Key Data and Practice Considerations for Agents Targeting HER2

The clinical evidence supporting HER2-targeted therapies in biliary tract cancer comes from 2 distinct phase 2 trials with different approaches. Trastuzumab deruxtecan’s approval was based on the tumor-agnostic DESTINY-PanTumor02 trial, which evaluated the agent across multiple HER2-positive cancer types defined as either IHC 3+ or 2+. This study demonstrated an overall objective response rate of 37.1% across all tumor types, leading to FDA accelerated approval for the tumor-agnostic indication in patients with HER2-positive IHC 3+ disease. Specifically for the 41 patients with biliary tract cancer enrolled, the overall response rate was 22%, but this increased substantially to 56.3% when analyzing only the IHC 3+ subgroup, with an impressive progression-free survival of 7.4 months in previously treated patients.

Zanidatamab’s development followed a more disease-specific approach through the HERIZON-BTC-01 trial, which exclusively enrolled patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancers following progression on gemcitabine-based therapy. This focused study design yielded promising results with a confirmed overall response rate of 52% in the HER2-positive cohort (including patients with both IHC 2+ and 3+ disease). The median progression-free survival specifically in patients with IHC 3+ disease reached 7.2 months, leading to FDA approval for zanidatamab in patients with biliary tract cancer with HER2-positive disease and IHC 3+ status.

Clinical decision-making between these 2 HER2-targeted agents requires individualized assessment since head-to-head comparative data are unavailable. Both agents demonstrated clinically meaningful activity in patients with HER2-positive disease, particularly those with IHC 3+ status, with numerically impressive results from their respective phase 2 trials. Treatment selection must therefore rely on case-by-case evaluation considering factors such as individual toxicity profiles, dosing schedules, prior treatment history, and existing treatment-related sequelae.