The study evaluated the efficacy of the investigational combination of zanidatamab plus tislelizumab plus chemotherapy compared with trastuzumab plus chemotherapy for PD-L1 subgroup analysis as first-line treatment for patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma.

HERIZON-GEA-01 was a randomized study in which eligible patients, irrespective of PD-L1 status, were assigned in a 1:1:1 ratio to zanidatamab plus tislelizumab plus chemotherapy, zanidatamab plus chemotherapy, or trastuzumab plus chemotherapy. PD-L1 expression was retrospectively assessed using the VENTANA SP263 assay according to tumor area positivity (TAP) and combined positive score (CPS). The dual primary endpoints were progression-free survival (PFS) assessed by blinded independent central review and overall survival (OS). Efficacy by PD-L1 status was evaluated as a prespecified analysis.

With a median follow‑up of 26 months, PFS (HR, 0.63; P<0.001) and OS (HR, 0.72; P=0.004) were significantly prolonged with zanidatamab plus tislelizumab plus chemotherapy compared with trastuzumab plus chemotherapy in the intention‑to‑treat population. In patients treated with zanidatamab plus tislelizumab plus chemotherapy, similar prolongation of PFS and OS was observed in both PD‑L1–negative and PD‑L1–positive subgroups, with consistent findings across TAP and CPS assessments. Among patients with PD‑L1 TAP <1% and ≥1%, 18‑month PFS rates were 50.3% and 42.6%, respectively, and 24‑month OS rates were 63.7% and 53.5%. In the trastuzumab plus chemotherapy arm, OS was longer in PD‑L1–positive than in PD‑L1–negative patients. Subsequent therapies differed between treatment arms: in the trastuzumab plus chemotherapy arm, 15% of patients received subsequent immune checkpoint inhibitors and 29% received subsequent HER2‑targeted therapies, compared with 2% and 13%, respectively, in the zanidatamab plus tislelizumab plus chemotherapy arm.