Efficacy, Safety, and Immunogenicity of HLX04 Versus Reference Bevacizumab in Combination with XELOX or mFOLFOX6 as First-Line Treatment for Metastatic Colorectal Cancer: Results of a Randomized, Double-Blind Phase III Study

Background HLX04 is a proposed biosimilar of bevacizumab. Objective 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). Methods 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 (PFSR 36w ) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Prespecified equivalence margins of PFSR 36w were set as − 11 to 15% (rate difference) and 0.8 to 1.25 (rate ratio). Secondary endpoints included efficacy, safety, immunogenicity, and pharmacokinetics. Results A total of 677 patients were randomized (HLX04 n = 340; bevacizumab n = 337) between April 2018 and April 2020. PFSR 36w 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. Conclusions 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. Trial registration Chinadrugtrials.org.cn, CTR20171503 (18 March 2018); ClinicalTrials.gov, NCT03511963 (30 April 2018).