Phase I study of the recombinant humanized anti-HER2 monoclonal antibody–MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors

作者：Yingying Xu, Yakun Wang, Jifang Gong, Xiaotian Zhang, Zhi Peng, Xinan Sheng, Chenyu Mao, Qingxia Fan, Yuxian Bai, Yi Ba, Da Jiang, Fen Yang, Changsong Qi, Jian Li, Xicheng Wang, Jun Zhou, Ming Shian Lu, Yanshuo Cao, Jiajia Yuan, Dan Liu, Zhenghang Wang, Jianmin Fang, Lin Shen · 发表于：Gastric Cancer · 年份：2021 · DOI：10.1007/s10120-021-01168-7 · 被引用次数：155 · 研究领域：HER2/EGFR in Cancer Research、Monoclonal and Polyclonal Antibodies Research、Cancer Cells and Metastasis

PURPOSE: RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer. PATIENTS AND METHODS: This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48. RESULTS: Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20). CONCLUSION: RC48 was well ...