HORIZON-GEA-01 Efficacy Results and Interpretation of Duration of Response

In this episode, Dr. Shameem, Dr. Shah, and Dr. Wainberg review the HERIZON-GEA-01 efficacy data and work through why the triplet's duration of response (DOR) appears to pull away from the doublet's. Dr. Shameem lays out the numbers against a KEYNOTE-811 benchmark of roughly 20 months overall survival (OS) and 10 months progression-free survival (PFS). HERIZON-GEA-01 reported median OS of 26.4 months for the triplet, 24.4 months for the doublet, and 19 months for the control arm. Both zanidatamab-containing arms met the PFS endpoint with statistical significance.

The DOR numbers are where Dr. Shameem focuses the discussion: about 21 months with the triplet, 14 months with the doublet, and 8 months with trastuzumab plus chemotherapy. He notes that 18-month PFS rates doubled with the triplet regimen compared with control. For Dr. Shameem, the durable responses in the triplet arm are a notable feature of the biomarker-driven combination.

Dr. Shah offers a mechanistic hypothesis to explain the DOR gap. Unlike breast cancer, gastric cancer is subclonal for HER2, meaning HER2-positive and HER2-negative clones can coexist in the same tumor. He proposes that adding tislelizumab to the regimen may activate a broadly acting immune response that reaches non–HER2-positive subclones as well, on top of HER2 pathway inhibition itself. Dr. Shah describes this as a hypothesis that would benefit from supporting data.

In the next episode, “Planned HERIZON-GEA-01 Analyses and the Doublet-vs-Triplet Question,” the panel discusses the planned data cuts and considers how to weigh the triplet if the doublet arm ultimately meets OS.