Early Stable Disease in BTC Predicts Improved Survival With Zanidatamab

The newest data from the HERIZON-BTC-01 trial (NCT04466891) show zanidatamab monotherapy can prolong overall survival (OS) in adult patients who have HER2-positive advanced biliary tract cancer (BTC),¹ a significant advancement considering the rare cancer is most often fatal with a median OS of less than 13 months from diagnosis. These data from the completed trial were presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The dual HER-2 targeted bispecific monoclonal antibody received accelerated approval from the FDA in November 2024 for this indication,² and it has since received conditional approval in China³ and the European Union.⁴

To be included in HERIZON-BTC-01, patients were required to have histologically or cytologically confirmed intra-hepatic cholangiocarcinoma (ICC; 27%), extra-hepatic cholangiocarcinoma (ECC; 19%), and gallbladder cancer (53%; be ineligible for curative resection, transplantation, or ablative therapies; have disease progression or be refractory to at least 1 prior gemcitabine-containing systemic chemotherapy regimen; and have Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 or below, adequate organ function, and adequate cardiac function, as defined by preserved ejection fraction.⁵

Patients were enrolled between September 15, 2020, and March 16, 2022, after which they were placed into 1 of 2 groups by immunohistochemistry (IHC) score:

• Cohort 1: IHC 2+ or 3+
• Cohort 2: IHC 0 or 1+

The treatment regimen was intravenous zanidatamab 20 mg/kg every 2 weeks, and tumor response was evaluated after the eighth week, plus or minus 1 week. Landmark survival analyses took place in week 9 (the initial evaluation) and week 25 (the final evaluation), by which point all responders had experienced a complete response (CR) or a partial response (PR). The primary outcome of interest was best response prior to week 25.

Overall, for the patients with IHC3+ tumors who were included in this post hoc analysis (N = 27), most (88.9%; n = 24) experienced a PR by week 9, and the remaining 3 cases were CRs. Median OS was 70% greater for any-responders vs patients with stable disease (SD) and 175% greater vs all others:

• Any-responders: 24.5 months (95% CI, 16.6 months-not estimable [NE])
• Patients with SD: 14.4 months (95% CI, 6.5-21.1)
• All others: 8.9 months (95% CI, 2.3-14.3)

These numbers are equivalent to a 60% reduced risk of disease progression or death (HR, 0.40; 95% CI, 0.19-0.83) for any-responders compared with patients with SD and a 62% reduced risk of disease progression or death (HR, 0.38; 95% CI, 0.17-0.82) for patients with SD compared with all others. Overall death risk reductions were 70% by week 9 and 79% by week 25 for the patients who exhibited responses to zanidatamab.

In addition, by week 25, 7 of 20 patients who had reached SD status by week 9 had progressed to a PR, and there were 36 overall responders, 3 CRs and 33 PRs; of this group, 12 patients had stable disease, and 6 patients experienced progressive disease. Post the 9-week analysis, survival results remained positive and consistent, the authors highlighted, with any responders to zanidatamab exhibiting a median OS of 20 months (95% CI, 13.0-29.3); patients with SD, 8.4 months (95% CI, 0.5-15.2); and patients with progressive disease, 5.4 months (95% CI, 1.8-NE).

Breaking these data down further, the following results were seen:

• Asian patients had the highest rate of CR or PR (69%) but also the highest rate of PD (62%)
• White patients had the highest rate of SD (50%)
• Patients with an ECOG PS of 1 vs 0 had higher rates of CR/PR (77% vs 23%) and SD (57% vs 43%) but also higher PD (54% vs 46%)
• Cases of GBC vs ICC and ECC had the highest rate of CR/PR (63% vs 20% vs 17%, respectively) but also the highest rate of PD (54% vs 15% vs 31%)
• ICC vs GBC and ECC had the highest rate of SD (57% vs 29% vs 14%)
• Patients with stage IV disease at diagnosis had the highest rate of CR/PR (54%) vs those diagnosed at stage I (3%), II (17%), or III (20%), and of SD (50% vs 36% vs 7% vs 7%, respectively), but also the highest rate of PD (62% vs 31% vs 8% vs 0%)

“These results support a prognostic association between objective response or SD with zanidatamab and longer OS in BTC,” the authors wrote. “Additionally, findings suggest a clinical benefit for patients who achieve early SD and support continued zanidatamab treatment.”

The patients in this study were primarily female patients (55%), of an Asian race (61%), had an ECOG PS of 1 (68%), and were diagnosed at stage IV disease status (55%).

Combination zanidatamab and standard-of-care treatment for HER2-positive BTC is being evaluated for first-line administration in the ongoing phase 3 HERIZON-BTC-302 trial (NCT06282575).

References

1. Harding JJ, Fan J, Oh DY, et al. Landmark analysis of overall survival (OS) by objective response in patients (pts) with previously treated, advanced HER2-positive biliary tract cancer (BTC): post hoc analysis of the HERIZON-BTC-01 trial. Presented at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 8-10, 2026; San Francisco, CA. Abstract 545.
2. Santoro C. FDA approves zanidatamab-hrii for HER2+ biliary tract cancer. AJMC^®. November 21, 2024. Accessed January 9, 2026. https://www.ajmc.com/view/fda-approves-zanidatamab-hrii-for-her2-biliary-tract-cancer
3. Zymeworks announces NMPA approval of zanidatamab in China for adults with previously treated, unresectable or metastatic HER2-high expression (IHC3+) biliary tract cancer. News release. Zymeworks. May 30, 2025. Accessed January 9, 2026. https://ir.zymeworks.com/news-releases/news-release-details/zymeworks-announces-nmpa-approval-zanidatamab-china-adults
4. Doherty K. Zanidatamab nets European approval in pretreated HER2+ biliary tract cancer. OncLive^®. July 1, 2025. Accessed January 9, 2026. https://www.onclive.com/view/zanidatamab-nets-european-approval-in-pretreated-her2-biliary-tract-cancer
5. A study of ZW25 (zanidatamab) in subjects with advanced or metastatic HER2-amplified biliary tract cancers (HERIZON-BTC-01). ClinicalTrials.gov. Updated September 15, 2025. Accessed January 9, 2026. https://clinicaltrials.gov/study/NCT04466891