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

Abstract

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 (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.

Results: 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.

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).

Conflict of interest statement

Wenying Kang is an employee of Shanghai Henlius Biotech, Inc. 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, and Kehe Chen have no conflicts of interest that are directly relevant to the content of this article.

© 2021. The Author(s).

Figures

Fig. 1

Participant disposition. A patient who had not received HLX04 was excluded from the full analysis set, the pharmacokinetic set, and the safety set of the HLX04 group after randomization. Another HLX04-treated patient was excluded from the full analysis set because of diagnosis of primary liver cancer. Patients were excluded from the per protocol set because of a lack of valid tumor assessment (HLX04, n = 11; bevacizumab, n = 5), receiving fewer than two doses of study drug (HLX04, n = 7; bevacizumab, n = 4), noncompliance (HLX04, n = 2; bevacizumab, n = 4), and major protocol violation (HLX04, n = 4; bevacizumab, n = 1). FAS full analysis set, PKS pharmacokinetic set,PPS per protocol set, SS safety set

Fig. 2

PFSR36w by CIR in a FAS and b PPS.CI confidence interval, CIR Central Images Reading Group, FAS full analysis set, PFSR36w progression-free survival rate at week 36, PPS per protocol set

Fig. 3

a Overall survival rate within 12 months, b progression-free survival by CIR, c time to response by CIR, andd duration of response by CIR (full analysis set). CI confidence interval,CIR Central Images Reading Group,CR complete response, DOR duration of response, HR hazard ratio, NE not estimable, NRnot reached, OS overall survival,PD disease progression, PFS progression-free survival, PR partial response, TTR time to response

Fig. 3

a Overall survival rate within 12 months, b progression-free survival by CIR, c time to response by CIR, andd duration of response by CIR (full analysis set). CI confidence interval,CIR Central Images Reading Group,CR complete response, DOR duration of response, HR hazard ratio, NE not estimable, NRnot reached, OS overall survival,PD disease progression, PFS progression-free survival, PR partial response, TTR time to response

Fig. 4

Mean serum concentrations of HLX04 and bevacizumab (pharmacokinetic set). C cycle,mFOLFOX6 5-fluorouracil, leucovorin, and oxaliplatin, W week,XELOX capecitabine plus oxaliplatin