Neoadjuvant pyrotinib vs pertuzumab therapy for HER2-positive early breast cancer: The HELEN HER-013 randomized clinical trial.

509 Background: Docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) is a standard neoadjuvant regimen for stage II–III human epidermal growth factor receptor 2 (HER2)–positive breast cancer; however, its use is associated with substantial treatment burden, particularly hematologic toxicity, highlighting the need for alternative strategies that maintain efficacy with different toxicity profiles.This study to determine whether a chemotherapy-de-escalated regimen of nanoparticle albumin–bound paclitaxel, trastuzumab, and the tyrosine kinase inhibitor pyrotinib (nab-PHPy) is noninferior to standard TCHP with respect to pathological complete response (pCR). Methods: The HELEN HER-013 trial was a multicenter, randomized, open-label, phase 3 noninferiority trial conducted at 15 centers in China. Women with previously untreated, operable stage II–III HER2-positive breast cancer were enrolled between May 2023 and May 2025.Participants were randomly assigned (1:1) to receive six 21-day cycles of either nab-paclitaxel, trastuzumab, and oral pyrotinib (nab-PHPy group) or TCHP group.The primary end point was pCR (ypT0/Tis ypN0), assessed in the modified intention-to-treat (mITT) population (patients who received ≥1 dose of study treatment). The prespecified noninferiority margin was −5.5%( ClinicalTrials.gov Identifier: NCT05918328 ). Results: Among 709 screened individuals, 610 were randomized, and 589 were included in the mITT population (295 in the nab-PHPy group and 294 in the TCHP group; all female). Median age was 51 years (interquartile range [IQR], 43–56) in the nab-PHPy group and 52 years (IQR, 45–57) in the TCHP group. The primary end point of pCR was achieved in 186 patients (63.1%; 95% CI, 57.4%–68.4%) in the nab-PHPy group and 174 patients (59.2%; 95% CI, 53.4%–64.8%) in the TCHP group. The between-group difference was 3.9% (95% CI, -4.2% to 11.9%), which met the prespecified criterion for noninferiority (noninferiority P = .01). Grade 3 or higher treatment-emergent adverse events occurred in 113 patients (38.3%) receiving nab-PHPy and 107 patients (36.4%) receiving TCHP. The most common grade 3 or higher adverse events were diarrhea (31.5% vs 17.0%), anemia (1.7% vs 10.2%), and nausea (0% vs 5.8%). No treatment-related deaths were reported. Conclusions: Among women with operable stage II–III HER2-positive breast cancer, neoadjuvant treatment with nab-PHPy was noninferior to TCHP with respect to pCR and was associated with a distinct toxicity profile, supporting its role as an alternative neoadjuvant strategy. Clinical trial information: NCT05918328 .