Outcomes of subsequent treatment regimens after trastuzumab deruxtecan in patients with metastatic breast cancer.

BACKGROUND Most patients with metastatic breast cancer (MBC) are eligible for treatment with trastuzumab deruxtecan (T-DXd). No data are available to guide treatment after exposure to T-DXd. METHODS We utilized a nationwide electronic health record-derived, deidentified database to review data of patients with MBC who initiated T-DXd between 12/2019 and 9/2023 and who received an additional line of treatment after T-DXd. Tumors were categorized as HER2-positive if ever positive before T-DXd, HER2-negative if never HER2-positive before T-DXd. We compared real-world progression-free survival (rwPFS) and overall survival for post-T-DXd treatments using the Kaplan-Meier method and the log-rank test. RESULTS We identified 793 patients receiving a post-T-DXd treatment. Post-T-DXd treatment outcomes differed significantly by MBC subtype: median rwPFS was 4.6 months for HER2-positive, 3.4 months for hormone receptor- (HR)-positive/HER2-negative and 2.8 months for triple-negative MBC (p < .001). Outcomes with post-T-DXd treatments also varied significantly according to treatment regimen (p < .001). Among patients with HER2-positive MBC, median rwPFS ranged from 6.7 months with endocrine treatment regimens to 2.3 months with sacituzumab govitecan (SG). Among patients with HR-positive/HER2-negative MBC, rwPFS ranged from 5.9 months with eribulin to 2.5 months with SG. Among patients with triple-negative MBC, poor outcomes (rwPFS ≤3 months) were observed with most treatment regimens, including SG (3 months), eribulin (2 months) and multiagent chemotherapy (2.5 months). CONCLUSIONS Outcomes of post-T-DXd treatments differ significantly by MBC subtype and type of regimen administered. The use of SG immediately after T-DXd was associated with relatively short rwPFS across subtypes, highlighting some degree of cross-resistance with T-DXd. TRIAL REGISTRATION N/A.