Abstract Background: Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate (ADC) that has demonstrated improved survival outcomes in patients with metastatic human epidermal growth factor receptor 2 (HER2)-low breast cancer, and is approved by Food and Drug Administration (FDA) for these patients. However, real-world evidence regarding the efficacy of T-DXd remains limited. Methods We retrospectively collected clinical and demographic data of HER2-low mBC patients treated with T-DXd between November 2021 and December 2024 at Fudan University Shanghai Cancer Center. Real-world progression-free survival (rwPFS) was estimated using the Kaplan-Meier method. Treatment response was assessed according to RECIST 1.1 criteria. A T-DXd-prognostic score was established, according to regression coefficients found in the multivariate Cox regression analysis. Results: A total of 126 Chinese female patients with HER2-low mBC treated with T-DXd was enrolled. The median age was 56 years (IQR: 48 to 64), and 40 patients was TNM-IV stage. In this cohort, 72 (57.14%) had HER2-1+ mBC and 54 (42.86%) had HER2-2+ mBC. Hormone receptor (HR) status was positive in 82 (65.08%) patients and negative in 44 (34.92%). The median number of prior lines of advanced therapy was 3 (IQR: 2 to 5). Last follow-up was conducted on December 30, 2024, the median rwPFS was 9.10 months, which was significantly longer than the median rwPFS of 3.50 months observed with the last prior treatment chosen by physician. In patients with HR positive, those with low PR expression (≤ 10%) have significantly higher rwPFS than other patients (17.77 vs. 6.13 months; p 0.01). Among 111 patients with measurable disease, the objective response rate (ORR) was 30.63%, and the disease control rate (DCR) was 72.07%. We developed a prognostic score using the regression coefficients from the multivariate Cox regression model, which included age, HER2 expression, and HR status as covariates. And then, patients were stratified into low- and high-risk groups by the prognostic score. According to risk stratification, the median rwPFS was 5.13 months in the high-risk group and 12.40 months in the low-risk group (hazard ratio HR 2.25, 95% confidence interval CI 1.31 - 3.88, p 0.01). Conclusion: In this real-world cohort of Chinese patients with HER2-low mBC, T-DXd demonstrated meaningful clinical benefit, with notably longer rwPFS than last prior treatment. Furthermore, we established a risk stratification model that effectively predict patient prognosis. Citation Format: K. Zhang, X. Zhu, X. Ying, Z. Wang. Real-world Clinical Outcomes With Tratuzumab Deruxtecan in Metastatic HER2-low Breast Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-05-06.
Zhang et al. (2026) studied this question.