Efficacy and safety of neoadjuvant SHR-A1811 with or without pyrotinib in women with locally advanced or early HER2-positive breast cancer: a randomized, open-label, phase II trial

Standard neoadjuvant regimens for HER2-positive breast cancer include trastuzumab and pertuzumab combined with chemotherapy, and the efficacy and safety of third-generation HER2-direted antibody-drug conjugate (ADC) remain to be elucidated. This open-label, randomized, phase 2 study enrolled patients aged 18 years or older with stage II-III Her2-positive breast cancer. Patients were randomly assigned (1:1:1) to receive neoadjuvant treatment either with SHR-A1811 monotherapy, SHR-A1811 with pyrotinib, or nab-paclitaxel combined with carboplatin, trastuzumab, and pertuzumab (PCbHP) for 24 weeks. The primary endpoint was pathological complete response (pCR). Safety was analysed in patients who received at least one dose of study medication. Between December 27, 2022, and February 11, 2024, 265 patients were randomly allocated to neoadjuvant, mono-SHR-A1811 (n=87), SHR-A1811 plus pyrotinib (n=88), or PCbHP (n=90). The baseline characteristics were well balanced; approximately 45% of the patients were hormone receptor (HR)-positive, and 70% of the patients were stage III. The pCR rate was 63.2% for mono-SHR-A1811 (50% for HR+ and 74.5% for HR-), 62.5% for SHR-A1811 plus pyrotinib (44.7% for HR+ and 76% for HR-) and 64.4% for PCbHP (54.1% for HR+ and 71.7% for HR-), with no significant difference between the groups. Grade 3 or higher treatment-related adverse events occurred in 44.8% of patients with mono-SHR-A1811, 71.6% with SHR-A1811 plus pyrotinib and 38.8% with PCbHP. One patient experienced grade 2 interstitial lung disease in SHR-A1811, 9.1% of patients experienced grade 3 diarrhea in SHR-A1811 plus pyrotinib, and no treatment-related deaths occurred. This is the first study to report the efficacy and safety of third-generation HER2-directed ADC in the neoadjuvant setting for HER2-positive breast cancer. SHR-A1811 showed robust activity, with a tolerable safety profile. (ClinicalTrials.gov, NCT05582499).