A real-world study on treatment after TKI progression in HER2-positive MBC

Background: After disease progression on anti-human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitors (TKIs), trastuzumab deruxtecan (T-DXd) is recommended as a subsequent therapy. Because T-DXd has only recently been covered by insurance, patients previously opted for alternative regimens. Objectives: This study aimed to report real-world data on HER2-positive metastatic breast cancer (MBC) patients whose disease progressed during TKI therapy and provide a basis for further research. Design: This retrospective study included 216 HER2-positive MBC patients who progressed after TKI therapy between July 2014 and February 2025. Methods: All patients received anti-HER2 TKI therapy (including pyrotinib and lapatinib) in 28-day cycles. Treatment doses and combinations with chemotherapy, HER2-targeted agents, or endocrine therapy were decided by physicians. The primary objectives were to determine the proportion of patients receiving different regimens after TKI failure and evaluate progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events. Results: As of April 1, 2025, treatment distribution was 26.9% in the antibody–drug conjugate (ADC) group, 45.8% in the monoclonal antibody (mAb) group, and 27.3% in the TKI group. The expansion of ADC reimbursement under China’s healthcare policy, beginning in 2023, led to increased clinical adoption. Median PFS was 10.2 months (95% confidence interval (CI), 6.7–13.6) in the ADC group, 7.3 months (95% CI, 5.7–9.0) in the mAb group, and 7.2 months (95% CI, 5.8–8.6) in the TKI group, with no significant differences ( p = 0.282). T-DXd demonstrated substantial antitumor activity with a 12-month PFS rate of 50.0%. Patients who are acquired-resistant to TKI had better outcomes than primary-resistant ones, particularly among those continuing TKI therapy. No unexpected toxic effects were reported. Conclusion: After progression following TKI therapy, T-DXd exhibited notable antitumor activity, although no significant efficacy differences were observed among ADC, mAb, and TKI groups.