaluating this quadruplet combination. Methods: This multi-institutional, open-label, phase Ib/II study (KCSG-HB23-05; NCT05749900) enrolled treatment-naïve pts with locally advanced/unresectable or metastatic, HER2-positive BTC (defined as centrally confirmed HER2 IHC3+, or IHC2+/ISH+, or ERBB2 gene copy number ≥6.0 by NGS). Pts received trastuzumab 6mg/kg (after 8mg/kg load) D1, nivolumab 360mg D1, cisplatin 25mg/m 2 D1,8, and gemcitabine 1000mg/m 2 (dose level 0) or 800mg/m 2 (dose level -1) D1,8 every 3 weeks. The primary endpoints were recommended phase II dose (RP2D, phase Ib) and ORR per RECIST v1.1 (phase II). Secondary endpoints included PFS, DCR, OS, safety. Exploratory biomarker analyses included AI-powered whole-slide image (WSI) profiling of HER2 expression and immune phenotype assessment. Results: Dose level 0 was established as RP2D with no DLT. Among total of 40 pts, 29 (72.5%) had gallbladder cancer and 26 (62.5%) were HER2 IHC 3+. The primary endpoint was met with an ORR of 55% (95%CI: 38.5 – 70.7; 1 CR, 21 PR) and a DCR of 95% (95%CI: 83.5 – 99.4); median duration of response was 12.6 months (95%CI: 5.7 – NR). With a median follow-up of 17.0 months, median PFS was 10.6 months (95%CI: 7.8 – 17.4) and median OS was not yet reached. Three pts (7.5%) underwent curative-intent conversion surgery. Pts with HER2 IHC 3+ showed a numerically longer PFS compared to IHC 2+/ISH+ (17.4 vs 9.7 months; HR 0.46, 95%CI: 0.20 – 1.07). Common grade ≥3 treatment-related adverse events (TRAEs) included neutropenia (57.5%), anemia (30.0%), and thrombocytopenia (22.5 %). A grade 2 decreased ejection fraction occurred in 1 pt (2.5%); no grade ≥3 immune-related AEs were observed. AI-based WSI analyses revealed that ≥10% HER2 3+ tumor cells proportion was associated with higher ORR (80% vs 36.4%, P = 0.009) and numerically superior PFS (17.4 vs 9.1 months; HR 0.54, 95%CI: 0.23 – 1.28). Pts with inflamed immune phenotype (n = 4) showed durable responses (ORR 75%; mPFS and mOS NR). Conclusions: The HERBOT trial demonstrates that adding trastuzumab to first-line ICI plus GemCis provides robust antitumor activity and manageable safety in HER2-positive BTC. This study is the first to report the efficacy of a HER2-targeted quadruplet regimen in the first-line setting, providing strong clinical rationale for integrating HER2-targeted strategies into first-line treatment and complementing ongoing global phase III trials in this molecularly defined subgroup. Clinical trial information: NCT05749900 .