Zanidatamab in HER2-Positive Metastatic Biliary Tract Cancer: Final Results From HERIZON-BTC-01

Shubham Pant; Jia Fan; Do-Youn Oh; Hye Jin Choi; Jin Won Kim; Heung-Moon Chang; Lequn Bao; Hui-Chuan Sun; Teresa Macarulla; Feng Xie; Jean-Phillippe Metges; Jie’er Ying; John Bridgewater; Myung-Ah Lee; Mohamedtaki A Tejani; Emerson Y Chen; Harpreet Wasan; Michel Ducreux; Yuanyuan Bao; Xiaotian Wu; Yi Zhao; Phillip M Garfin; Jonathon Gable; James J Harding

doi:10.1001/jamaoncol.2025.4736

. 2025 Nov 20:e254736. Online ahead of print. doi: 10.1001/jamaoncol.2025.4736

Zanidatamab in HER2-Positive Metastatic Biliary Tract Cancer

Final Results From HERIZON-BTC-01

Shubham Pant ¹, Jia Fan ², Do-Youn Oh ³, Hye Jin Choi ⁴, Jin Won Kim ⁵, Heung-Moon Chang ⁶, Lequn Bao ⁷, Hui-Chuan Sun ², Teresa Macarulla ⁸, Feng Xie ⁹, Jean-Phillippe Metges ¹⁰, Jie’er Ying ¹¹, John Bridgewater ¹², Myung-Ah Lee ¹³, Mohamedtaki A Tejani ¹⁴, Emerson Y Chen ¹⁵, Harpreet Wasan ¹⁶, Michel Ducreux ¹⁷, Yuanyuan Bao ¹⁸, Xiaotian Wu ¹⁹, Yi Zhao ¹⁸, Phillip M Garfin ²⁰, Jonathon Gable ²⁰, James J Harding ^21,^22,^✉, for the HERIZON-BTC-01 Study Group

¹MD Anderson Cancer Center, Houston, Texas

²Zhongshan Hospital of Fudan University, Shanghai, China

³Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea

⁴Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea

⁵Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea

⁶Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

⁷Hubei Cancer Hospital, Wuhan, China

⁸Vall d’Hebrón University Hospital, Vall d’Hebrón Institute of Oncology, Barcelona, Spain

⁹The Third Affiliated Hospital of the Chinese People’s Liberation Army Naval Military Medical University, Shanghai, China

¹⁰CHRU de Brest - Hôpital Morvan, ARPEGO Network, Brest, France

¹¹Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China

¹²University College London Cancer Institute, London, United Kingdom

¹³The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, South Korea

¹⁴AdventHealth, Altamonte Springs, Florida

¹⁵Oregon Health & Science University, Portland

¹⁶Hammersmith Hospital, Imperial College London, London, United Kingdom

¹⁷Université Paris-Saclay, Gustave Roussy, Villejuif, France

¹⁸BeOne Medicines, Beijing, China

¹⁹Jazz Pharmaceuticals, Philadelphia, Pennsylvania

²⁰Jazz Pharmaceuticals, Palo Alto, California

²¹Memorial Sloan Kettering Cancer Center, New York, New York

²²Weill Cornell Medical College, New York, New York

Group Information: Members of the HERIZON-BTC-01 Study Group appear in Supplement 3.

Accepted for Publication: August 26, 2025.

Published Online: November 20, 2025. doi:10.1001/jamaoncol.2025.4736

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2025 Pant S et al. JAMA Oncology.

^✉

Corresponding Author: James J. Harding, MD, Memorial Sloan Kettering Cancer Center, 300 E 66th St, New York, NY 10065 (hardinj1@mskcc.org).

Author Contributions: Drs Pant and Harding had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Pant, Fan, Oh, Xie, Wu, Garfin, Harding.

Acquisition, analysis, or interpretation of data: Oh, Choi, Kim, Chang, L. Bao, Sun, Macarulla, Metges, Ying, Bridgewater, Lee, Tejani, Chen, Wasan, Ducreux, Y. Bao, Wu, Zhao, Garfin, Gable, Harding.

Drafting of the manuscript: Pant, Oh, Lee, Garfin, Gable, Harding.

Critical review of the manuscript for important intellectual content: Fan, Oh, Choi, Kim, Chang, L. Bao, Sun, Macarulla, Xie, Metges, Ying, Bridgewater, Lee, Tejani, Chen, Wasan, Ducreux, Y. Bao, Wu, Zhao, Garfin, Gable, Harding.

Statistical analysis: Kim, Chang, Xie, Y. Bao, Wu, Gable, Harding.

Administrative, technical, or material support: Pant, Choi, Chang, Sun, Xie, Ying, Bridgewater, Lee, Tejani, Chen, Zhao, Garfin, Harding.

Supervision: Fan, Oh, Sun, Macarulla, Lee, Tejani, Ducreux, Garfin, Harding.

Conflict of Interest Disclosures: Dr Pant reported serving as a consultant for Ipsen, Novartis, Daiichi Sankyo, Janssen, Jazz Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, USWorldmeds, Alligator Bioscience, Revolution Medicine, Arcus, BMS, Merck, Pfizer, and Immuneering; grants from Novartis, Astellas, Incyte, CG Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Arcus, Elicio, Pfizer, ImmunoMET, Immuneering, Amal Therapeutics, Jazz Therapeutics, and Revolution Medicine; and owns stock in Oncomed LLC and Telperian outside the submitted work. Dr Sun reported personal fees from AstraZeneca, BeiGene, Eisai, Hengrui, Innovent, Merck Sharpe & Dohme, Qilu Pharmaceutical, Roche, and Zelgen as well as grants from Sino Biopharmaceutical, Eisai, Innovent, Roche, and Merck Sharpe & Dohme. Dr Macarulla reported grants from AstraZeneca, Servier, and Incyte as well as personal fees from Jazz Pharmaceutical during the conduct of the study. Dr Metges reported travel support from Jazz Pharmaceuticals and Astellas outside the submitted work. Dr Chen reported grants from Jazz Pharmaceuticals during the conduct of the study; grants from Merck Sharp & Dohme, G1 Therapeutics, and Taiho Oncology; personal fees from Horizon CME; travel support from Daiichi Sankyo and AstraZeneca; and serves as a consultant for MDoutlook outside the submitted work. Dr Wasan reported personal fees from Zymeworks and Jazz Pharmaceuticals as well as travel support from Jazz Pharmaceuticals during the conduct of the study; personal fees from Zymeworks; and being an advisory board member and/or invited speaker at Amgen, Bayer, Bristol Myers Squibb/Celgene, BTG Pharmaceuticals, Erytech Pharma, Incyte, Merck, Pierre Fabre, Pfizer, Roche/Genentech/Foundation Medicine, Servier, Sirtex Medical, Seagen, and Zymeworks outside the submitted work. Dr Ducreux reported personal fees from Jazz Pharmaceuticals during the conduct of the study; personal fees from Roche, Daichii Sankyo, AstraZeneca, BeiGene, Pierre Fabre, Merck Sharpe & Dohme, Merck Serono, Servier, and Amgen outside the submitted work. Dr Zhao reported owning stocks in BeiGene. Dr Garfin reported owning stocks in Jazz Pharmaceuticals and Zymeworks outside the submitted work. Dr Gable reported owning stocks in Jazz Pharmaceuticals outside the submitted work. Dr Harding reported personal fees from Jazz Pharmaceuticals; grants from Jazz Pharmaceuticals and Zymeworks; and nonfinancial support from Jazz Pharmaceuticals during the conduct of the study; grants from AbbVie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Incyte, Kinnate, Rayze Bio, and Servier; and personal fees from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Elevar, Exelixis, Merck, Servier, and Cogent outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by BeOne Medicines, Jazz Pharmaceuticals, and Zymeworks.

Role of the Funder/Sponsor: Zymeworks and BeOne Medicines were involved in the design and conduct of the study; Zymeworks, BeOne Medicines, and Jazz Pharmaceuticals were involved with the collection, management, analysis, and interpretation of the data; Zymeworks, BeOne Medicines, and Jazz Pharmaceuticals were involved with the preparation, review, or approval of the manuscript; and Jazz Pharmaceuticals was involved with the decision to submit the manuscript for publication.

Group Information: Members of the HERIZON-BTC-01 Study Group appear in Supplement 3.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank all patients and their families and all investigators, clinical trial researchers, personnel, and staff who contributed to or participated in the HERIZON-BTC-01 trial. Medical writing support, under the direction of the authors, was provided by CMC Connect, a division of IPG Health Medical Communications, and Adam Schroer, PhD, of Red Nucleus, in accordance with Good Publication Practice (GPP 2022) guidelines and was funded by Jazz Pharmaceuticals.

^✉

Corresponding author.

PMCID: PMC12635922 PMID: 41264278

Abstract

This follow-up analysis of the phase 2 HERIZON-BTC-01 trial evaluates the efficacy, patient-reported outcomes, and safety profile of zanidatamab in patients with ERBB2-amplified biliary tract cancer with an HER2 immunohistochemistry score of 3+ or 2+ after 33 months of follow-up.

Metastatic biliary tract cancer (BTC) has a poor prognosis (median overall survival [OS] <13 months with first-line therapies and 6-9 months for subsequent chemotherapy). Human epidermal growth factor receptor 2 (HER2; encoded by ERBB2) overexpression occurs in a subset of BTC and is a precision therapy target.

Zanidatamab, a dual HER2-targeted bispecific antibody, received accelerated US approval for adults with previously treated, unresectable, or metastatic HER2-positive (immunohistochemistry [IHC] score of 3+) BTC and conditional authorization in the European Union and China based on the phase 2 HERIZON-BTC-01 trial. Here, we report the final analysis of HERIZON-BTC-01, which includes OS and patient-reported outcome of worst pain in patients with ERBB2-amplified BTC with an IHC score of 3+ or 2+ after 33 months of follow-up.

Methods

In HERIZON-BTC-01 (NCT04466891), patients with ERBB2-amplified, locally advanced, or metastatic BTC with disease progression with or following prior gemcitabine-based therapy received zanidatamab, 20 mg/kg, intravenously every 2 weeks in 28-day cycles. Trial sites received local independent ethics committee approval. Participants provided written informed consent. The trial protocol is in Supplement 1 and the statistical analysis plan in Supplement 2.

The primary end point was confirmed objective response rate (cORR) by independent central review. Secondary end points included duration of response, disease control rate, progression-free survival, OS, and safety outcomes. Patient-reported worst pain in the last 24 hours was evaluated using the Brief Pain Inventory-Short Form (rated 0 [no pain] to 10 [worst pain imaginable]). Analyses were conducted using SAS version 9.4.

Results

Between September 15, 2020, and March 16, 2022, 80 patients (45 [56%] female; 35 [44%] male; median [range] age, 64 [32-79] years) with IHC 2+ or 3+ tumors were enrolled. The median (range) follow-up was 33.4 (28.0-45.0) months, an additional 21 months from the initial report. Thirty-five patients (44%) received anticancer therapy after discontinuing zanidatamab.

The cORR was 41.3% (95% CI, 30.4-52.8), the median duration of response was 14.9 months (95% CI, 7.4-24.0), and the median OS was 15.5 months (95% CI, 10.4-18.7) (Table; Figure, A). At the time of best overall response, zanidatamab responders demonstrated reduced mean (SD) worst pain scores compared with baseline (complete response, −4.0 [not evaluable]; partial response, −1.0 [2.5]), and those with progressive disease reported an increase (2.4 [2.9]); 59 patients (74%) completed the question at both assessments.

Table. Disease Response by Independent Central Review in Patients With HER2-Overexpressing Advanced Biliary Tract Cancer.

Measure	Patients, No. (%)
Measure	All patients (n = 80)	IHC 3+ tumors (n = 62)	IHC 2+ tumors (n = 18)
cORR, No. (%; 95% CI)	33 (41; 30-53)	32 (52; 39-65)	1 (6; 1-27)
Confirmed BOR
Complete response	3 (4)	3 (5)	0
Partial response	30 (38)	29 (47)	1 (6)
Stable disease	22 (28)	17 (27)	5 (28)
Progressive disease	24 (30)	13 (21)	11 (61)
Not evaluable^a	1 (1)	0	1 (6)
DCR, No. (%; 95% CI)^b	55 (69; 57-79)	49 (79; 67-88)	6 (33; 13-59)
DOR
Total, No.	33	32	1
Median (95% CI), mo	14.9 (7.4-24.0)	14.9 (7.4-24.0)	NE^c
PFS, median (95% CI), mo	5.5 (3.7-7.3)	7.2 (5.4-9.4)	1.7 (1.1-3.3)

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Abbreviations: BOR, best overall response; cORR, confirmed object response rate; DCR, disease control rate; DOR, duration of response; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; NE, not evaluable; PFS, progression-free survival.

^{^a}

No evaluable postbaseline response assessment.

^{^b}

Disease control was defined as a BOR of stable disease or confirmed complete response or partial response.

^{^c}

The responder in the IHC 2+ tumor subset was censored at 7.5 months.

In 62 patients with IHC 3+ tumors, cORR was 51.6% (95% CI, 38.6-64.5), and median OS was 18.1 months (95% CI, 12.2-22.9) (Table; Figure, A). Among 18 patients with IHC 2+ tumors, there was 1 partial response (cORR, 5.6%; 95% CI, 0.1-27.3), and median OS was 5.2 months (95% CI, 3.1-10.2).

Overall, 61 patients (76%) experienced 1 or more treatment-related adverse event (TRAE). Grade 3 TRAEs occurring in more than 2 patients were diarrhea (4 [5.0%]), decreased ejection fraction (3 [3.8%]), and anemia (3 [3.8%]) (Figure, B). There were no treatment-related deaths. Two patients (3%) discontinued zanidatamab due to TRAEs.

Discussion

To our knowledge, HERIZON-BTC-01 remains the largest trial with the longest reported median follow-up (33.4 months) of a HER2-targeted treatment in HER2-positive BTC. The median OS of 15.5 months (18.1 months in the IHC 3+ subset) is notable for this treatment-refractory population. Relative to IHC 3+ tumors, the more modest activity in IHC 2+/amplified tumors observed here supports reflex IHC testing and identifies a cohort for deeper investigation.

Durable responses were maintained; 2 patients with partial response from the primary analysis converted to complete response, supporting continued benefit with zanidatamab. Furthermore, pain reduction among zanidatamab responders suggests potential positive impact on quality of life. No new safety concerns or treatment-related deaths were observed, and treatment-related discontinuations remained low with extended use. Limitations include the post hoc nature of the subset analyses and the potential of nonrandom missing data for pain scores.

These findings support the clinically meaningful benefit of zanidatamab for patients with treatment-refractory HER2-positive BTC. The ongoing phase 3 HERIZON-BTC-302 trial (NCT06282575) is evaluating zanidatamab with standard-of-care first-line treatment in patients with HER2-positive (IHC 3+ or IHC 2+/amplified) BTC.

Supplement 1.

Trial Protocol

jamaoncol-e254736-s001.pdf^{(866KB, pdf)}

Supplement 2.

Statistical Analysis Plan

jamaoncol-e254736-s002.pdf^{(621.3KB, pdf)}

Supplement 3.

Group Information. HERIZON-BTC-01 Study Group

jamaoncol-e254736-s003.pdf^{(80.1KB, pdf)}

Supplement 4.

Data Sharing Statement

jamaoncol-e254736-s004.pdf^{(18.2KB, pdf)}

References

1.Oh DY, Ruth He A, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. Published online August 1, 2022. doi: 10.1056/EVIDoa2200015 [DOI] [PubMed] [Google Scholar]
2.Hyung J, Kim I, Kim KP, et al. Treatment with liposomal irinotecan plus fluorouracil and leucovorin for patients with previously treated metastatic biliary tract cancer: the phase 2b NIFTY randomized clinical trial. JAMA Oncol. 2023;9(5):692-699. doi: 10.1001/jamaoncol.2023.0016 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Galdy S, Lamarca A, McNamara MG, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev. 2017;36(1):141-157. doi: 10.1007/s10555-016-9645-x [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Harding JJ, Fan J, Oh DY, et al. ; HERIZON-BTC-01 study group . Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24(7):772-782. doi: 10.1016/S1470-2045(23)00242-5 [DOI] [PubMed] [Google Scholar]
5.Jazz Pharmaceuticals . Jazz Pharmaceuticals receives European Commission marketing authorization for Ziihera (zanidatamab) for the treatment of advanced HER2-positive biliary tract cancer. Accessed July 9, 2025. https://investor.jazzpharma.com/node/21951/pdf
6.Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58. doi: 10.1200/JCO.23.02005 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

jamaoncol-e254736-s001.pdf^{(866KB, pdf)}

Supplement 2.

Statistical Analysis Plan

jamaoncol-e254736-s002.pdf^{(621.3KB, pdf)}

Supplement 3.

Group Information. HERIZON-BTC-01 Study Group

jamaoncol-e254736-s003.pdf^{(80.1KB, pdf)}

Supplement 4.

Data Sharing Statement

jamaoncol-e254736-s004.pdf^{(18.2KB, pdf)}

[cld250024r1] 1.Oh DY, Ruth He A, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. Published online August 1, 2022. doi: 10.1056/EVIDoa2200015 [DOI] [PubMed] [Google Scholar]

[cld250024r2] 2.Hyung J, Kim I, Kim KP, et al. Treatment with liposomal irinotecan plus fluorouracil and leucovorin for patients with previously treated metastatic biliary tract cancer: the phase 2b NIFTY randomized clinical trial. JAMA Oncol. 2023;9(5):692-699. doi: 10.1001/jamaoncol.2023.0016 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cld250024r3] 3.Galdy S, Lamarca A, McNamara MG, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev. 2017;36(1):141-157. doi: 10.1007/s10555-016-9645-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[cld250024r4] 4.Harding JJ, Fan J, Oh DY, et al. ; HERIZON-BTC-01 study group . Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24(7):772-782. doi: 10.1016/S1470-2045(23)00242-5 [DOI] [PubMed] [Google Scholar]

[cld250024r5] 5.Jazz Pharmaceuticals . Jazz Pharmaceuticals receives European Commission marketing authorization for Ziihera (zanidatamab) for the treatment of advanced HER2-positive biliary tract cancer. Accessed July 9, 2025. https://investor.jazzpharma.com/node/21951/pdf

[cld250024r6] 6.Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58. doi: 10.1200/JCO.23.02005 [DOI] [PMC free article] [PubMed] [Google Scholar]

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Zanidatamab in HER2-Positive Metastatic Biliary Tract Cancer

Shubham Pant, MD

Jia Fan, MD, PhD

Do-Youn Oh, MD, PhD

Hye Jin Choi, MD

Jin Won Kim, MD

Heung-Moon Chang, MD, PhD

Lequn Bao, MD

Hui-Chuan Sun, MD

Teresa Macarulla, MD, PhD

Feng Xie, MD

Jean-Phillippe Metges, MD

Jie’er Ying, MD

John Bridgewater, MD

Myung-Ah Lee, MD

Mohamedtaki A Tejani, MD

Emerson Y Chen, MD

Harpreet Wasan, MD

Michel Ducreux, MD

Yuanyuan Bao, MS

Xiaotian Wu, MS

Yi Zhao, MD

Phillip M Garfin, MD

Jonathon Gable, MPA

James J Harding, MD

Abstract

Methods

Results

Table. Disease Response by Independent Central Review in Patients With HER2-Overexpressing Advanced Biliary Tract Cancer.

Figure. Long-Term Outcomes in Patients With HER2-Overexpressing Advanced Biliary Tract Cancer.

Discussion

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Zanidatamab in HER2-Positive Metastatic Biliary Tract Cancer

Shubham Pant, MD

Jia Fan, MD, PhD

Do-Youn Oh, MD, PhD

Hye Jin Choi, MD

Jin Won Kim, MD

Heung-Moon Chang, MD, PhD

Lequn Bao, MD

Hui-Chuan Sun, MD

Teresa Macarulla, MD, PhD

Feng Xie, MD

Jean-Phillippe Metges, MD

Jie’er Ying, MD

John Bridgewater, MD

Myung-Ah Lee, MD

Mohamedtaki A Tejani, MD

Emerson Y Chen, MD

Harpreet Wasan, MD

Michel Ducreux, MD

Yuanyuan Bao, MS

Xiaotian Wu, MS

Yi Zhao, MD

Phillip M Garfin, MD

Jonathon Gable, MPA

James J Harding, MD

Abstract

Methods

Results

Table. Disease Response by Independent Central Review in Patients With HER2-Overexpressing Advanced Biliary Tract Cancer.

Figure. Long-Term Outcomes in Patients With HER2-Overexpressing Advanced Biliary Tract Cancer.

Discussion

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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