Ep. 1: Zanidatamab Redefines First-Line Therapy in HER2-Positive Upper GI Malignancies
Key Points
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HERIZON-GEA-01 demonstrated superior progression-free survival (PFS) with zanidatamab plus chemotherapy compared with trastuzumab-based therapy in the frontline setting.
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Adding tislelizumab to zanidatamab and chemotherapy further improved both PFS and overall survival (OS), regardless of PD-L1 status.
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These results support a shift away from trastuzumab-based regimens as the default first-line approach for HER2-positive metastatic gastric and gastroesophageal junction (GEJ) cancers.
Zanidatamab and the Current Frontline Landscape
During a Clinical Insights discussion at an event coinciding with the 2026 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI 2026), Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, were joined by Geoffrey Ku, MD, of Memorial Sloan Kettering Cancer Center; Rutika Mehta, MD, MB, MPH, of Weill Cornell Medicine; Manish Shah, MD, of Weill Cornell Medicine; and Nataliya Uboha, MD, PhD, of the University of Wisconsin School of Medicine and Public Health, to review emerging frontline data in HER2-positive upper gastrointestinal malignancies. The panel highlighted the treatment paradigm’s rapid evolution, particularly following perioperative advances such as MATTERHORN, as well as metastatic data from HERIZON-GEA-01.
Dr. Uboha outlined the current standard of care for patients with advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma, emphasizing the role of comprehensive biomarker testing. “When a patient walks into the door with stage IV, or advanced, unresectable metastatic GEA cancer, we’re typically looking at four different biomarkers: MMR, HER2, PD-L1, and Claudin 18.2,” she said. Currently, HER2-positive, PD-L1–negative tumors are treated with chemotherapy plus trastuzumab, while PD-L1–positive disease receives the addition of pembrolizumab.
HERIZON-GEA-01 Design, Efficacy, and Clinical Impact
The panel then turned to HERIZON-GEA-01, a global phase III trial evaluating zanidatamab, a bispecific HER2 antibody binding 2 extracellular domains of the HER2 receptor. Dr. Shah described the mechanism, noting that dual binding allows for increased receptor clustering and immune activation. This differentiated mechanism underpinned the evaluation of zanidatamab in 3 frontline regimens: trastuzumab plus chemotherapy, zanidatamab plus chemotherapy, and zanidatamab combined with tislelizumab and chemotherapy.
Dr. Ku summarized the efficacy findings, stating that the data “showed very clearly that zanidatamab plus chemotherapy is superior to trastuzumab plus chemotherapy in terms of progression-free survival.”
Although OS data remain immature, early analyses demonstrated a clinically meaningful benefit approaching statistical significance. Importantly, the triplet regimen incorporating tislelizumab produced statistically significant and clinically substantial improvements in both PFS and OS compared with the control arm, independent of PD-L1 expression. These findings suggest that zanidatamab-based regimens may represent a new frontline standard for HER2-positive metastatic gastric and GEJ cancers, with implications for treatment selection and sequencing across biomarker subgroups.