Biliary tract cancer (BTC) is a rare and aggressive malignancy associated with poor outcomes, with HER2 overexpression or gene amplification occurring in a subset of cases. Zanidatamab, a dual HER2-targeted bispecific antibody, has received FDA accelerated approval in the United States and conditional approvals in the European Union and China for patients with previously treated, unresectable, advanced or metastatic HER2-positive, IHC 3+ BTC.
HERIZON-BTC-01 (NCT04466891) was a global, single-arm phase 2 trial that included patients with HER2-amplified, locally advanced, unresectable, or metastatic BTC who had progressed on or after gemcitabine-containing therapy. In patients with HER2 IHC 3+ tumors (n=62), zanidatamab demonstrated antitumor activity with manageable safety, with a confirmed objective response rate of 52% and a median progression-free survival and median overall survival (OS) of 7.2 months and 18.1 months, respectively. This post-hoc analysis, presented at ASCO GI 2026, assessed the prognostic association between tumor response to zanidatamab and OS.
Patients were treated with zanidatamab 20 mg/kg intravenously every 2 weeks. The analysis only included patients whose tumors were IHC 3+, and landmark survival models were applied at week 9, the time of initial response assessment, and at week 25 when all responses had been observed. Responders were defined as all patients with a best response of having at least 1 assessment of complete response or partial response prior to the landmark time point.
Between September 15, 2020, and March 16, 2022, 62 patients with IHC 3+ tumors were enrolled. The median follow-up duration was 34.0 months (range, 28-45). The median age of patients was 64 years (range, 38-79), and 55% of patients were diagnosed with stage IV disease at initial diagnosis. At week 9 (n=60), post-landmark median OS was 24.5 months for responders, 14.4 months for patients with stable disease (SD), and 8.9 months for those with progressive disease (PD) or no evaluation. Compared with patients with PD or no evaluation, patients with SD had a 62% lower risk of death (hazard ratio [HR], 0.38; 95% CI, 0.17-0.82), while responders showed a longer OS versus SD (HR, 0.40; 95% CI, 0.19-0.83).
At the week-25 landmark (36 responders, 12 SD, 6 PD), the median OS was 20.0 (95% CI, 13.0-29.3), 8.4 (95% CI, 0.5-15.2), and 5.4 (95% CI, 1.8-not evaluable) months, respectively. Patients in the SD group showed 42% lower risk of death versus patients in the PD group (HR, 0.58; 95% CI, 0.21-1.63), and responders continued to demonstrate longer OS compared with patients in the SD group (HR, 0.24; 95% CI, 0.11-0.56). Patients with SD prior to week 9 demonstrated a median OS of 14.4 months, with 35% subsequently converting to a response by week 25.
These results highlight a possible prognostic association between objective response with zanidatamab and longer survival in HER2-positive BTC. The ongoing phase 3 HERIZON-BTC-302 trial (NCT06282575) will further investigate zanidatamab combined with standard-of-care therapy in the first-line setting for patients with HER2-positive BTC.
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