Hao Han,1,* Congcong Wang,2,* Fenge Jiang,2 Ping Sun,2 Jiannan Liu2 1Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, 261053, People’s Republic of China; 2Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ping Sun, Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, 264000, People’s Republic of China, Email sunping20039@hotmial.com Jiannan Liu, Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, 264000, People’s Republic of China, Email ljnwcc@163.comBackground: HER2-positive advanced breast cancer poses significant treatment challenges. In China, T-DM1 and pyrotinib are key second-line therapies. A comprehensive evaluation of the comparative efficacy and safety profiles of these therapies is imperative for optimizing therapeutic strategies and enhancing patient outcomes. This study aims to compare the clinical efficacy and safety of T-DM1 against pyrotinib plus capecitabine.Methods: Patients are females with HER2-positive, locally advanced, or metastatic breast cancer who at least 18 years old and have received anti-HER2 therapy in the past. This study included 148 patients who satisfied the inclusion criteria. Of these, 74 patients received intravenous T-DM1 (3.6 mg/kg) every 21 days, while the other 74 patients got oral pyrotinib (400 mg, once daily) plus capecitabine (1000 mg/m2, twice daily on days 1– 14 of each 21-day cycle). Progression-free survival (PFS) was the main outcome, while overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were the secondary outcomes.Results: The median PFS was 12.2 months for the pyrotinib group vs 9.1 months for the T-DM1 group. The median follow-up was 12.7 months for pyrotinib and 9.3 months for T-DM1. The pyrotinib group had better DCR (56.8% vs 54.1%) and ORR (40.5% vs 29.7%). While adverse events were manageable, the most common severe AE in the pyrotinib group was diarrhea (24.3%), and in the T-DM1 group, it was thrombocytopenia (16.2%). However, by reducing the drug dosage or providing symptomatic treatment, most adverse events could be controlled at grades 1 to 2, indicating that the adverse events were manageable. Neither group recorded any adverse event-related deaths.Conclusion: Pyrotinib plus capecitabine significantly improves median PFS compared to T-DM1 in patients with HER2-positive advanced breast cancer, demonstrating a favorable efficacy profile alongside manageable safety concerns.Keywords: breast cancer, T-DM1, pyrotinib, capecitabine, HER2