Tumor microenvironment delineates differential responders to trastuzumab emtansine in HER2-positive metastatic breast cancer patients previously treated with pyrotinib: an exploratory biomarker analysis of a phase II study (NJMU-BC02).

Trastuzumab emtansine (T-DM1) has been approved for the treatment of HER2-positive breast cancer. However, the efficacy of T-DM1 for patients after failure of pyrotinib and/or trastuzumab plus pertuzumab has not been clear. Additionally, no biomarker has been reported to predict the effect of T-DM1. In this multicenter phase II trial (NCT06125834), 36 participants with HER2-positive metastatic breast cancer were enrolled to receive T-DM1 therapy on a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints included the disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), and toxicity. The primary endpoint was an ORR of 47.2% (17/36, 95% CI 30.4-64.5). The treatment exhibited a manageable toxicity profile. The DCR was 66.7% (24/36, 95% CI 49.0-81.4), and the CBR was 50.0% (18/36, 95% CI 32.9-67.1). The median PFS was 6.6 (95% CI 5.2-NA) months. Single-cell RNA sequencing revealed that the low cell cycle activity of cancer cells, activated macrophages and CD8+ T cells was associated with the good efficacy of T-DM1, which was validated in a neoadjuvant cohort. This study suggests that T-DM1 is effective with a measurable safety profile in patients with metastatic HER2-positive breast cancer after failure of pyrotinib and/or trastuzumab plus pertuzumab. Our preliminary findings suggest potential biomarkers that may help predict T-DM1 efficacy, generating hypotheses for novel therapeutic targets that may address T-DM1 resistance.