Zanidatamab vs 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 has not been directly compared with this standard.

METHODS

We searched PubMed, Scopus, and the ASCO/ESMO libraries for phase II/III trials of 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 the reference. Restricted mean survival time 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 than the pembrolizumab standard, though direct randomized comparisons are needed.