Global clinical trials validating bioequivalence with China-manufactured trastuzumab biosimilar, HLX02, and trastuzumab

Abstract

Background: HLX02 is being developed to address the current global need for high‐quality yet affordable trastuzumab biosimilar (trastuzumab) for patients with breast cancer. Methods: Following the step‐wise clinical approach for the development of biosimilar, we first enrolled 12 healthy males to evaluate safety and tolerability after a single infusion of HLX02 at 2, 4, 6 and 8 mg/kg. Upon successful demonstration of safety and PK (AUC0‐∞, Cmax, AUC0‐tau) equivalence between HLX02 and reference trastuzumab in 109 healthy males received a single infusion of 6 mg/kg either HLX02, trastuzumab sourced from EU or US, we subsequently conducted a multi‐national, randomized, double‐blind, parallelcontrolled, phase 3 study (HLX02‐BC01) investigating the efficacy and safety profiles of HLX02 and trastuzumab‐EU with docetaxel in adult females with HER2+ breast cancer from 83 centers in 4 countries. The primary efficacy endpoint was best overall response rate up to week 24 (ORR24), and safety endpoints included immunogenicity and incidence of adverse events. Results: After different concentrations of HLX02 demonstrated acute and dose‐dependent effect on serum concentration of 12 healthy males in a phase 1a clinical trial, a total of 109 healthy males was randomized to receive 6mg/kg of HLX02 (n = 37), trastuzumab‐EU(n = 37) or trastuzumab‐US(n = 35). The geometric mean ratio of the AUC0‐∞ [90% confidence intervals] for HLX02 / trastuzumab‐EU, HLX02 / trastuzumab‐US and trastuzumab‐US / trastuzumab‐EU were 0.914 [0.858‐0.973], 0.950 [0.891‐1.013] and 0.962 [0.902‐1.025], respectively, all within the bioequivalence margin of 0.80‐1.25 (Table). No deaths, SAE or ADA‐positive results were observed in any of the treatment groups. Based on these results, 653 previously‐untreated females with HER2‐overexpressing metastatic breast cancer in China, Poland, Ukraine and Philippines were randomized in an ongoing phase 3 pivotal study. Conclusions: The three‐way PK and safety equivalence of HLX02 and reference trastuzumab were demonstrated leading to the pivotal phase 3 study which has completed the enrolment in June 2018. To the best of our knowledge, the ongoing phase 3 study was the first Chinamanufactured trastuzumab biosimilar being investigated in a global setting. (Table Presented) .