Real-World Effectiveness and Safety of Tucatinib, Trastuzumab, and Capecitabine in HER2-Positive Advanced Breast Cancer: A Multicenter Portuguese Study

Objective: The HER2CLIMB trial demonstrated the benefit of tucatinib, trastuzumab and capecitabine (TTC) in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). However, it predated the clinical use of trastuzumab deruxtecan (T-DXd), leaving limited evidence for TTC after T-DXd exposure. This national multicenter study assessed the real-world effectiveness and safety of TTC in patients, including those previously treated with T-DXd. Materials and Methods: This retrospective, non-interventional study included patients with HER2-positive ABC treated with TTC across 17 centers in Portugal (October 2021-May 2025). Outcomes included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: = 50) had prior T-DXd exposure. Median follow-up was 21.0 months; ORR and DCR were 24.4% and 64.1%, respectively. Median PFS (mPFS) was 9.0 months (m) [95% confidence interval (CI): 5.9-12.1], and median OS (mOS) was 14.0 months (m) (95% CI: 10.5-17.5). In patients previously treated with T-DXd, the median mPFS 7.0 m (95% CI: 3.6-10.4) and 13.0 m (95% CI: 9.3-16.7), respectively. Among patients with brain metastases, mPFS was 12.0 m (95% CI: 6.7-17.3) and mOS was 17.0 m (95% CI: 12.9-21.1). The most frequent all grade adverse events were fatigue (58.0%) and diarrhea (56.8%); CTCAE grade ≥3 events occurred in 16.0%. Treatment discontinuation due to toxicity occurred in 7.4% of participants; there were no treatment-related deaths. Conclusion: In this national real-world cohort, TTC demonstrated clinically meaningful activity and was not associated with any new safety signals in HER2-positive ABC, including patients previously exposed to T-Dxd and those with brain metastases.