Background
Open-label, phase 3 trial, 1:1:1 randomization. N=914 with previously untreated, centrally confirmed HER2-positive advanced gastroesophageal adenocarcinoma (gastric/GEJ/esophageal). Zanidatamab is a dual-HER2-targeted bispecific antibody. The trial compared zanidatamab-based regimens (with or without the anti–PD-1 tislelizumab) against the trastuzumab + chemotherapy standard.
Results
Interventions and follow up: Arm A: Zanidatamab + tislelizumab + chemotherapy (n=302)
Arm B: Zanidatamab + chemotherapy (n=304)
Arm C (control): Trastuzumab + chemotherapy (n=308)
Primary endpoints: PFS and OS
mFollow up: 25.9 months (interim analysis)
Results: PFS, zanidatamab–tislelizumab–chemo vs trastuzumab–chemo: median 12.4 vs 8.1 months, HR 0.63, 95% CI 0.51–0.78, P<.001
PFS, zanidatamab–chemo vs trastuzumab–chemo: median 12.4 months, HR 0.65, 95% CI 0.52–0.81, P<.001
OS, zanidatamab–tislelizumab–chemo vs trastuzumab–chemo: median 26.4 vs 19.2 months, HR 0.72, 95% CI 0.57–0.90, P=.004
OS, zanidatamab–chemo vs trastuzumab–chemo: median 24.4 months, HR 0.80, 95% CI 0.64–1.01, P=.06 (NS at interim)
Arm B: Zanidatamab + chemotherapy (n=304)
Arm C (control): Trastuzumab + chemotherapy (n=308)
Primary endpoints: PFS and OS
mFollow up: 25.9 months (interim analysis)
Results: PFS, zanidatamab–tislelizumab–chemo vs trastuzumab–chemo: median 12.4 vs 8.1 months, HR 0.63, 95% CI 0.51–0.78, P<.001
PFS, zanidatamab–chemo vs trastuzumab–chemo: median 12.4 months, HR 0.65, 95% CI 0.52–0.81, P<.001
OS, zanidatamab–tislelizumab–chemo vs trastuzumab–chemo: median 26.4 vs 19.2 months, HR 0.72, 95% CI 0.57–0.90, P=.004
OS, zanidatamab–chemo vs trastuzumab–chemo: median 24.4 months, HR 0.80, 95% CI 0.64–1.01, P=.06 (NS at interim)
Adverse events
Grade ≥3 AE (any): 83.3% (zani–tis–chemo) vs 73.8% (zani–chemo) vs 74.5% (trastuzumab–chemo)
Most common grade ≥3 — diarrhea: 24.8% vs 20.0% vs 12.9%
Most common grade ≥3 — diarrhea: 24.8% vs 20.0% vs 12.9%
Conclusions
In 1L HER2+ advanced gastroesophageal adenocarcinoma, zanidatamab + chemotherapy (with or without tislelizumab) significantly prolonged PFS vs trastuzumab + chemotherapy. The zanidatamab–tislelizumab–chemo triplet also improved OS (26.4 vs 19.2 months) at interim; the chemo-doublet's OS benefit was not yet significant. Diarrhea was the most common grade ≥3 event.
Key Limitations
Open-label design. At interim, OS reached significance only for the tislelizumab-containing triplet; zanidatamab–chemo OS (HR 0.80) was not significant and awaits further analysis, leaving the relative contribution of tislelizumab vs zanidatamab alone unresolved. Higher grade ≥3 toxicity (notably diarrhea) with the triplet. PD-L1 / HER2-expression subgroup effects and mature OS pending.
Clinical Context
Standard 1L for HER2+ gastroesophageal adenocarcinoma is trastuzumab + chemotherapy + pembrolizumab (KEYNOTE-811). HERIZON-GEA-01 is the first phase 3 to show a HER2 bispecific antibody improving outcomes over trastuzumab in this setting. Zanidatamab is FDA-approved for previously-treated HER2+ biliary tract cancer (2024); for 1L gastroesophageal it is under FDA priority review (sBLA accepted; PDUFA target Aug 25, 2026). Not yet in NCCN/ESMO frontline guidance pending approval; cross-trial positioning vs the KEYNOTE-811 trastuzumab–pembrolizumab regimen remains to be defined.