Zanidatamab (zani) + chemotherapy (CT) ± tislelizumab (TIS) for first-line (1L) HER2-positive (HER2+) advanced/metastatic gastroesophageal adenocarcinoma (mGEA): Second interim analysis (IA) from HERIZON-GEA-01

HERIZON-GEA-01

Paziente / Popolazione Intervento / Esposizione Confronto Esito

In patients with untreated HER2-positive advanced or metastatic gastroesophageal adenocarcinoma, zanidatamab plus chemotherapy improved overall survival compared with trastuzumab plus chemotherapy.

N

914pazienti

Disegno

Phase 3 trial randomising 914 patients with untreated HER2-positive advanced or metastatic gastroesophageal adenocarcinoma 1:1:1 to zanidatamab plus chemotherapy (capecitabine/oxaliplatin or 5-FU/cisplatin), zanidatamab plus chemotherapy plus tislelizumab, or trastuzumab plus chemotherapy (NCT05152147).

Esito

Co-primary endpoints of progression-free survival by blinded independent central review and overall survival. At this second interim analysis, overall survival was tested in sequence: zanidatamab plus chemotherapy vs trastuzumab plus chemotherapy, then zanidatamab plus chemotherapy plus tislelizumab vs zanidatamab plus chemotherapy.

RisultatoMedian overall survival with zanidatamab plus chemotherapy 22.9 months (95% CI 19.9-27.6) vs 19.6 months (95% CI 16.9-22.2) with trastuzumab plus chemotherapy (HR 0.76, 95% CI 0.62-0.93; P = 0.0088), at a median follow-up of 35.3 months. Median overall survival with zanidatamab plus tislelizumab plus chemotherapy 27.0 months (95% CI 23.7-32.2), 4 months longer than with zanidatamab plus chemotherapy (HR 0.81, 95% CI 0.65-1.00; P = 0.0502, not statistically significant). Zanidatamab plus chemotherapy plus tislelizumab vs trastuzumab plus chemotherapy HR 0.65 (95% CI 0.52-0.80). Estimated 36-month overall survival 39.8% with zanidatamab plus chemotherapy plus tislelizumab, 31.5% with zanidatamab plus chemotherapy and 22.9% with trastuzumab plus chemotherapy. Median duration of treatment 46.6 vs 31.1 vs 30.0 weeks. Safety profiles were consistent with the first interim analysis.

Shitara K, Rha SY, Elimova E, et al. Presented at ESMO Congress 2026, abstract LBA79, 23 October. Not yet published.

Discussione e critica

With a median follow-up of 35.3 months, this second interim analysis shows a statistically significant overall survival gain for zanidatamab plus chemotherapy over trastuzumab plus chemotherapy, a hard endpoint against an active HER2-directed comparator. Adding tislelizumab to zanidatamab plus chemotherapy narrowly missed significance (P = 0.0502), so its contribution beyond the doublet is not established, and the HR of 0.65 for the triplet vs trastuzumab plus chemotherapy was not one of the two comparisons formally tested at this analysis. The abstract does not state whether treatment was blinded, and it gives no updated progression-free survival, adverse event rates or subgroup results such as by PD-L1 status. Safety is described only as consistent with the earlier analysis, which leaves the tolerability of the longer triplet exposure hard to judge from this source.