Zanidatamab Combinations Outperform Trastuzumab in HER2-Positive Gastroesophageal Cancer
A phase III trial found that the bispecific antibody zanidatamab combined with chemotherapy improved progression-free and overall survival compared with trastuzumab plus chemotherapy as first-line treatment for metastatic HER2-positive gastroesophageal adenocarcinoma. Adding the PD-1 inhibitor tislelizumab to the zanidatamab regimen also outperformed the older anti-HER2 antibody combination. The results mark a rapid evolution in a field that had seen no major advances since 2010.
The HERIZON-GEA-01 results mark the second major shift in first-line treatment within a few years, following the KEYNOTE-811 regimen that added pembrolizumab to trastuzumab and chemotherapy. Notably, that earlier advance showed benefit concentrated in patients whose tumors expressed PD-L1, with possible harm in the PD-L1-negative subgroup. HER2 testing via immunohistochemistry at diagnosis is now considered essential, with fluorescence in situ hybridization reserved for intermediate results.
Beyond first-line therapy, trastuzumab deruxtecan has emerged as a second-line option based on the DESTINY-Gastric04 trial, which showed superiority over ramucirumab plus paclitaxel. However, the drug carries a substantially elevated risk of pneumonitis and interstitial lung disease, a safety consideration clinicians must weigh. A real-world analysis of 101 patients treated with T-DXd in second line was also referenced in the presentation.
The rapid succession of new standards in HER2-positive gastroesophageal cancer could meaningfully extend survival for a patient population that saw no progress for over a decade. Patients with PD-L1-negative tumors, who may have been harmed by earlier immunotherapy combinations, could benefit from the new zanidatamab-based options. However, the higher pneumonitis risk with T-DXd may complicate treatment decisions, and access to these therapies could vary across healthcare systems, potentially widening disparities in outcomes.