Abstract GS1-04: HER2-Directed Antibody-Drug Conjugate SHR-A1811 in the Neoadjuvant Treatment of HER2-positive Early Breast Cancer: a Prospective, Randomized, Open-label, Phase 2 Trial

Abstract Background: Standard neoadjuvant regimens for HER2 positive breast cancer include trastuzumab and pertuzumab combined with chemotherapy. No data has been reported for the efficacy and safety of HER2-direted Antibody-drug conjugate (ADC) monotherapy or combined with Tyrosin kinase inhibitor (TKI) in the neoadjuvant setting. We assessed the antitumor activity and safety of a novel ADC SHR-A1811 in neoadjuvant treatment of HER2+ breast cancer. Methods: This open label, randomized, phase 2 study enrolled 265 HER2 positive patients, aged 18 years or older with stage II–III disease. Patients were randomly assigned (1:1:1) to receive nab-paclitaxel (100mg/m2 i.v. day 1, day 8, and day 21 in a 28-day per cycle) combined with carboplatin(AUC 1.5 i.v. day 1, day 8, and day 21 in a 28-day per cycle), trastuzumab(initial dose 8mg/kg, subsequent dose 6mg/kg i.v. every 3weeks), and pertuzumab (initial dose 840mg, subsequent dose 420mg i.v. every 3weeks) for 6 cycles (PCbHP), SHR-A1811 monotherapy (4.8mg/kg i.v. day 1 every 3weeks) for 8 cycles, or SHR-A1811 with pyrotinib (240mg orally once a day daily) for 8 cycles. SHR-A1811 is composed of anti-HER2 antibody trastuzumab, a cleavable linker, and the topoisomerase I inhibitor payload SHR169265 with a DAR of 5.7. Primary endpoints were pathological complete response (pCR) in all randomly assigned patients in the intention-to-treat population. This study is registered with ClinicalTrials.gov (NCT05582499). Findings: 265 patients were randomly assigned, 90 to PCbHP, 87 to mono-SHR-A1811, 88 to SHR-A1811 plus pyrotinib. Baseline characteristics were well balanced between the treatment groups, about 45% were Hormone receptor (HR) positive, 70% were stage III. The pCR rate was 63% in mono-SHR-A1811 (44% in HR+ and 78% in HR-), 62% in SHR-A1811 plus pyrotinib (44% in HR+ and 76% in HR-) and 66% in PCbHP (54% in HR+ and 75% in HR-), with no statistical difference between each group. Grade 3 or higher adverse events occurred 45% in mono-SHR-A1811, 72% in SHR-A1811 plus pyrotinib and 34% in PCbHP. 1 patient occurred grade 2 interstitial lung disease in SHR-A1811, 9% patients occurred grade 3 diarrhea in SHR-A1811 plus pyrotinib, no treatment related death was occurred. Interpretation: This is the first study to report the efficacy of third generation HER2-directed ADC in the neoadjuvant setting of HER2 positive breast cancer. SHR-A1811 exhibited promising antitumor activity and acceptable tolerability, with monotherapy pCR rate up to 63%. Citation Format: Junjie Li, Zhong-Hua Wang, Li Chen, Wen-Juan Zhang, Linxiaoxi Ma, Jiong Wu, Guang-Yu Liu, Yi-Feng Hou, Ke-Da Yu, Geng-Hong Di, Lei Fan, Yi-Zhou Jiang, Shu-Hao Jiang, Qian-Nan Liang, Yu Shen, Zhi-Ming Shao. HER2-Directed Antibody-Drug Conjugate SHR-A1811 in the Neoadjuvant Treatment of HER2-positive Early Breast Cancer: a Prospective, Randomized, Open-label, Phase 2 Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS1-04.