Zanidatamab Plus Chemotherapy Prolongs Progression-Free Survival in advanced GE adenocarcinoma: NEJM

Study participants included adults who had never been treated before for their HER2 positive advanced gastro-esophageal cancer, with the diagnosis confirmed by central testing. Participants met eligibility criteria and were then randomized strictly using a 1:1:1 proportion in order to be put into three different groups for the administration of three separate first-line therapy strategies aimed at studying both single and synergistic effects from the treatments.

In the first experimental group, triple combination therapy including zanidatamab (bispecific antibody), tislelizumab (anti-PD-1 checkpoint inhibitor), and systemic chemotherapy was administered. In the second group, double combination of zanidatamab and chemotherapy was used for the purpose of isolating the impact of the bispecific antibody on patients’ condition. The third, active control group included only trastuzumab in combination with the same chemotherapy. Both progression free survival and overall survival served as primary outcome measures.

Key findings:

• The successful randomization was achieved in the international phase 3 trial involving 914 patients in total, where 302 patients were assigned to the triple immunotherapy treatment group, 304 patients were randomized into the doublet group of zanidatamab, and another 308 patients were randomized into the trastuzumab standard chemotherapy control group.
• With a median follow-up period of 25.9 months, the median progression-free survival for both groups receiving zanidatamab combined either with tislelizumab and chemotherapy or with chemotherapy alone achieved 12.4 months compared to 8.1 months for the control group with trastuzumab plus chemotherapy (P < 0.001).
• In terms of hazard ratios, the risk of developing disease progression or death in the first group was significantly reduced to 0.63 (95% CI: 0.51-0.78), while in the second one – to 0.65 (95% CI: 0.52-0.81).
• Moreover, in terms of overall survival, the median time was 26.4 months for those who had the first treatment compared to only 19.2 months for the control group (HR: 0.72; 95% CI: 0.57-0.90; P = 0.004).
• At the current interim analysis point, however, there was no significant difference in terms of OS between zanidatamab-chemotherapy (median: 24.4 months) and trastuzumab-chemotherapy (HR: 0.80; 95% CI: 0.64–1.01; P = 0.06).
• The absolute incidence of grade 3 or higher adverse events was 83.3% with the triplet immunochemotherapy regimen, 73.8% with zanidatamab doublet therapy, and 74.5% with the trastuzumab control protocol.
• Diarrhea was confirmed as the most common severe complication across all cohorts, appearing in 24.8% of the triplet arm, 20.0% of the doublet zanidatamab arm, and 12.9% of the trastuzumab-chemotherapy control patients.

In summary, the addition of zanidatamab, either with or without tislelizumab, to chemotherapy resulted in prolonged progression-free survival in patients with HER2 positive advanced gastroesophageal adenocarcinoma as compared to trastuzumab combined with chemotherapy. In this interim analysis, the addition of zanidatamab combined with tislelizumab to chemotherapy showed better overall survival results than the addition of trastuzumab with chemotherapy, while future analyses will be required to examine the effects of zanidatamab with chemotherapy.

Reference:

Shitara, K., Elimova, E., Liu, T., Tabernero, J., Lee, K.-W., Schenker, M., Tebbutt, N. C., Ajani, J., Salimin, N., Ku, G., Gwang Kim, J., Ales Diaz, I., Zhang, J., Pietrantonio, F., Bai, L.-Y., Le Sourd, S., Zhao, J., Hierro, C., Kiberu, A., … HERIZON-GEA-01 Investigators. (2026). Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. The New England Journal of Medicine, 394(20), 2002–2014. https://doi.org/10.1056/NEJMoa2517729