Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): Primary analysis from HERIZON-GEA-01.

Eligible patients (pts) with previously untreated HER2+ mGEA, regardless of PD-L1 status, were randomized (1:1:1) to zanidatamab (1800 mg [<70 kg] / 2400 mg [≥70 kg] IV Q3W) + tislelizumab (200 mg IV Q3W) + capecitabine/oxaliplatin (CAPOX) or 5-FU/cisplatin (FP); zanidatamab + CAPOX or FP; or tras + CAPOX or FP. Dual primary endpoints were progression-free survival (PFS) by blinded independent central review and overall survival (OS).

914 pts were randomized (Dec 2021 to Feb 2025). Demographics and baseline disease characteristics were balanced. At data cutoff (Oct 2025), median follow-up was 26 mo. Compared with tras + CT, PFS was significantly prolonged in zanidatamab-containing arms (Table). A statistically significant OS benefit was observed with zanidatamab + tislelizumab + CT (Table). OS for zanidatamab + CT was not significant at the first interim analysis, although a strong trend favoring zanidatamab + CT was observed. Improvements in PFS and OS occurred across major subgroups, including by region and PD-L1 TAP score. Grade ≥3 treatment-related AEs (TRAEs) occurred in 71.8% of pts with zanidatamab + tislelizumab + CT, 59.0% with zanidatamab + CT, and 59.6% with tras + CT. Grade ≥3 TRAEs occurring in >10% of pts in either zanidatamab-containing arm were diarrhea, hypokalemia, and anemia; the tras + CT arm were diarrhea, anemia, neutrophil count decreased, and platelet count decreased. HER2-targeted therapy was discontinued for related AEs in 11.9% of pts with zanidatamab + tislelizumab + CT, 8.5% with zanidatamab + CT, and 2.3% with tras + CT.