Impact of early tumor shrinkage on survival outcomes in patients with HER2-positive advanced gastric cancer treated with trastuzumab deruxtecan in third- or later-line settings.

Background: Trastuzumab deruxtecan (T-DXd) has been approved for a third- or later-line treatment of HER2-positive advanced gastric cancer (AGC) in Japan. However, clinical data on the use of T-DXd in real-world practice remain insufficient. Although early tumor shrinkage (ETS) serves as an early on-treatment indicator of high treatment sensitivity, the use of ETS in predicting T-DXd efficacy remains unclear. Objectives: This study aimed to evaluate the clinical efficacy and safety of T-DXd and investigate the clinical utility of ETS as a predictor of long-term efficacy and survival. Design: Single-center retrospective cohort study. Methods: This study consecutively enrolled patients with HER2-positive AGC who received T-DXd as a third- or later-line treatment between March 2018 and December 2023. Data on patient characteristics, adverse events (AEs), and clinical outcomes were obtained from electronic medical records. Clinical efficacy was assessed using progression-free survival (PFS) and overall survival (OS). In patients with measurable lesions, the overall response rate (ORR), ETS, and depth of response (DpR) were evaluated. Prognostic outcomes were assessed using the log-rank test and the Cox proportional hazards model. Results: A total of 65 patients received T-DXd, with a median age of 66 years (range, 31-82 years); 77% had HER2 immunohistochemistry score of 3+, 71% received T-DXd as a third-line treatment, and 32% required initial dose reduction. At a median follow-up of 33.6 months, the median PFS and OS were 4.5 months and 7.7 months, respectively. Among the 47 patients with measurable lesions, the ORR was 36%. A median DpR of 15.8% was observed, with higher DpR correlating with longer OS. ETS was achieved in 38% of the patients and was an independent predictor of favorable PFS (hazard ratio (HR), 0.21; 95% confidence interval (CI), 0.09-0.49; Conclusion: T-DXd demonstrated notable efficacy and a manageable safety profile in patients with HER2-positive AGC. Rapid and deep tumor shrinkage may have a significant impact on survival.