HER2-Directed Therapy in Biliary Tract Cancer

Human epidermal growth factor receptor 2 (HER2) represents an actionable therapeutic target in biliary tract cancer (BTC); however, protein overexpression, ERBB2 amplification, and activating mutations do not confer therapeutic equivalence. Clinical decision-making requires integrating comprehensive genomic profiling with precise HER2 phenotyping to optimize treatment selection and sequencing.

Contemporary clinical trial data illustrate the differential efficacy of HER2-targeted agents based on expression levels and assessment methodology: • In the final HERIZON-BTC-01 analysis, the confirmed objective response rate (ORR) assessed by independent central review reached 51.6% among patients in the immunohistochemistry (IHC) 3+ cohort (n=62), compared with 5.6% in the IHC 2+ cohort (n=18). • In the DESTINY-PanTumor02 trial, the investigator-assessed ORR was 22.0% (9/41) across the entire BTC cohort and 56.3% (9/16) in centrally reassessed IHC 3+ disease. Independent central review showed an overall ORR of 26.8% (11/41), without a published IHC-specific central-review estimate. The review highlights that these assessor-dependent outcomes are not directly comparable with each other or with HERIZON-BTC-01. • Evidence from HERALD/EPOC1806 indicates that plasma-detected ERBB2 amplification can serve as a selection route for trastuzumab deruxtecan across solid tumors, though the study included only four patients with BTC.

Prospective investigations are currently evaluating HER2-directed combinations in the first-line setting. At present, IHC 3+ status provides the strongest BTC-specific treatment signal. Conversely, non-IHC 3+ scenarios—including IHC 2+/in situ hybridization-positive (ISH+), activating ERBB2 mutations, and low-expression or amplification-only states—require individualized, treatment-specific interpretation. Post-HER2 sequencing remains evidence-poor; clinical decisions should account for prior drug exposure, cumulative toxicities, clinical tempo, organ function, and regional treatment access.