Introduction: It is critical to select subsequent treatments for patients after the failure of trastuzumab therapy. Following the failure of standard trastuzumab therapy guidelines in the Chinese Society of Clinical Oncology, pyrotinib and capecitabine is a grade I recommended regimen for treating patients with HER2-positive metastatic breast cancer. Concurrently, in treating patients with HER2-positive metastatic breast cancer, lapatinib and capecitabine are also recommended regimens for those who have previously received taxanes, anthracyclines, and trastuzumab therapy. However, there is currently no systematic review and meta-analysis comparing pyrotinib with lapatinib among HER2+ MBC patients. Therefore, this study aims to perform a systematic review and meta-analysis and assess whether pyrotinib is superior to lapatinib in efficacy and safety.Methods: Relevant trials were searched in CNKI, Wanfang, VIP, PubMed, Embase, and Cochrane CENTRAL databases from inception until March 27^th, 2022. The primary outcomes were PFS and OS, and the secondary outcomes were ORR and grade ≥3 AEs.Results: Five relevant studies were included in this study, including 2 RCTs and 3 retrospective cohort studies. Pyrotinib combined with chemotherapy is superior to lapatinib combined with chemotherapy among HER2+ metastatic breast cancer patients, with a significant improvement in PFS (prior trastuzumab therapy) (HR: 0.47, 95% CI: 0.39–0.57,p<0.001, I²= 0%, FEM), PFS (trastuzumab resistance) (HR: 0.52, 95% CI: 0.39–0.68,p<0.001, I²= 40%, FEM) and ORR (RR: 1.45, 95% CI: 1.26–1.67,p<0.001, I²= 8%, FEM), but has higher grade ≥3 diarrhea incidence (RR: 2.68, 95% CI: 1.85–3.90,p<0.001, I²= 44%, FEM).Conclusions: The efficacy of pyrotinib combined with chemotherapy is superior to lapatinib combined with chemotherapy but has more safety risks.

HER2-positive breast cancer is an aggressive subtype that benefits from targeted therapies. Some studies have shown that pyrotinib (P) plus trastuzumab (H) has a good efficacy against early or locally advanced HER2-positive breast cancer. However, there is still no systematic review and meta-analysis supporting the efficacy and safety of pyrotinib plus trastuzumab versus standard regimens in the neoadjuvant treatment of early or locally advanced breast cancer. This study is the first systematic review and meta-analysis to compare the efficacy and safety of pyrotinib combined with trastuzumab versus trastuzumab combined with pertuzumab (Per) and trastuzumab monotherapy in the neoadjuvant treatment of HER2-positive breast cancer. We conducted a systematic literature search in PubMed, Embase, the Cochrane Library, CNKI, Wan Fang and VIP databases for relevant studies published up to August 30th, 2024. RCTs, cohort studies and retrospective studies with HER2-positive breast cancer patients who had not received breast cancer-related treatments previously were included. Treatment of P + H, H or Per + H arms with chemotherapy combined with pyrotinib plus trastuzumab, trastuzumab or pertuzumab plus trastuzumab as neoadjuvant treatment. The primary outcome was the total pathological complete response (tpCR), and secondary outcomes included breast pathological complete response (bpCR), ORR, DCR, and grade III/IV AEs. The quality of evidence was assessed using the GRADE. A total of nine studies (4 RCTs, 1 prospective cohort study and 4 retrospective analysis) involving 1745 patients were included. The P + H arm showed no significant difference in tpCR compared to Per + H (RR: 0.94, 95 % CI: 0.80-1.11, p = 0.46) but demonstrated a significant improvement in tpCR over trastuzumab monotherapy (RR: 1.83, 95 % CI: 1.56-2.15, p < 0.001). This finding was further confirmed in meta-analysis of RCTs (RR: 1.87, 95 % CI: 1.42-2.47, p < 0.001). The P + H arm had a higher incidence of grade III/IV diarrhea (RR: 10.54, 95 % CI: 5.96-18.63, p < 0.001) but similar rates of other AEs compared to the H arm. The evidence quality for tpCR (P + H vs. H, RCT) was high, and that for tpCR (P + H vs. H) was moderate, while that for tpCR (P + H vs. Per + H) was low. Pyrotinib combined with trastuzumab may offer an effective neoadjuvant treatment option for HER2-positive breast cancer, with a superior efficacy over trastuzumab alone. However, pyrotinib plus trastuzumab did not show better efficacy compared with Per + H. Pyrotinib plus trastuzumab was associated with more diarrhrea than trastuzumab monotherapy. In addition, P + H is less cost-effective compared with the combination of Per + H.

HER2-positive breast cancer is an aggressive subtype that benefits from targeted therapies. According to the Chinese Society of Clinical Oncology (CSCO) gu