Barriers to becacizumab (Avastin®) access involved not only treatment costs but lack of treatment guidelines and drug supplies across the USA, Europe and emergent market. The limit access to treatment resulted in reducing the number of planned bevacizumab cycle treatments with impact on patient quality-of-life and survival. HLX04, a proposed bevacizumab biosimilar, is required to demonstrate pharmacokinetics (PK) and safety bioequivalence in compared with reference product, attempting to address unmet medical needs in which bevacizumab is frequently used in metastatic colorectal cancer (mCRC).
We completed a PK, safety and immunogenicity equivalence study evaluating HLX04 and Avastin® sourced from US, the European Union (EU), and China (CN).The primary PK endpoints were serum area-under-the concentration time curves AUC0-∞ and AUC0-tau. Other endpoints included Cmax, safety and immunogenicity. The equivalence was achieved if 90% confidence intervals (CIs) for the test-to-reference ratios of PK parameters were within the 80-125% equivalence margin ranges by pairwise comparisons. Subsequently, we initiated a multi-center, randomized, double-blind, parallel-controlled, phase 3 study (HLX04-mCRC03) comparing the efficacy, safety and immunogenicity profiles of HLX04 or Avastin® with oxaliplatin and fluorouracil-based chemotherapy (XELOX or mFOLFOX6) regimen for the first-line treatment of mCRC. The primary efficacy endpoint was progression free survival rate up to month 9 (PFSR9m); safety endpoints included immunogenicity and adverse events.
Based on a total of 208 healthy males being randomized at 1:1:1:1 ratio to each study arm (HLX04 and bevacizumab sourced from US, EU or CN at 3 mg/kg) and were followed up uo 99 days, a four-way PK equivalence among HLX04 and all three reference products (Table) was established. Adverse drug reactions (ADRs) were noted in 153 (76.1%) subjects: 42 (82.4%), 38 (74.5%), 39 (75.0%) and 34 (72.3%) from the HLX04 and bevacizumab sourced from US, EU and CN arms, respectively. The most common ADR was elevated transaminases (n = 38 [18.9%]). One subject from EU arm suffered from a grade 4 non-drug-related AE (hypertriglyceridemia). No grade 5 AEs were reported. No anti-drug antibodies were detected in all arms. Based on these results, approximately 640 patients with mCRC will be randomized in 60 centers at 1:1 ratio to receive either HLX04 or Avastin® in an ongoing phase 3 pivotal study.Table: 105P
Statistical comparison of key PK parameters
|AUC0-∞ (μg·h/mL)||HLX04 vs bevacizumab-CN bevacizumab-CN vs bevacizumab-EU HLX04 vs bevacizumab-EU HLX04 vs bevacizumab-US bevacizumab-US vs bevacizumab-EU||95.4 100.5 95.9 99.0 96.9||90.6, 100.5 95.1,106.3 91.3,100.9 93.5,104.9 91.2,102.9|
|AUC0-t (μg·h/mL)||HLX04 vs bevacizumab-CN bevacizumab-CN vs bevacizumab-EU HLX04 vs bevacizumab-EU HLX04 vs bevacizumab-US bevacizumab-US vs bevacizumab-EU||95.9 100.3 96.2 99.4 96.8||91.2,100.9 95.1, 105.9 91.7, 101.0 94.0, 105.0 91.4, 102.7|
|Cmax (ng/mL)||HLX04 vs bevacizumab-CN bevacizumab-CN vs bevacizumab-EU HLX04 vs bevacizumab-EU HLX04 vs bevacizumab-US bevacizumab-US vs bevacizumab-EU||104.1 98.1 102.2 105.4 97.0||99.8, 108.6 94.0, 102.4 98.1, 106.5 101.0, 109.8 93.0, 101.1|
The four-way PK and safety equivalence of HLX04 and bevacizumab sourced from US, EU and China were established. To the best of our knowledge, we are first reporting the 4-way PK equivalence among HLX04, a proposed bevacizumab biosimilar, and three differently sourced Avastin®.
Clinical trial identification
Legal entity responsible for the study
Shanghai Henlius Biotech, Inc.
Shanghai Henlius Biotech, Inc.
X. Zhang, A. Luk: Employment: Shanghai Henlius Biotech, Inc. E. Liu: Employment: Henlix Biotech, Inc. W. Jiang, S. Liu: Employment: Shanghai Henlius Biotech, Inc.; Stock ownership of Shanghai Henlius, Inc. All other authors have declared no conflicts of interest.