Patients with HER2-positive metastatic breast cancer who received the antibody-drug conjugate trastuzumab emtansine (T-DM1) after treatment with trastuzumab deruxtecan (T-DXd) experienced limited clinical benefit from the sequential switch, according to a single-center study published in Breast Cancer Research. The open-access paper, authored by Akshara S. Raghavendra, Zhongya Wang, Roland Bassett, Rashmi Murthy, Paula R. Pohlmann, Debu Tripathy and Vicente Valero, was published on 8 October 2026 and reports outcomes from a cohort of just 21 patients, making its findings preliminary but relevant to a growing clinical question.
The study addressed a practical dilemma facing oncologists. Many patients with HER2-positive metastatic breast cancer now progress after treatment with pertuzumab and trastuzumab, and subsequently after fam-trastuzumab deruxtecan, a highly active antibody-drug conjugate. Data on what happens when these patients are then treated with T-DM1, an earlier-generation antibody-drug conjugate targeting the same receptor, have remained limited. The researchers set out to evaluate overall survival, progression-free survival and time to progression in patients who received T-DM1 following prior T-DXd therapy.
The retrospective single-center analysis included patients with histologically confirmed HER2-positive metastatic breast cancer at the most recent determination before starting T-DM1, all of whom had previously received T-DXd. Sufficient documentation was required to assess baseline characteristics, treatment exposure and outcomes. The primary outcome was overall survival, with progression-free survival and time to progression as secondary outcomes, evaluated using the Kaplan-Meier method and compared with the log-rank test. Univariable Cox proportional hazards models explored associations between survival and clinical variables.
The cohort consisted entirely of women, with a median age of 53 years and a range spanning 20 to 82 years. Median follow-up, estimated using the reverse Kaplan-Meier method, was 18.83 months. The median duration of prior T-DXd treatment was 5.52 months, ranging from 0.69 to 25.07 months, indicating that most patients had received the deruxtecan-based therapy for a relatively short period before switching.
The efficacy results were sobering. Median overall survival from the start of T-DM1 was 11.30 months, with a 95 percent confidence interval of 4.14 to 25.0 months. Median progression-free survival was just 2.20 months (95 percent CI, 1.38 to 2.69), and median time to progression was 2.23 months (95 percent CI, 1.61 to 2.76). These short intervals suggest that, in this heavily pretreated population, T-DM1 provided little delay in disease progression.
Response rates were equally striking in their absence. No complete or partial responses to T-DM1 were observed, yielding an overall response rate of 0 percent. Six patients, representing 29 percent of the cohort, achieved stable disease, but only two of those patients maintained stable disease for longer than 24 weeks, amounting to 10 percent of the total cohort by the study’s definition of clinical benefit.
An exploratory analysis examined the four patients with documented HER2-low status and suggested shorter progression-free survival and time to progression in that subgroup. The authors explicitly caution that these findings should be considered hypothesis-generating only, given the very small subgroup size and the absence of adjustment for multiple comparisons. No firm conclusions about HER2-low biology or treatment sequencing can be drawn from this observation.
The investigators conclude that the study provides real-world evidence consistent with limited clinical activity of T-DM1 following prior T-DXd in HER2-positive metastatic breast cancer, raising the hypothesis of partial resistance between sequentially administered HER2-targeted antibody-drug conjugates. They emphasize that further research is warranted to develop novel therapeutic strategies for patients who progress after T-DXd. Because the analysis is a small, single-center experience with a modest sample size and wide confidence intervals, the results should be interpreted as an early signal rather than a definitive answer, and they underscore how much remains unknown about optimal sequencing of antibody-drug conjugates after deruxtecan-based therapy.
Subject of Research: Clinical outcomes of trastuzumab emtansine after trastuzumab deruxtecan in HER2-positive metastatic breast cancer
Article Title: Clinical outcomes of trastuzumab emtansine (T-DM1) following trastuzumab deruxtecan (T-DXd) in metastatic breast cancer: a single-center experience
Article References: Raghavendra, A. S., Wang, Z., Bassett, R., Murthy, R., Pohlmann, P. R., Tripathy, D., & Valero, V. (2026). Clinical outcomes of trastuzumab emtansine (T-DM1) following trastuzumab deruxtecan (T-DXd) in metastatic breast cancer: a single-center experience. Breast Cancer Research. https://doi.org/10.1186/s13058-026-02394-6
Image Credits: AI Generated
DOI: 10.1186/s13058-026-02394-6
Keywords: HER2-positive breast cancer, metastatic breast cancer, trastuzumab emtansine, trastuzumab deruxtecan, antibody-drug conjugates, overall survival, progression-free survival, drug sequencing, treatment resistance, real-world evidence, single-center study, Breast Cancer Research
News Source: Nathaniel Bowman. (October 28, 2026). T-DM1 Shows Limited Activity After T-DXd in HER2-Positive Metastatic Breast Cancer. Scienmag.
