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HER2 sequence in gastric cancer: zanidatamab/trastuzumab + chemo ± PD-1 → T-DXd
For HER2-positive stomach cancer, an antibody-plus-chemotherapy first, then Enhertu when it progresses. Both steps now have phase 3 proof.
First line: trastuzumab + chemotherapy + pembrolizumab (KEYNOTE-811, PD-L1 CPS ≥1) or zanidatamab + chemotherapy ± tislelizumab (HERIZON-GEA-01, PFS 12.4 vs 8.1 months). Second line: T-DXd (DESTINY-Gastric04, OS 14.7 vs 11.4 months). HER2 loss after first-line therapy occurs in ~30%, so re-biopsy or ctDNA before T-DXd is advisable.
Rationale
Antibody blockade and ADC payload delivery are distinct mechanisms; HER2 expression usually persists at progression.
Evidence
Phase 3 for each step; the sequence itself is inferred, not randomised.