Efficacy, Safety, and Immunogenicity of HLX04Versus Reference Bevacizumab in Combination with XELOX or mFOLFOX6 as First-Line Treatmentfor Metastatic Colorectal Cancer: Results of a Randomized, Double-Blind Phase IIIStudy
Shukui Qin, Jin Li, Yuxian Bai, Yongqian Shu, Wei Li, Xianli Yin, Ying Cheng, Guoping Sun, Yanhong Deng, Haijun Zhong, Yunfeng Li, Xiaoping Qian, Liangming Zhang, Jingdong Zhang, Kehe Chen, Wenying Kang, HLX04-mCRC03 Investigators, Yuxian Bai, Yongqian Shu, Wei Li, Xianli Yin, Ying Cheng, Guoping Sun, Yanhong Deng, Haijun Zhong, Jin Li, Yunfeng Li, Xiaoping Qian, Shukui Qin, Liangming Zhang, Jingdong Zhang, Kehe Chen, Yuping Sun, Yuan Lin, Tianshu Liu, Bai Li, Shirong Cai, Hong Zong, Helong Zhang, Wei Wang, Sanyuan Sun, Jianping Xiong, Jianfeng Zhou, Bangwei Cao, Hongming Pan, Suxia Luo, Yi Ba, Nong Xu, Jianwei Lu, Jiemin Zhao, Tao Zhang, Zhendong Chen, Jun Liang, Qiu Li, Peiguo Cao, Dong Wang, Wangjun Liao, Yueyin Pan, Longzhen Zhang, Yan Tan, Yunpeng Liu, Xi Chen, Jianwei Yang, Tao Ma, Xiaoyan Lin, Shan Zeng, Minghui Zhang, Xiuli Wang, Enxiao Li, Yiye Wan, Guohua Yu, Weijian Guo, Ying Yuan, Yuansong Bai, Guangyu An, Jianming Xu, Lei Yang, Houjie Liang, Jiang Liu, Wenling Wang
Abstract
HLX04 is a proposed biosimilar of bevacizumab. This phase III study aimed to evaluate the efficacy, safety, and immunogenicity of HLX04 compared with reference bevacizumab in combination with XELOX or mFOLFOX6 as first-line treatment for recurrent/metastatic colorectal cancer (CRC). In this double-blind, parallel-group study, patients were randomized 1:1 to receive HLX04 or bevacizumab (7.5 mg/kg every 3 weeks when combined with XELOX; 5 mg/kg every 2 weeks when combined with mFOLFOX6). The primary endpoint was progression-free survival rate at week 36 (PFSR36w) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Prespecified equivalence margins of PFSR36w were set as − 11 to 15% (rate difference) and 0.8 to 1.25 (rate ratio). Secondary endpoints included efficacy, safety, immunogenicity, and pharmacokinetics. A total of 677 patients were randomized (HLX04 n = 340; bevacizumab n = 337) between April 2018 and April 2020. PFSR36w was 46.4% (95% confidence interval [CI] 41.1–51.8) with HLX04 and 50.7% (95% CI 45.4–56.1) with bevacizumab. The rate difference (− 4.2%; 90% CI − 10.6 to 2.1) and rate ratio (0.92; 90% CI 0.80–1.05) both fell within the prespecified equivalence margins. No notable differences were observed between treatment groups in any efficacy endpoints or their subgroup analyses. Safety, immunogenicity, and pharmacokinetic profiles were comparable between the two treatment groups. HLX04 demonstrated equivalent efficacy with similar safety and immunogenicity profiles to reference bevacizumab among patients with recurrent/metastatic CRC, thus offering an alternative treatment option to patients. Chinadrugtrials.org.cn, CTR20171503 (18 March 2018); ClinicalTrials.gov, NCT03511963 (30 April 2018). Colorectal cancer (CRC) is the third most common cancer worldwide. Approximately 20% of patients with CRC have metastases at their first visit. Bevacizumab is a biologic antibody approved in many countries for the treatment of metastatic CRC. However, high treatment costs significantly limit patient access to bevacizumab. Therefore, HLX04, a potential bevacizumab biosimilar, which is almost identical to bevacizumab but less expensive and more accessible, has been developed. This randomized clinical trial was designed to evaluate the efficacy (ability of a drug to produce the desired treatment effects), safety, and immunogenicity (ability of a drug to induce immune response that would affect its efficacy and safety) of HLX04 compared with the reference bevacizumab in patients with recurrent/metastatic CRC. Efficacy of the tested drug was evaluated by comparing the proportion of patients without disease progression or death at week 36 (PFSR36w). Safety was monitored using adverse events and other clinical evaluations. Immunogenicity was assessed by the incidence of antidrug antibodies. Of the 677 patients enrolled in the study, 340 received HLX04 and 337 received bevacizumab. Statistical analyses showed that HLX04 was equivalent to bevacizumab in efficacy evaluations (the difference in PFSR36w between the two treatment groups fell within the prespecified “equivalence margins”). Moreover, the two treatments were similar with respect to safety and immunogenicity evaluations. In summary, patients responded equally well to HLX04 and bevacizumab, supporting the development of HLX04 as a proposed biosimilar to bevacizumab for patients with recurrent/metastatic CRC.