Survival outcomes for zanidatamab-hrii compared to chemotherapy in previously treated HER2-positive (IHC3+) biliary tract cancer (BTC): HERIZON-BTC-01 vs a real-world (RW) external control arm (ECA).
Authors: Richard D. Kim, Xiaozhou Fan, Javier Sabater, Wayne Su, Kathleen Hurwitz, Kayla Hendrickson, Kara Bennett, Catherine Wiener, Phillip M. Garfin, Joan Zape, Mark Ozog, John Bridgewater, Juan W. Valle, Farshid Dayyani
Journal: Journal of Clinical Oncology (2025)

4101 Background: Zanidatamab-hrii, a bispecific HER2-directed antibody, received accelerated approval for adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC based on results from the single-arm phase 2 HERIZON-BTC-01 trial. The results here compare survival outcomes with zanidatamab-hrii from HERIZON-BTC-01 vs a comparable RW cohort of patients who received second-line (2L) chemotherapy. Methods: HERIZON-BTC-01 (NCT04466891) evaluated zanidatamab-hrii (20 mg/kg IV every 2 weeks) in patients with HER2-amplified, unresectable locally advanced or metastatic BTC (gallbladder cancer [GBC], intra-/extra-hepatic cholangiocarcinoma [ICC/ECC]) who had received prior gemcitabine-containing therapy. HERIZON-BTC-01 patients with HER2 IHC3+ (n = 62) were included in this analysis. The US-based ECA was constructed using deidentified data from the Flatiron Health Electronic Health Record. Key inclusion criteria for the ECA included a diagnosis of GBC or ICC/ECC with initiation of 2L chemotherapy between 2011-2023, HER2 IHC3+ prior to 2L initiation, and 1L treatment with a gemcitabine-containing regimen. Patients with ECOG &gt; 1 or CNS metastases were excluded. Standardized mortality ratio (SMR) weighting was used to account for potential imbalance of key prognostic factors. Overall survival (OS) and progression-free survival (PFS) were evaluated using SMR-weighted Kaplan-Meier and Cox proportional hazards regression. Results: Among 290 RW patients initiating 2L treatment with HER2 testing, 12 met all eligibility criteria and were included in the ECA. The most common reason for exclusion was lack of HER2-positivity (n = 209). Median follow-up times were 16.1 (interquartile range [IQR]: 9.4, 19.9) and 4.7 (IQR: 2.6, 8.1) months for the zanidatamab-hrii and ECA arms, respectively. After weighting, baseline characteristics were similar across arms with standardized mean differences ≤0.2. The most common 2L chemotherapy regimen in the ECA was FOLFOX (n =6), followed by gemcitabine-based regimens (n = 3) and FOLFORI (n = 2). Compared with chemotherapy, zanidatamab-hrii resulted in longer median OS (18.07 vs 3.29 months; hazard ratio [HR]:0.29) and PFS (7.26 vs 2.30; HR: 0.47) (Table). The 6- and 12-month survival for zanidatamab-hrii patients were 90% and 65% (vs. 29% and 13% for the ECA), respectively. Conclusions: Among patients with previously-treated HER2-positive (IHC3+) BTC, zanidatamab-hrii resulted in longer survival, including a &gt; 14 month increase in median OS, vs ECA patients treated with chemotherapy. Zanidatamab-hrii (N=62) ECA (N=12) OS Median, mos 18.07 3.29 Survival % (95% CI) 6 mos 90% (83%, 98%) 29% (11%, 75%) 12 mos 65% (54%, 78%) 13% (3%, 55%) PFS Median, mos 7.26 2.30 Survival % (95% CI) 6 mos 55% (44%, 69%) 14% (4%, 47%) 12 mos 32% (22%, 46%) 14% (4%, 47%)