What question did this study set out to answer?

This analysis aimed to evaluate the efficacy of zanidatamab combined with chemotherapy and tislelizumab based on PD-L1 expression in HER2-positive mGEA.

May 29, 2026

Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced or metastatic gastroesophageal adenocarcinoma (mGEA): PD-L1 subgroup analysis from HERIZON-GEA-01.

Key Points

This analysis aimed to evaluate the efficacy of zanidatamab combined with chemotherapy and tislelizumab based on PD-L1 expression in HER2-positive mGEA.
Patients with untreated HER2+ mGEA were randomized to receive either zanidatamab plus chemotherapy with or without tislelizumab.
PD-L1 expression was assessed using the VENTANA SP263 assay, focusing on TAP and CPS scores.
The primary endpoints included progression-free survival (PFS) and overall survival (OS).
The addition of tislelizumab to zanidatamab plus chemotherapy significantly prolonged PFS (HR, 0.63; P < 0.001) and OS (HR, 0.72; P = 0.004).
In PD-L1 negative and positive patients, similar improvements in PFS and OS were observed when treated with zanidatamab plus tislelizumab.
In PD-L1 TAP <1% group, the 24-month OS was 63.7%, and the TAP ≥1% group had an OS of 53.5%.

Abstract

4010 Background: In HERIZON-GEA-01 (NCT05152147), 1L zanidatamab + CT ± tislelizumab significantly improved progression-free survival (PFS) and, with tislelizumab, yielded a statistically significant overall survival (OS) benefit in HER2+ mGEA. Here we report efficacy in PD-L1 subgroups. Methods: Eligible patients (pts) with previously untreated HER2+ mGEA, irrespective 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. PD-L1 expression was retrospectively assessed using the VENTANA SP263 assay according to tumor area positivity (TAP) score and combined positive score (CPS). Primary endpoints were PFS (BICR) and OS; efficacy by PD-L1 status (TAP) was prespecified. Results: With 26 mo median follow-up, PFS (HR, 0.63; P <0.001) and OS (HR, 0.72; P = 0.004) were significantly prolonged with zanidatamab + tislelizumab + CT vs tras + CT in the ITT population. In pts treated with zanidatamab + tislelizumab + CT, similarly prolonged PFS and OS were observed in PD-L1–negative and PD-L1–positive pts (Table); data were consistent between TAP and CPS. In PD-L1 TAP <1% and ≥1% pts, the 18-mo PFS was 50.3% and 42.6%, respectively, and the 24-mo OS was 63.7% and 53.5% with zanidatamab + tislelizumab + CT. In the tras + CT arm, OS was prolonged in PD-L1–positive vs –negative pts. Of note, in the tras + CT arm, 15% of pts received subsequent checkpoint inhibitors and 29% received subsequent HER2-targeted therapies vs 2% and 13%, respectively, in the zanidatamab + tislelizumab + CT arm. Additional details on these subgroups will be presented at the congress. Conclusions: In HERIZON-GEA-01, zanidatamab + tislelizumab + CT demonstrated meaningful improvements in PFS and OS in both PD-L1–positive and PD-L1–negative pts as determined by TAP or CPS. The longer OS observed with tras + CT in PD-L1–positive vs –negative pts may be at least partially explained by differences in subsequent therapies. These findings are notable as they demonstrate benefit for this regimen regardless of PD-L1 status. Clinical trial information: NCT05152147 . Zanidatamab + Tislelizumab + CT Tras + CT ITT NmPFS (95% CI), momOS (95% CI), mo 30212.4 (9.8, 18.5)26.4 (21.5, 30.3) 3088.1 (7.0, 8.9)19.2 (16.8, 21.8) TAP <1%n (%)mPFS (95% CI), momOS (95% CI), mo 90 (29.8)18.5 (9.7, 25.2)29.7 (24.7, NE) 98 (31.8)7.9 (5.8, 9.6)15.8 (12.6, 21.4) CPS <1n (%)mPFS (95% CI), momOS (95% CI), mo 78 (25.8)18.5 (9.7, 25.2)30.3 (25.7, NE) 80 (26.0)8.1 (5.8, 9.8)15.7 (12.6, 21.4) TAP ≥1%n (%)mPFS (95% CI), momOS (95% CI), mo 187 (61.9)11.3 (9.6, 18.5)26.4 (18.7, 35.9) 188 (61.0)8.3 (6.9, 9.7)21.2 (17.7, 25.2) CPS ≥1n (%)mPFS (95% CI), momOS (95% CI), mo 198 (65.6)12.3 (9.7, 18.5)26.4 (18.7, 34.6) 206 (66.9)8.2 (6.9, 9.1)20.8 (17.3, 23.9)

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