Real-world clinical outcome of trastuzumab derutexcan (T-DXd) in metastatic breast cancer.

e23323 Background: Trastuzumab derutexcan (T-DXd) is an anti-HER2 antibody-drug conjugate (ADC) which showed promises in patients (pts) with metastatic breast cancer (MBC) across different HER2 spectrum. This study was performed for a better understanding of the use of T-DXd in a real-world setting. Methods: A single-institution retrospective study of pts with MBC treated with T-DXd at Cedars-Sinai Medical Center from 2018 to 2025. Clinicopathological and genomic data, treatment variables, clinical outcome were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. “Cross-resistance” was defined as progressive disease (PD) observed at the first restaging scan on the second ADC after T-DXd. A multivariate Cox proportional analysis was performed to assess the association of pt and treatment characteristics and genomic alterations with PFS and OS in pts treated with T-DXd. Results: A total of 130 pts treated with T-DXd were included (HR+, n = 71; TNBC, n = 20; HER2+, n = 39). The median age of the cohort was 61, with 66.2% White, 13.8% Black, and 12.3% Asian. Visceral metastatic disease was present in 96 pts (73.8%), and brain metastasis was present in 27 pts (20.8%). The median lines of prior chemotherapy was 1 (0-5) for HR+, 2 (0-6) for TNBC, and 1 (0-4) for HER2+ cohort. In the HER2-low cohort (n = 91), 57 pts (62.6%) were HER2 IHC 1+, and 32 (35.2%) were HER2 IHC 2+. 13 pts (14.3%) received sacituzumab govitecan (SG) prior to T-DXd. Among 53 pts (58.2%) who received post-T-DXd therapies, the most common immediate therapies were: SG (n = 14), eribulin (n = 6) and capecitabine (n = 5). Of the pts received SG immediately after T-DXd, cross-resistance was observed in 8/14 pts, absent in 2/14 pts, with 4/14 pending. The median PFS of T-DXd across BC subtypes were: 14.5 mo in HER2+, 7.0 mo in HR+ and 3.6 mo in TNBC (p < 0.0001). No significant difference in PFS was found between HER2 2+ (median PFS 7.0 mo) and HER2 1+ (median PFS 6.1 mo) (p = 0.53), nor in the sequence of T-DXd use as 1st or 2nd ADC in all cohorts. Next generation sequencing (NGS) data were available for 71 pts (54.6%). Most common mutations were: TP53 (52.1%), PIK3CA (45.1%) and ESR1 (23.9%). Multivariate Cox proportional analysis in HER2-low cohort revealed that brain metastasis [HR 5.64 (0.98-32.5), p = 0.053], and TP53 mutation [HR 3.66 (1.2-10.9), p = 0.02] were associated with worse PFS. Additionally, higher TMB trended toward improved PFS [HR 0.89 (0.8-1.0), p = 0.066]. Conclusions: This study highlights the differential efficacy of T-DXd across breast cancer subtypes and HER2 expression levels in a real-world cohort of MBC pts. A considerable amount of cross-resistance of SG use immediately after T-DXd was observed. Notably, the presence of brain metastases and TP53 mutations were associated with worse PFS in HER2-low cohort. Further validation of these findings is required to better understand the optimal clinical use of T-DXd.