Impact of prior immune checkpoint inhibitor on trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory analysis of the EN-DEAVOR study.

[BACKGROUND] Human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) presents significant therapeutic challenges due to its molecular heterogeneity. Previous studies suggest that immune checkpoint inhibitors (ICIs) may enhance the efficacy of subsequent HER2-targeted therapy. However, evidence suggesting an optimal sequence for nivolumab and trastuzumab deruxtecan (T-DXd) treatment is limited. This exploratory analysis of EN-DEAVOR evaluated the effectiveness and safety of administering T-DXd relative to the timing of prior ICI administration.

[METHODS] This study assessed real-world outcomes of T-DXd in patients with HER2-positive AGC stratified by prior ICI exposure: within 2 months of nivolumab (Group A), >2 months (Group B), and no prior nivolumab (Group C). The primary effectiveness endpoints included real-world progression-free survival (rwPFS) and objective response rate (ORR). Safety endpoints included grade ≥ 3 adverse events (AEs).

[RESULTS] Among 311 eligible patients, Group A showed the longest median rwPFS (n = 63; 6.9 months) compared with Group B (n = 63; 4.6 months) and Group C (n = 185; 4.2 months). The risk of progression was significantly lower in Group A compared with Group B (hazard ratio [95% confidence interval]: 0.6 [0.4-0.9]; P = .0074). ORR was numerically highest in Group A (54.9%) versus Group B (30.8%) and Group C (43.4%). More patients in Group B (58.7%) experienced grade ≥ 3 AEs than in Group A (50.8%) and Group C (43.8%). No new safety signals were observed.

[CONCLUSIONS] Initiating T-DXd within 2 months post-ICI may enhance therapeutic efficacy in HER2-positive AGC without affecting safety, supporting a potential sequencing option after ICI therapy.