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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & J, 2025. "Zanidatamab monotherapy or combined with chemotherapy in HER2-expressing gastroesophageal adenocarcinoma: a phase 1 trial," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59279-z
    DOI: 10.1038/s41467-025-59279-z
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    1. Nina E. Weisser & Mario Sanches & Eric Escobar-Cabrera & Jason O’Toole & Elizabeth Whalen & Peter W. Y. Chan & Grant Wickman & Libin Abraham & Kate Choi & Bryant Harbourne & Antonios Samiotakis & Andr, 2023. "An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Yelena Y. Janjigian & Akihito Kawazoe & Patricio Yañez & Ning Li & Sara Lonardi & Oleksii Kolesnik & Olga Barajas & Yuxian Bai & Lin Shen & Yong Tang & Lucjan S. Wyrwicz & Jianming Xu & Kohei Shitara , 2021. "The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer," Nature, Nature, vol. 600(7890), pages 727-730, December.
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