Exploratory analysis of HER2 status based on central and local testing results from the DESTINY-Gastric04 study.

434 Background: In the phase 3 DESTINY-Gastric04 study (NCT04704934), T-DXd significantly improved overall survival versus ramucirumab + paclitaxel as second-line treatment in patients (pts) with HER2-positive (HER2+) metastatic gastric cancer. Accurate determination of HER2+ status is crucial to reliably identify pts likely to benefit from T-DXd. Methods: In DESTINY-Gastric04, biopsies were obtained from pts after progression following prior trastuzumab-based therapy. HER2 status was determined by central testing using immunohistochemistry (IHC; Agilent HercepTest) and in situ hybridization (ISH; Agilent IQ-FISH) from first tissue screening in 2021 until a protocol amendment in 2023, and by central or local testing thereafter. We analyzed HER2 status based on central testing and evaluated concordance between local and central HER2 testing. HER2+ was defined as IHC 3+ or IHC 2+/ISH+. Results: Of 1088 pts who underwent tissue screening, 638 pts underwent main screening, and 494 pts were randomly assigned to the treatment arms. Of 833 pre-randomized subjects with central HER2 testing results, 68% were HER2+ with consistent rates in primary and metastatic tissue specimens (Table) and across laboratory locations. Retrospective central HER2 testing was done for 122 of 133 pts who were randomized in DESTINY-Gastric04 based on HER2+ status by local test. In these pts, positive percentage agreement (PPA) was ~80% regardless of biopsy site (Table). PPA was higher for specimens that were IHC 3+ vs IHC 2+/ISH+ by local test (91% 95% CI, 84%-96% vs 43% 95% CI, 25%-63%). Concordance between local and central HER2 status varied across assay types. Conclusions: Results support the use of existing HER2 assays to select pts with gastric cancer for second-line treatment when needed and suggest that both primary and metastatic tissue specimens may be suitable for HER2 testing. Clinical trial information: NCT04704934 . All cases Primary tissue Metastatic tissue Cases with central testing results n = 833 n = 550 n = 283 HER2+, n (%) 564 (68) 366 (67) 198 (70) IHC 3+ 488 (59) 323 (59) 165 (58) IHC 2+/ISH+ 76 (9) 43 (8) 33 (12) Cases with local and central testing results (retrospective) n = 122 n = 82 n = 40 PPA (95% CI), % 80 (71-86) 79 (69-87) 80 (64-91)