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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

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机构： [1]Department of Medical Oncology, Phase I Clinical Trial Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. [2]Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China. [3]Breast Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. [4]Department of Breast Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Provincial Clinical Research Center for Breast Cancer, Wuhan Clinical Research Center for Breast Cancer, Wuhan, China. [5]Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. [6]Macquarie Medical School, Macquarie University, Sydney, NSW, Australia. [7]Hematology & Medical Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. [8]Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China. [9]Medical Oncology, Alfred Health, Melbourne, VIC, Australia. [10]Central Clinical School, Monash University, Melbourne, VIC, Australia. [11]Clinical Research & Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [12]Department of Urinary Surgery, Hunan Cancer Hospital, Changsha, China. [13]Medical Oncology, Montefiore-Einstein Center for Cancer Care, Bronx, NY. [14]Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China. [15]Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, China. [16]Department of Breast Surgery, National Agency for Clinical Trial of Medicines, Xiangya Hospital Central South University, Changsha, China. [17]Hematology & Oncology, Seoul National University, Seoul, Korea. [18]Hematology & Oncology, PASO Medical, Melbourne, VIC, Australia. [19]Medical Oncology, Mary Crowley Cancer Research, Dallas, TX. [20]Breast Surgery Department, Sichuan Cancer Hospital, Chengdu, China. [21]Breast Surgery, Nanfang Hospital Southern Medical University, Guangzhou, China. [22]Department of Medical Oncology, Southern Oncology Clinical Research Unit, Adelaide, SA, Australia. [23]Division of Hematology and Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan. [24]Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. [25]Radioactive Interventional Department, Hunan Cancer Hospital, Changsha, China. [26]Hematology & Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. [27]Gynecologic Oncology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China. [28]Hepatic Biliary Pancreatic Surgery, Hubei Cancer Hospital, Wuhan, China. [29]Oncology Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co, Ltd, Shanghai, China. [30]Department of Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

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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.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.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.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.

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大类 | 1 区

医学

小类 | 1 区肿瘤学

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大类 | 1 区

医学

小类 | 1 区肿瘤学

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Q1 ONCOLOGY

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Q1 ONCOLOGY

影响因子： 42.1 最新[2023版] 37.4 最新五年平均 42.1 出版当年[2023版] 0 出版当年五年平均 42.1 出版前一年[2023版]

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第一作者机构： [1]Department of Medical Oncology, Phase I Clinical Trial Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

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