Zanidatamab versus Trastuzumab with or without PD-1 blockade in HER2-positive metastatic gastric cancer: a reconstructed patient-level pooled analysis

BACKGROUND: First-line treatment of HER2-positive advanced gastric/GEJ adenocarcinoma now includes pembrolizumab added to trastuzumab plus chemotherapy (KEYNOTE-811). Zanidatamab, a bispecific anti-HER2 antibody, improved outcomes in HERIZON-GEA-01 but was not directly compared with this standard. METHODS: We searched PubMed, Scopus, and ASCO/ESMO libraries for phase 2/3 trials in previously untreated HER2-positive metastatic gastric/GEJ adenocarcinoma. Individual patient data were reconstructed from published Kaplan-Meier curves. Cox frailty models estimated hazard ratios using the pembrolizumab regimen as reference. RMST analysis was performed at 12, 24, and 36 months. RESULTS: Nine trials were included: trastuzumab + chemotherapy (n = 1466), pembrolizumab + trastuzumab + chemotherapy (n = 430), zanidatamab + chemotherapy (n = 350), and zanidatamab + tislelizumab + chemotherapy (n = 335). Median PFS was 12.5 months with both zanidatamab regimens vs 10.0 months with pembrolizumab. The zanidatamab-tislelizumab triplet significantly reduced progression hazard (HR 0.78, 95% CI 0.62-0.99; p = 0.042). Median OS was 27.0 and 25.3 months with zanidatamab arms vs 20.3 months with pembrolizumab. Both zanidatamab arms showed significantly longer OS at 36 months by RMST. CONCLUSIONS: Zanidatamab-based regimens were associated with longer PFS and OS compared with the pembrolizumab standard, though direct randomized comparisons are needed.