Highlights
- Zanidatamab produced a confirmed objective response rate (cORR) of 41.3% and a median overall survival (OS) of 15.5 months in patients with previously treated, ERBB2‑amplified metastatic biliary tract cancer (BTC) in the final analysis of HERIZON‑BTC‑01.
- Responses were concentrated in HER2 IHC 3+ tumors (cORR 51.6%; median OS 18.1 months); activity in IHC 2+/amplified tumors was limited.
- Responses were durable (median duration of response 14.9 months) and responders reported reductions in worst pain scores; safety was manageable with few treatment discontinuations and no treatment‑related deaths.
Background and Clinical Context
Biliary tract cancers (BTCs), including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder carcinoma, are aggressive malignancies with late presentation and limited systemic therapy options. First‑line gemcitabine‑based combinations yield median overall survival in the order of approximately 11–12 months in pivotal trials, and outcomes after progression on first‑line therapy remain poor. Targetable genomic alterations are present in subsets of BTC; among these, HER2 (ERBB2) overexpression or amplification is found in a minority of cases, particularly gallbladder cancers and some extrahepatic cholangiocarcinomas. HER2 therefore represents a validated precision target in selected patients, but effective HER2‑directed strategies for BTC have been limited until recent developments.
Study Design
HERIZON‑BTC‑01 (NCT04466891) is a single‑arm, open‑label, multicenter phase 2 trial that evaluated zanidatamab — a bispecific antibody that binds two distinct HER2 epitopes — in adults with ERBB2‑amplified, locally advanced or metastatic BTC that progressed on or after gemcitabine‑based therapy. Patients received zanidatamab 20 mg/kg intravenously every 2 weeks in 28‑day cycles. Central independent review assessed objective responses; secondary endpoints included duration of response (DOR), disease control rate (DCR), progression‑free survival (PFS), overall survival (OS), safety, and patient‑reported worst pain (Brief Pain Inventory‑Short Form). The final analysis reported here includes a median follow‑up of 33.4 months and expands on previously reported outcomes with longer observation.
Key Results
Between September 15, 2020, and March 16, 2022, 80 patients with HER2 IHC 2+ or 3+ tumors were enrolled (median age 64 years; 56% female). Median follow‑up for the final analysis was 33.4 months.
Overall efficacy
The overall confirmed objective response rate (cORR) by independent central review was 41.3% (33 of 80 patients; 95% CI, 30.4–52.8). Median duration of response was 14.9 months (95% CI, 7.4–24.0). Median OS for the overall cohort was 15.5 months (95% CI, 10.4–18.7). Median progression‑free survival (PFS) was 5.5 months (95% CI, 3.7–7.3).
Effect by HER2 IHC subgroup
The clinical benefit was concentrated in the IHC 3+ subgroup (n=62): cORR 51.6% (95% CI, 38.6–64.5) and median OS 18.1 months (95% CI, 12.2–22.9). By contrast, patients with IHC 2+ tumors (n=18) had minimal objective responses (1 partial response; cORR 5.6%; 95% CI, 0.1–27.3) and a median OS of 5.2 months (95% CI, 3.1–10.2). These divergent outcomes support the view that strong HER2 overexpression (IHC 3+) is the principal predictor of benefit from zanidatamab in BTC.
Disease control and durability
Disease control rate for the cohort was 69% (55 of 80; 95% CI, 57–79). Importantly, responses were durable: the median DOR among responders was 14.9 months. Two patients who had partial responses at earlier reporting converted to complete responses on continued therapy, underscoring extended antitumor activity in some individuals.
Patient‑reported outcomes
Among the 59 patients (74%) who completed the Brief Pain Inventory item at baseline and at best response, mean worst pain scores declined for responders. At best overall response, mean change from baseline in worst pain was −4.0 for complete responders (small numbers preclude precise estimate) and −1.0 for partial responders (SD 2.5); patients with progressive disease reported a mean increase of 2.4 (SD 2.9). These data suggest symptomatic benefit among tumor responders, which is clinically meaningful in a disease where palliation is an important endpoint.
Safety
Overall, 76% of patients experienced at least one treatment‑related adverse event (TRAE). Grade 3 TRAEs occurring in more than two patients were diarrhea (4 patients, 5.0%), decreased left ventricular ejection fraction (3 patients, 3.8%), and anemia (3 patients, 3.8%). There were no treatment‑related deaths, and only 2 patients (3%) discontinued therapy because of TRAEs. These findings indicate a manageable safety profile with zanidatamab in this population; cardiac monitoring is prudent given reported decreases in ejection fraction in a small subset.
Interpretation and Clinical Implications
The final HERIZON‑BTC‑01 results provide mature evidence that zanidatamab induces clinically meaningful and durable responses in a substantial proportion of patients with previously treated HER2‑positive BTC, especially those with IHC 3+ tumors. The median OS of 15.5 months overall and 18.1 months in the IHC 3+ subgroup is notable in a refractory population where median survival after first‑line progression is generally limited. The concentration of benefit in IHC 3+ tumors supports reflex IHC testing for HER2 overexpression in BTC and suggests that IHC 3+ should remain the primary biomarker selection criterion for zanidatamab activity, while the role of IHC 2+/amplified tumors requires further study and possibly more refined biomarker stratification.
Durable responses and reductions in worst pain among responders indicate that zanidatamab may offer both disease control and symptom relief. The safety profile appears acceptable relative to potential benefit, with few discontinuations and no treatment‑related fatalities in this analysis.
Mechanistic Rationale
Zanidatamab is a bispecific antibody that binds two distinct HER2 epitopes, potentially enabling more potent HER2 pathway blockade and enhanced immune‑mediated tumor cell killing compared with monospecific HER2 antibodies. Preclinical models have suggested that bispecific engagement can produce receptor clustering and immune effector recruitment, which may translate into improved activity in HER2‑driven malignancies that are less responsive to single‑epitope agents. The observed deep and durable responses in IHC 3+ tumors are biologically plausible given higher HER2 expression and dependence.
Limitations
- HERIZON‑BTC‑01 is a single‑arm phase 2 study without a randomized comparator, so cross‑trial comparisons with other agents and historical controls should be made cautiously.
- Subgroup analyses (IHC 3+ vs 2+) are post hoc and based on small numbers in the IHC 2+ cohort (n=18), limiting precision and generalizability for that subgroup.
- Patient‑reported pain data had missing values (approximately 26% did not complete both assessments), which can bias symptom analyses if missingness is nonrandom.
- Longer follow‑up and randomized data are needed to confirm survival benefit and define optimal sequencing with other systemic therapies.
Ongoing Research and Practice Implications
The results support ongoing randomized evaluation of zanidatamab in earlier lines of therapy. The phase 3 HERIZON‑BTC‑302 trial (NCT06282575) is testing zanidatamab in combination with standard first‑line therapy in patients with HER2‑positive BTC (IHC 3+ or IHC 2+/amplified). If the phase 3 program confirms benefit, zanidatamab could become a component of earlier‑line therapy for a molecularly defined BTC subgroup. Meanwhile, clinicians should ensure routine HER2 testing (IHC, with reflex confirmatory testing where indicated) in BTC to identify potential candidates for HER2‑directed therapies or clinical trials.
Conclusion
The final analysis of HERIZON‑BTC‑01 demonstrates that zanidatamab has meaningful and durable antitumor activity with an acceptable safety profile in patients with previously treated HER2‑overexpressing metastatic BTC, particularly in the IHC 3+ subgroup. These data reinforce HER2 as an actionable target in BTC and justify continued randomized evaluation of zanidatamab in the frontline setting. Pending confirmatory phase 3 results, zanidatamab provides a promising new option for patients with refractory, HER2‑positive BTC.
Funding and clinicaltrials.gov
Funding/Support: This work was supported by BeOne Medicines, Jazz Pharmaceuticals, and Zymeworks.
ClinicalTrials.gov identifier: NCT04466891. Ongoing phase 3 trial: NCT06282575 (HERIZON‑BTC‑302).
References
- Pant S, Fan J, Oh DY, et al; HERIZON‑BTC‑01 Study Group. Zanidatamab in HER2‑Positive Metastatic Biliary Tract Cancer: Final Results From HERIZON‑BTC‑01. JAMA Oncol. 2025 Nov 20:e254736. doi: 10.1001/jamaoncol.2025.4736. PMID: 41264278; PMCID: PMC12635922.
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- Lamarca A, Barriuso J, McNamara MG, et al. Biliary tract cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow‑up. Ann Oncol. 2021;32(9):1166–1185. (Guideline document summarizing contemporary management and targeted therapy considerations.)
