TY - JOUR
T1 - 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
T2 - A Global Phase i Trial
AU - Yao, Herui
AU - Yan, Min
AU - Tong, Zhongsheng
AU - Wu, Xinhong
AU - Ryu, Min Hee
AU - Park, John J.
AU - Kim, Jee Hyun
AU - Zhong, Yahua
AU - Zhao, Yiming
AU - Voskoboynik, Mark
AU - Yin, Yongmei
AU - Liu, Kan
AU - Kaubisch, Andreas
AU - Liu, Caigang
AU - Zhang, Jian
AU - Wang, Shouman
AU - Im, Seock Ah
AU - Ganju, Vinod
AU - Barve, Minal
AU - Li, Hui
AU - Ye, Changsheng
AU - Roy, Amitesh C.
AU - Bai, Li Yuan
AU - Yen, Chia Jui
AU - Gu, Shanzhi
AU - Lin, Yung Chang
AU - Wu, Lingying
AU - Bao, Lequn
AU - Zhao, Kaijing
AU - Shen, Yu
AU - Rong, Shangyi
AU - Zhu, Xiaoyu
AU - Song, Erwei
PY - 2024/10/10
Y1 - 2024/10/10
N2 - PURPOSESHR-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.METHODSThis 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.RESULTSFrom 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.CONCLUSIONSHR-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.
AB - PURPOSESHR-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.METHODSThis 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.RESULTSFrom 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.CONCLUSIONSHR-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.
KW - SHR-A1811
KW - Clinical pharmacology
KW - Oncology
UR - http://www.scopus.com/inward/record.url?scp=85201739381&partnerID=8YFLogxK
U2 - 10.1200/JCO.23.02044
DO - 10.1200/JCO.23.02044
M3 - Article
C2 - 38900984
AN - SCOPUS:85201739381
SN - 0732-183X
VL - 42
SP - 3453
EP - 3465
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 29
ER -
