Safety, Efficacy, and Pharmacokinetics of SHR-A1811, a Human Epidermal Growth Factor Receptor 2–Directed Antibody-Drug Conjugate, in Human Epidermal Growth Factor Receptor 2–Expressing or Mutated Advanced Solid Tumors: A Global Phase I Trial
Herui Yao, Min Yan, Zhongsheng Tong, Xinhong Wu, Min‐Hee Ryu, John Park, Jee Hyun Kim, Yahua Zhong, Yiming Zhao, Mark Voskoboynik, Yongmei Yin, Kan Liu, Andreas Kaubisch, Caigang Liu, Jian Zhang, Shouman Wang, Seock‐Ah Im, Vinod Ganju, Minal Barve, Hui Li, Changsheng Ye, Amitesh Roy, Li‐Yuan Bai, Chia-Jui Yen, Shanzhi Gu, Yung‐Chang Lin, Lingying Wu, Lequn Bao, Kaijing Zhao, Yu Shen, Shangyi Rong, Xiaoyu Zhu, Erwei Song
Abstract
PURPOSE: SHR-A1811 is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors. METHODS: This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose. RESULTS: From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors. CONCLUSION: SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.