The objective of this planned second interim analysis (IA2) of the phase 3 HERIZON-GEA-01 trial was to evaluate overall survival (OS) in patients with previously untreated HER2-positive advanced/metastatic gastroesophageal adenocarcinoma (mGEA) receiving zanidatamab plus chemotherapy with or without tislelizumab compared with trastuzumab plus chemotherapy.

Patients with untreated HER2+ mGEA were randomized 1:1:1 to zanidatamab plus chemotherapy, zanidatamab plus tislelizumab and chemotherapy, or trastuzumab plus chemotherapy. Progression-free survival by blinded independent central review and OS were the primary endpoints. At IA2, OS comparisons were formally tested sequentially for zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy, followed by zanidatamab plus tislelizumab and chemotherapy versus zanidatamab plus chemotherapy.

A total of 914 patients were randomized. With a median follow-up of 35.3 months (data cutoff: 15 July 2026; 9.4 months longer than IA1 ), OS showed a significant improvement with zani + CT versus tras + CT (HR, 0.76; 95% CI, 0.62–0.93; P=0.0088), with median OS of 22.9 months (95% CI, 19.9–27.6) and 19.6 months (95% CI, 16.9–22.2), respectively. A 4-month longer median OS was observed with zani + TIS + CT (27.0 months [95% CI, 23.7–32.2]) vs zani + CT (HR 0.81 [95% CI, 0.65–1.00]), although the difference was not statistically significant (P=0.0502). The OS benefit of zani + TIS + CT versus tras + CT observed at IA1 (HR, 0.72) was sustained at IA2 with an improved HR (0.65; 95% CI, 0.52–0.80).

Estimated 36-month OS rates were 39.8%, 31.5%, and 22.9% for zani + TIS + CT, zani + CT, and tras + CT, respectively. Median duration of treatment was 46.6 (40.5 for zani) weeks with zani + CT + TIS, 31.1 (30.1 for zani) weeks with zani + CT, and 30.0 (28.2 for tras) weeks with tras + CT.

Safety profiles were reported as consistent with the first interim analysis.