The HORIZON-GEA-01 trial's control arm used a standard of care (trastuzumab + chemo) that was superseded in the US by the addition of pembrolizumab during the trial. This design was appropriate at launch but creates a slight disconnect with current US practice, requiring clinicians to interpret results in a new context.
The high rate of grade 3 diarrhea seen in the Zanidatamab trial was likely exacerbated by the capecitabine-based chemotherapy common in the global study. US oncologists, who often prefer a Folfox regimen, may see less severe GI toxicity, potentially improving patient tolerance and adherence to this highly effective regimen.
The combination of Zanidatamab, chemotherapy, and the PD-1 inhibitor Tisilzumab achieved a median overall survival of 26.4 months. This crosses the two-year threshold for the first time in this patient population, establishing a new and significantly higher benchmark for first-line HER2+ gastric cancer treatment.
Unlike existing standards that often require PD-L1 positivity for immunotherapy benefit, the Zanidatamab/Tisilzumab combination showed efficacy irrespective of PD-L1 status. This significantly expands first-line immunotherapy-based options to the minority of HER2+ patients who are PD-L1 negative and currently have fewer effective treatments.