Zanidatamab Monotherapy or Combined With Chemotherapy in HER2-Expressing Gastroesophageal Adenocarcinoma: A Phase 1 Trial

Authors

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
Elena Elimova

Publication Date

5-8-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-59279-z

PMID

40341383

PMCID

PMC12062219

PubMedCentral® Posted Date

5-8-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Female, Receptor, ErbB-2, Middle Aged, Male, Adenocarcinoma, Aged, Esophageal Neoplasms, Stomach Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Adult, Capecitabine, Paclitaxel, Antibodies, Bispecific, Esophagogastric Junction, Progression-Free Survival, Treatment Outcome, Aged, 80 and over

Published Open-Access

yes

Recommended Citation

Meric-Bernstam, Funda; Rha, Sun Young; Hamilton, Erika; et al., "Zanidatamab Monotherapy or Combined With Chemotherapy in HER2-Expressing Gastroesophageal Adenocarcinoma: A Phase 1 Trial" (2025). Faculty, Staff and Student Publications. 3999.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/3999