Clinical outcomes of trastuzumab emtansine (T-DM1) following trastuzumab deruxtecan (T-DXd) in metastatic breast cancer: a single-center experience

HER2-positive metastatic breast cancer (MBC) remains an oncological challenge after disease progression to pertuzumab-trastuzumab, and fam-trastuzumab deruxtecan (T-DXd). Data on treatment outcomes with trastuzumab emtansine (T-DM1) following treatment on T-DXd remain limited. This study evaluates the clinical outcomes of patients with HER2-positive MBC who received T-DM1 after prior therapy with T-DXd. Patients were eligible if they had histologically confirmed HER2+ MBC at the most recent determination prior to receiving T-DM1 following prior T-DXd, with sufficient documentation to assess baseline characteristics, treatment exposure, and outcomes. Demographics and clinical characteristics were summarized for the whole cohort. Continuous variables were summarized using medians and ranges, while categorical variables were summarized using frequencies and percentages. The primary outcome was overall survival (OS), and secondary outcomes were progression-free survival (PFS) and time to progression (TTP). The survival endpoints were evaluated using the Kaplan–Meier method, and differences in survival curves were compared using the log-rank test. Univariable cox proportional hazards regression models assessed associations between survival outcomes and clinical variables. Overall response rate (ORR) was defined as the proportion of patients achieving a complete response (CR) or partial response (PR). Clinical benefit rate (CBR) was defined as the proportion of patients achieving CR, PR, or stable disease (SD) lasting ≥ 24 weeks. A p -value <0.05 was considered significant. Analyses were performed using SAS version 9.4 and R version 4.2.2. All 21 patients were female with a median age of 53 years (range, 20–82). Median follow-up estimated using the reverse Kaplan–Meier method was 18.83 months (95% CI, 4.96–not estimable [NE]). Median OS was 11.30 months (95% CI: 4.14–25.0), median PFS was 2.20 months (95% CI: 1.38–2.69), and median TTP was 2.23 months (95% CI: 1.61–2.76). The median duration of prior T-DXd treatment was 5.52 months (Range: 0.69–25.07). No complete or partial response to T-DM1 were observed (ORR, 0%). Six patients achieved stable disease (29%), however only 2 patients had SD greater than 24 weeks (10%). Exploratory analyses suggested shorter PFS and TTP among the four patients with documented HER2-low status; however, these findings should be considered hypothesis-generating because of the small subgroup and absence of adjustment for multiple comparisons. This study provides real-world evidence consistent with limited clinical activity of T-DM1 following prior T-DXd in HER2+ MBC, raising the hypothesis of partial resistance between sequential HER2-targeted ADCs. Further research is warranted to develop novel therapeutic strategies for patients progressing after T-DXd.