Risk factors and long-term prognostic impact of trastuzumab deruxtecan-related interstitial lung disease in metastatic breast cancer.

1043 Background: Trastuzumab deruxtecan (T-DXd) has demonstrated substantial efficacy in HER2-positive and HER2-low metastatic breast cancer (MBC). Interstitial lung disease (ILD), however, remains a clinically significant safety concern. While ILD incidence has been reported, its long-term prognostic impact and associated risk factors are not well established. Methods: This retrospective, single-center study evaluated patients with MBC treated with T-DXd. ILD was defined as clinically and radiologically confirmed ILD, which led to T-DXd discontinuation per institutional protocol. Time to treatment failure (TTF) and overall survival (OS) were analyzed according to ILD occurrence. Potential clinical and treatment-related risk factors for ILD were assessed using univariable and penalized multivariable Cox regression models. Results: At a median follow-up of 12.7 months, 15 of 132 patients (11.4%) developed ILD leading to treatment discontinuation. Among these 15 patients, 9 (60%) had grade 1 disease, 3 (20%) had grade 2, and 3 (20%) had grade 3 disease; no grade 4 or fatal events were observed. There were no significant differences in TTF (P = 0.59) or OS (P = 0.21) between patients with and without ILD. Among patients who developed ILD, onset occurred significantly earlier in those with HER2-low disease compared with HER2-positive disease (median 6.0 vs. 14.6 months, P = 0.029). In univariable analyses, age ≥65 years (HR 3.39, 95% CI 1.18-9.68; P = 0.023), prior immune checkpoint inhibitor (ICI) therapy (HR 4.74, 95% CI 1.01-22.34; P = 0.049), and prior abemaciclib exposure (HR 4.11, 95% CI 1.19-14.14; P = 0.025) were significantly associated with ILD. In the penalized multivariable model, prior abemaciclib exposure remained the only independent risk factor (HR 10.38, 95% CI 1.07-NA; P = 0.042). Conclusions: Although ILD onset tended to occur earlier in HER2-low MBC, its development did not significantly affect long-term TTF or OS. Prior exposure to abemaciclib is a significant independent risk factor for T-DXd-related ILD, warranting careful monitoring in this population.