Biliary tract cancers (BTCs) — including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer — have poor outcomes and limited treatment options. Although first-line chemoimmunotherapy incorporating immune checkpoint inhibitors (ICIs) with gemcitabine and cisplatin has become standard, median progression-free survival (PFS) remains around 7 months and overall survival (OS) only slightly exceeds 1 year in many series, underscoring the need for improved strategies.
Approximately 15% of BTCs exhibit HER2 overexpression or amplification, which is associated with worse prognosis but represents a targetable alteration. Prior clinical development of HER2-directed agents in BTC has generally focused on later-line settings and has shown promising activity. Preclinical and translational evidence supports synergy between HER2-targeted antibodies and ICIs: HER2-directed antibodies can promote antigen release, enhance cross-presentation and antibody-dependent cellular cytotoxicity, while chemotherapy can increase antigen availability through tumor cell death. These mechanisms provide a biological rationale to evaluate upfront combination of trastuzumab with an anti–PD-1 ICI plus standard chemotherapy.
The HERBOT study (KCSG-HB23-05) was a multi-institutional, open-label phase 1b/2 trial that evaluated a first-line quadruplet regimen composed of trastuzumab, nivolumab, gemcitabine and cisplatin in participants with HER2-positive advanced, unresectable BTC. The trial aimed to assess whether integrating HER2-targeted therapy into contemporary chemoimmunotherapy could improve objective response and disease control in this molecularly defined subgroup. The ClinicalTrials.gov identifier is NCT05749900.
Details on exact eligibility criteria, dosing schedules, cohort sizes beyond the reported 40 participants in the efficacy analysis, and stratification variables were reported in the source article but are not reproduced here in full.
The trial met its primary endpoint. Among 40 participants evaluable for response, the objective response rate (ORR) was 55% (95% confidence interval (CI) 38.5–70.7), comprising one complete response and 21 partial responses. The disease control rate was 95% (95% CI 83.5–99.4).
Median duration of response was 12.6 months (95% CI 5.7–not reached). With a median follow-up of 17.0 months, median progression-free survival (PFS) was 10.6 months (95% CI 7.8–17.4). Median overall survival was not reached at the time of reporting. Two participants (5.0%) were able to undergo curative-intent conversion surgery after treatment, indicating that downstaging occurred in a subset of patients.
These outcomes indicate higher response activity than historical benchmarks for chemotherapy plus ICI in unselected BTC populations, while acknowledging that cross-trial comparisons have limitations.
The quadruplet regimen produced hematologic toxicity as the most common high-grade treatment-related adverse events. Reported rates of grade ≥3 events included neutropenia in 57.5% of participants, anemia in 30.0% and thrombocytopenia in 22.5%. The source article lists these as the common grade ≥3 toxicities; additional safety details, including nonhematologic adverse events, immune-related events attributable to nivolumab and dose modifications or discontinuations, were described in the full manuscript but are not reproduced here beyond the reported high-grade frequencies.
A preplanned exploratory analysis applied artificial-intelligence-powered whole-slide image (WSI) analyses to tumor specimens. These analyses suggested a relationship between intratumoral HER2 expression patterns and clinical benefit: tumors with higher proportions of HER2 3+ cells were associated with greater clinical benefit from the quadruplet regimen. The study therefore provided imaging-based correlative evidence that stronger HER2 protein overexpression may predict improved response to upfront HER2-directed intensification combined with ICI and chemotherapy. Further methodological and quantitative details of the WSI analysis are presented in the source publication.
The HERBOT phase 1b/2 results indicate that upfront HER2-targeted therapeutic intensification in HER2-positive unresectable BTC is feasible and active, producing a 55% ORR, high disease control and a median PFS of 10.6 months with manageable but significant hematologic toxicity. The finding that a small proportion of patients could proceed to curative-intent surgery highlights potential for meaningful clinical benefit in selected cases.
These data support continued evaluation of integrating HER2-directed therapy into first-line regimens for BTC and are relevant to ongoing and planned phase 3 studies testing similar approaches. The exploratory AI-based WSI results raise the possibility that quantitative HER2 expression measures could help refine patient selection, but prospective validation is required. The full trial report contains additional methodological and safety detail for clinicians and investigators considering this strategy.
ClinicalTrials.gov identifier: NCT05749900.