Evaluation of Safety of Treatment With Anti-Epidermal Growth Factor Receptor Antibody Drug Conjugate MRG003 in Patients With Advanced Solid Tumors A Phase 1 Nonrandomized Clinical Trial

作者：Qiu, Miao-Zhen; Zhang, Yang; Guo, Ye; Guo, Wei; Nian, Weiqi; Liao, Wangjun; Xu, Zhongyuan; Zhang, Wenxue; Zhao, Hong-Yun; Wei, Xiaoli; Xue, Liqiong; Tang, Wenbo; Wu, Yunteng; Ren, Guoxin; Wang, Ling; Xi, Jingle; Jin, Yongshuai; Li, Hu; Hu, Chaohong; Xu, Rui-Hua^*

来源：JAMA Oncology, 2022, 8(7): 1042-1046.

DOI：10.1001/jamaoncol.2022.0503

• METASTATIC NASOPHARYNGEAL CARCINOMA
• ANTITUMOR-ACTIVITY
• RECURRENT
• CANCER
• HEAD
• PEMBROLIZUMAB
• NIVOLUMAB
• CETUXIMAB

IMPORTANCE The antibody drug conjugate drug MRG003 comprises an anti-epidermal growth factor receptor (EGFR) humanized immunoglobulin G1 monoclonal antibody that is conjugated with monomethyl auristatin E via a valine-citrulline linker. There is currently insufficient evidence of this drug's safety and efficacy. @@@ OBJECTIVE To evaluate the safety and maximum tolerated dose of MRG003 in a phase la study and investigate the preliminary antitumor activity in EGFR-expressing patients in a phase 1b study. @@@ DESIGN, SETTING. AND PARTICIPANTS This nonrandomized open-label, single-arm, phase 1, multicenter study of solid tumors was divided into 2 parts, phase la dose escalation and phase 1b dose expansion. Patients with advanced or metastatic solid tumors who had failed outcomes from or were not able to receive standard treatment were enrolled in phase la without EGFR prescreening. Phase 1b recruited EGFR-positive patients with refractory advanced squamous cell carcinomas of the head and neck (SCCHN), nasopharyngeal carcinoma (NPC), and colorectal cancer (CRC). This study was conducted at 7 Chinese centers between April 11, 2018, and March 29, 2021 (data cutoff date). Data analysis took place between April 2021 and June 2021. @@@ INTERVENTIONS An intravenous dose of 0.1 to 2.5 mg/kg of MRG003 was administered every 3 weeks during phase la. During phase 1b, patients were administered the recommended dose identified in phase 1a. @@@ MAIN OUTCOMES AND MEASURES The primary end points were dose-limiting toxic effects in phase la and objective response rate in phase 1b. The safety, tolerability, immunogenicity, and pharmacokinetics of MRG003 were assessed. Tumor assessment was evaluated by RECIST 1.1. @@@ RESULTS Twenty-two patients (mean [range] age, 54.5 [32.0-67.0] years; 9 women [41%]) were enrolled in phase la and 39 patients (mean [range] age, 50.4 [27.0-75.0] years; 8 women [21%]) in phase 1b. The recommended dose was identified as 2.5 mg/kg. Eighty-nine percent of adverse events (AEs) were associated with MRG003 treatment, and most AEs were grade 1 to 2. Nineteen patients (31%) reported grade 3 or greater treatment-related AEs, including hyponatremia, leukocytopenia, neutropenia, increased aspartate aminotransferase levels, and febrile neutropenia. In phase la, 1 patient (5%) achieved a partial response, and 5 (23%) achieved stable disease. In phase 1b, 8 patients (21%) achieved a confirmed partial response, and 12 (31%) achieved stable disease. The objective response rates for SCCHN, NPC, and CRC were 40%, 44%, and 0%, and the disease control rates were 100%, 89%, and 25%, respectively. @@@ CONCLUSIONS AND RELEVANCE The findings of this nonrandomized clinical trial suggest that MRG003 showed a manageable safety profile and promising antitumor activity in patients with EGFR-positive NPC and SCCHN.

• 单位
  上海交通大学; 中山大学; 同济大学; 重庆大学; 中国医学科学院; 南方医科大学