Neoadjuvant pyrotinib plus trastuzumab combined with chemotherapy for HER2+/HR+ early breast cancer: A multicenter phase 2 trail.

e12641 Background: HER2+/HR+ early breast cancer has a lower pathological complete response (pCR) rate after neoadjuvant therapy than HER2+/HR- subtype, underscoring an urgent need for new regimens. Pyrotinib is approved by National Medical Products Administration for neoadjuvant treatment of HER2+ breast cancer in China. Herein, we conducted this phase 2 multicenter trial to evaluate the efficacy and safety of pyrotinib plus trastuzumab combined with chemotherapy for this setting. Methods: This open-label multicenter phase 2 study enrolled untreated, histologically confirmed stage II-III HER2+/HR+ breast cancer patients. Patients received 6 cycles of neoadjuvant therapy: pyrotinib (initial dose: 240 mg qd) + trastuzumab + paclitaxel (nab-paclitaxel 260 mg/m² or docetaxel 75 mg/m², d1, q3w) + carboplatin (AUC = 5, d1, q3w). Diarrhea prophylaxis was permitted. Based on diarrhea severity, pyrotinib dose escalation was allowed, or the regimen could be switched to trastuzumab + pertuzumab (HP) + chemotherapy at physicians’ discretion if the patient cannot tolerate the diarrhea toxicity of pyrotinib. Patients completing or discontinuing neoadjuvant therapy underwent breast surgery. Adjuvant targeted/endocrine therapy was administered per physician judgment, and radiotherapy followed standard practice. Primary endpoint: pCR rate (ypT0/Tis ypN0). Secondary endpoints: objective response rate (ORR), breast pCR (bpCR), event-free survival (EFS), overall survival (OS), and safety. Results: As of December 2025, 16 patients completed neoadjuvant therapy and surgery. Median age was 52 years (range: 28-60 years); 10 (66.7%) had stage II and 6 (33.3%) stage III disease. 10 patients (66.7%) received pyrotinib + trastuzumab + chemotherapy (noted as Cohort 1), while 6 patients (33.3%) discontinued pyrotinib during treatment (after 1 to 4 cycles) and switched to HP + chemotherapy (noted as Cohort 2). Overall pCR rate was 50.0% (8/16): 60.0% (6/10) in Cohort 1 and 33.3% (2/6) in Cohort 2. With 1 additional patient achieving bpCR in Cohort 1, bpCR rate was 56.3% (9/16). ORR was 93.8% (15/16). Regarding treatment tolerance, 11 patients (68.8%) maintained 240 mg/day pyrotinib, 4 tolerated escalation to 320 mg/day, and 1 to 400 mg/day. Common treatment-related adverse events included diarrhea, nausea/vomiting, neutropenia, rash, and oral ulcers. Diarrhea occurred in 100% of patients for any grade and 43.8% (7/16) for grade ≥3. Only 1 patient required hospitalization for severe neutropenia with fever. No treatment-related deaths occurred. Conclusions: The neoadjuvant regimen of pyrotinib plus trastuzumab combined with chemotherapy showed promising efficacy and manageable safety in HER2+/HR+ early breast cancer, even with the low pyrotinib dose. This study is ongoing. Clinical trial information: ChiCTR2500102478.