Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer

Clinical Snapshot

Key Findings

• P Value: P<0.001 for both PFS comparisons; P=0.004 for OS (zanidatamab-tislelizumab vs trastuzumab)

• Effect Size: PFS hazard ratio 0.63-0.65; OS hazard ratio 0.72 for zanidatamab-tislelizumab vs trastuzumab

• Primary Outcome: Progression-free survival: 12.4 months (both zanidatamab arms) vs 8.1 months (trastuzumab); Overall survival: 26.4 months (zanidatamab-tislelizumab) vs 19.2 months (trastuzumab)

• Nnt Or Sensitivity: Median PFS benefit of 4.3 months; median OS benefit of 7.2 months with zanidatamab-tislelizumab combination

• Confidence Interval: PFS: 95% CI 0.51-0.78 (zanidatamab-tislelizumab), 0.52-0.81 (zanidatamab alone); OS: 95% CI 0.57-0.90

Clinical Application

Requires HER2 testing infrastructure and access to bispecific antibody therapy; manageable toxicity profile with increased diarrhoea monitoring Would require TGA approval and PBS listing; aligns with current HER2 testing practices; may impact current trastuzumab-based first-line protocols pending cost-effectiveness evaluation Patients with previously untreated HER2-positive advanced gastroesophageal adenocarcinoma suitable for systemic therapy

Abstract

BACKGROUND: Zanidatamab, a dual human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody, plus chemotherapy both with and without tislelizumab (anti-programmed death 1), showed encouraging efficacy and safety as first-line therapy in phase 2 studies involving patients with HER2-positive gastroesophageal adenocarcinoma. METHODS: In an open-label, phase 3 trial, we randomly assigned, in a 1:1:1 ratio, patients with previously untreated, centrally confirmed HER2-positive advanced gastroesophageal adenocarcinoma to receive zanidatamab and tislelizumab plus chemotherapy, zanidatamab plus chemotherapy, or trastuzumab plus chemotherapy. The two primary end points were progression-free survival and overall survival. RESULTS: At a median follow-up of 25.9 months, progression-free survival was longer with zanidatamab-tislelizumab-chemotherapy (median among 302 patients, 12.4 months) and zanidatamab-chemotherapy (median among 304 patients, 12.4 months) than with trastuzumab-chemotherapy (median among 308 patients, 8.1 months) (hazard ratio for progression or death with zanidatamab-tislelizumab-chemotherapy, 0.63 [95% confidence interval {CI}, 0.51 to 0.78]; hazard ratio with zanidatamab-chemotherapy, 0.65 [95% CI, 0.52 to 0.81]; P<0.001 for both comparisons). Overall survival was longer with zanidatamab-tislelizumab-chemotherapy than with trastuzumab-chemotherapy (median, 26.4 vs. 19.2 months; hazard ratio for death, 0.72; 95% CI, 0.57 to 0.90; P = 0.004). At this interim analysis, overall survival did not differ significantly between zanidatamab-chemotherapy (median, 24.4 months) and trastuzumab-chemotherapy (hazard ratio, 0.80; 95% CI, 0.64 to 1.01; P = 0.06). The incidence of grade 3 or higher adverse events was 83.3% with zanidatamab-tislelizumab-chemotherapy, 73.8% with zanidatamab-chemotherapy, and 74.5% with trastuzumab-chemotherapy; diarrhea was the most common such event, in 24.8%, 20.0%, and 12.9% of patients, respectively. CONCLUSIONS: Zanidatamab plus chemotherapy, both with and without tislelizumab, led to longer progression-free survival than trastuzumab plus chemotherapy among patients with HER2-positive advanced gastroesophageal adenocarcinoma. At this interim analysis, overall survival was longer with zanidatamab-tislelizumab-chemotherapy than with trastuzumab-chemotherapy; further analyses are planned to assess zanidatamab-chemotherapy. Diarrhea was a common adverse event. (Funded by Jazz Pharmaceuticals and others; HERIZON-GEA-01 ClinicalTrials.gov number, NCT05152147.).

References

1. 1.Shitara, K., Elimova, E., Liu, T., Tabernero, J., Lee, K.-W., Schenker, M., Tebbutt, N. C., Ajani, J., Salimin, N., Ku, G., Kim, J. G., Diaz, I. A., Zhang, J., Pietrantonio, F., Bai, L.-Y., Le Sourd, S., Zhao, J., Hierro, C., Kiberu, A., Van Herpe, F., Bao, Y., Zhang, H., Yang, L., Li, V., Gartner, E. M., Chen, Y., Grim, J., Rha, S. Y., & Shen, L. (2026). Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. *New England Journal of Medicine*. https://doi.org/10.1056/NEJMoa2517729