Zanidatamab monotherapy or combined with chemotherapy in HER2-expressing gastroesophageal adenocarcinoma: a phase 1 trial

Funda Meric-Bernstam (), Sun Young Rha, Erika Hamilton, Yoon-Koo Kang, Diana L. Hanna, Syma Iqbal, Keun-Wook Lee, Jeeyun Lee, Muralidhar Beeram, Do-Youn Oh, Jorge Chaves, Rachel A. Goodwin, Jaffer A. Ajani, Lin Yang, Rajen Oza and Elena Elimova
Additional contact information
Funda Meric-Bernstam: University of Texas MD Anderson Cancer Center
Sun Young Rha: Yonsei University College of Medicine
Erika Hamilton: Sarah Cannon Research Institute
Yoon-Koo Kang: University of Ulsan College of Medicine
Diana L. Hanna: USC Norris Comprehensive Cancer Center
Syma Iqbal: USC Norris Comprehensive Cancer Center
Keun-Wook Lee: Seoul National University Bundang Hospital
Jeeyun Lee: Sungkyunkwan University School of Medicine
Muralidhar Beeram: START Center for Cancer Care
Do-Youn Oh: Seoul National University Graduate School
Jorge Chaves: Northwest Medical Specialties
Rachel A. Goodwin: Ottawa Hospital Research Centre
Jaffer A. Ajani: The University of Texas MD Anderson Cancer Center
Lin Yang: Jazz Pharmaceuticals
Rajen Oza: Jazz Pharmaceuticals
Elena Elimova: Princess Margaret Cancer Centre

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract There is a need for novel therapies for patients with previously treated HER2-positive gastroesophageal adenocarcinoma (GEA). This phase 1 (NCT02892123) dose-escalation and expansion trial evaluated zanidatamab (a dual HER2-targeted bispecific antibody) ± chemotherapy in previously treated patients with HER2-expressing, locally advanced/metastatic cancers. Here, we report the outcomes for GEA cohorts receiving zanidatamab monotherapy or with chemotherapy (paclitaxel or capecitabine). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate, progression-free survival, pharmacokinetics, and immunogenicity. Seventy patients were enrolled (n = 29 monotherapy; n = 41 combination therapy); most received prior HER2-targeted agents (monotherapy, 93%; combination therapy, 95%). With monotherapy, 69% of patients had any-grade treatment-related AEs (TRAEs); 17% had grade ≥ 3 TRAEs. The most common any-grade TRAEs were diarrhea (41%) and infusion-related reactions (24%). With combination therapy, 98% of patients had any-grade TRAEs; 51% had grade ≥ 3 TRAEs. The most common any-grade TRAEs were diarrhea (68%) and fatigue (44%). Confirmed ORR was 32.1% (95% confidence interval [CI] 15.9–52.4) with monotherapy and 48.6% (95% CI 31.9–65.6) with combination therapy. In heavily pre-treated patients with HER2-expressing GEA, zanidatamab ± chemotherapy had a manageable safety profile and promising antitumor activity.

Date: 2025
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DOI: 10.1038/s41467-025-59279-z

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