Multinational phase 3 trial of first-line zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer

Zanidatamab is a dual HER2-targeted bispecific antibody. The multinational phase 3 HERIZON-GEA-01 trial evaluated first-line zanidatamab in patients with HER2-positive advanced gastroesophageal adenocarcinoma (GEA. Patients were randomized 1:1:1 to receive zanidatamab and tislelizumab plus chemotherapy (n=302), zanidatamab plus chemotherapy (n=304), or trastuzumab plus chemotherapy (n=308). Primary endpoints were progression-free survival and overall survival (PFS/OS). At an interiam analysis after median follow-up of 25.9 months, median PFS was longer with zanidatamab-tislelizumab-chemotherapy (12.4 months; HR 0.63; 95% CI 0.51-0.78; p<0.001) and zanidatamab-chemotherapy (12.4 months; HR 0.65; 95% CI 0.52-0.81; p<0.001) than with trastuzumab-chemotherapy (8.1 months). Median OS was longer with zanidatamab-tislelizumab-chemotherapy than with trastuzumab-chemotherapy (26.4 months versus 19.2 months; HR 0.72; 95% CI 0.57-0.90; p=0.004) but did not differ significantly between zanidatamab-chemotherapy (24.4 months) and trastuzumab-chemotherapy (HR 0.80; 95% CI 0.64-1.01; p=0.06). The incidence of grade 3 or higher adverse events was 83.3% with zanidatamab-tislezlizumab-chemotherapy, 73.8% with zanidatamab-chemotherapy, and 74.5% with trastuzumab-chemotherapy. The authors conclude that at this interim analysis, zanidatamab plus chemotherapy, with or without tislelizumab, led to longer PFS than trastzuzumab-chemotherapy among patients with HER2-positive advanced GEA, whereas OS was longer with zanidatamab-tislelizumab-chemotherapy than with trastuzumab-chemotherapy; further analyses are planned to assess zanidatamab-chemotherapy (quick take video summary).