Phase Ib/II Study of Zanidatamab in Combination with Tislelizumab and Chemotherapy in First-Line HER2-Positive Gastric/Gastroesophageal Junction Adenocarcinoma

Lee, Keun-Wook; Bai, Li-Yuan; Jung, Minkyu; Ying, Jieer; Im, Young-Hyuck; Oh, Do-Youn; Cho, Jae Yong; Oh, Sang Cheul; Chao, Yee; Kim, Jin Won; Chen, Ye; Li, Vincent; Chen, Shengnan; Kang, Yoon-Koo

doi:10.1158/1078-0432.CCR-24-4295

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Phase Ib/II Study of Zanidatamab in Combination with Tislelizumab and Chemotherapy in First-Line HER2-Positive Gastric/Gastroesophageal Junction Adenocarcinoma

Authors: Lee, Keun-Wook ; Bai, Li-Yuan ; Jung, Minkyu ; Ying, Jieer ; Im, Young-Hyuck ; Oh, Do-Youn ; Cho, Jae Yong ; Oh, Sang Cheul ; Chao, Yee ; Kim, Jin Won ; Chen, Ye ; Li, Vincent ; Chen, Shengnan ; Kang, Yoon-Koo

Citation: CLINICAL CANCER RESEARCH, Vol.32(2) : 312-323, 2026-01

Journal Title: CLINICAL CANCER RESEARCH

ISSN: 1078-0432

Issue Date: 2026-01

MeSH: Adenocarcinoma* / drug therapy ; Adenocarcinoma* / genetics ; Adenocarcinoma* / metabolism ; Adenocarcinoma* / mortality ; Adenocarcinoma* / pathology ; Adult ; Aged ; Antibodies, Bispecific ; Antibodies, Monoclonal, Humanized* / administration & dosage ; Antibodies, Monoclonal, Humanized* / adverse effects ; Antibodies, Monoclonal, Humanized* / pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols* / adverse effects ; Antineoplastic Combined Chemotherapy Protocols* / therapeutic use ; Capecitabine / administration & dosage ; Erb-b2 Receptor Tyrosine Kinases* / genetics ; Erb-b2 Receptor Tyrosine Kinases* / metabolism ; Esophageal Neoplasms* / drug therapy ; Esophageal Neoplasms* / mortality ; Esophageal Neoplasms* / pathology ; Esophagogastric Junction* / drug effects ; Esophagogastric Junction* / pathology ; Female ; Humans ; Male ; Middle Aged ; Oxaliplatin / administration & dosage ; Stomach Neoplasms* / drug therapy ; Stomach Neoplasms* / metabolism ; Stomach Neoplasms* / mortality ; Stomach Neoplasms* / pathology

Abstract: Purpose: This phase Ib/II trial (NCT04276493) assessed the antitumor activity, safety, and pharmacokinetics (PK) of zanidatamab in combination with tislelizumab and chemotherapy in patients with advanced HER2-positive (HER2+) gastric cancer/gastroesophageal junction cancer (GEJC).Patients and Methods: Adult patients with previously untreated, unresectable, locally advanced/metastatic HER2+ gastric cancer/GEJC received zanidatamab 30 mg/kg i.v. (cohort A) or zanidatamab 1800 mg i.v. (weight <70 kg)/2,400 mg i.v. (weight >= 70 kg; cohort B) once every 3 weeks (Q3W). Both cohorts received tislelizumab 200 mg i.v. once every 3 weeks and standard chemotherapy [capecitabine and oxaliplatin (CAPOX)] once every 3 weeks. Primary endpoints were investigator-assessed confirmed objective response rate (cORR) per RECIST v1.1, in addition to the frequency and severity of adverse events (AE) and serious AEs. Secondary endpoints included investigator-assessed progression-free survival (PFS), duration of response (DoR), overall survival (OS), PK, and immunogenicity of zanidatamab.Results: As of December 7, 2023, 33 patients (cohort A, n = 19; cohort B, n = 14) received treatment. The confirmed objective response rate was 75.8%; the median duration of response, progression-free survival, and overall survival were 23.3, 16.7, and 32.4 months, respectively. The most common treatment-related AEs (TRAEs) were diarrhea (100%), nausea (63.6%), and decreased appetite (48.5%). Treatment-related AEs of grade >= 3 were reported in 22 (66.7%) patients; diarrhea was the most common (27.3%).Conclusions: Zanidatamab, in combination with tislelizumab and CAPOX, demonstrated clinically meaningful antitumor activity with a manageable safety profile as first-line therapy for patients with HER2+ gastric cancer/GEJC. These results support a further development of zanidatamab and tislelizumab with chemotherapy in this patient population in the ongoing phase III HERIZON-GEA-01 trial (NCT05152147).