Digital Features for this Adis Biosimilar Brief can be found at https://doi.org/10.6084/m9.figshare.17074784.

FormalPara MYL-1402O: Key Points

Biosimilar to reference bevacizumab.

Equivalent efficacy and tolerability to reference bevacizumab in patients with stage IV non-squamous NSCLC.

Similar pharmacokinetic and pharmacodynamic properties to those of reference bevacizumab.

MYL-1402O (as Abevmy®) is approved for all indications for which reference bevacizumab is approved.

1 Introduction

MYL-1402O (Abevmy®, Lextemy®) is a biosimilar of the reference monoclonal anti-vascular endothelial growth factor antibody bevacizumab. Abevmy® is approved for the same indications as the reference drug in the EU (Table 1) [1]. Lextemy is approved for the same indications as bevacizumab, apart from recurrent ovarian cancer [2]. The pharmacokinetic similarity of MYL-1402O to EU- and US-sourced reference bevacizumab has been demonstrated [3]. This article summarizes, from an EU perspective, the key features of MYL-1402O and its clinical use in the treatment of solid cancers, focusing on non-squamous non-small cell lung cancer (NSCLC).

Table 1 MYL-1402O (Abevmy®) prescribing summary in the EUa,b [1]
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2 Clinical Pharmacology

Pharmacokinetic equivalence of MYL-1402O to EU- and US-sourced bevacizumab was demonstrated in a pharmacokinetic study in healthy male subjects (Table 2). A parallel study design was selected as the half-life of bevacizumab is approximately 20 days. Although a subtherapeutic dose (1 mg/kg) of bevacizumab was administered to limit exposure in healthy subjects, this dose was within the range where the pharmacokinetics of bevacizumab are expected to be linear [3].

Table 2 Biosimilarity summary of MYL-1402O
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MYL-1402O demonstrated pharmacodynamic equivalence and similarity in physicochemical properties to EU-sourced bevacizumab in pre-clinical studies (Table 2). Differences in post-translational modifications were detected in MYL-1402O (Table 2), which have the potential to affect the efficacy of biological products via changes in antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). However, as bevacizumab does not exhibit ADCC nor CDC, these differences in post-translational modifications are unlikely to be clinically relevant [4].

3 Clinical Efficacy

The efficacy of MYL-1402O and reference bevacizumab was investigated in a multicentre, randomised, double-blind phase III equivalence trial in 671 patients with stage IV non-squamous NSCLC (Table 2, Fig. 1). Patients aged ≥ 18 years were treated intravenously with MYL-1402O or reference bevacizumab 15 mg/kg in 3-week cycles for 18 weeks, in addition to carboplatin to a target area under the concentration-time curve of 6 mg/mL·min and paclitaxel 175 or 200 mg/m2. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred earlier. Treatment response was evaluated by independent review using Response Evaluation Criteria in Solid Tumours 1.1 criteria at any time point within the first 18 weeks of treatment. After the initial 18-week combination treatment period, monotherapy with MYL-1402O or reference bevacizumab 15 mg/kg once every 3 weeks was available in eligible patients [i.e. those with stable disease or who had achieved a complete (CR) or partial (PR) response] for a further 24 weeks. Patients who at week 42 had maintained stable disease or who had achieved a CR or PR continued to receive MYL-1402O or reference bevacizumab until disease progression or discontinuation of treatment or termination of study. Baseline characteristics were generally well balanced between treatment arms [5].

Fig. 1
figure 1

Response rates in the intent-to-treat population following treatment with MYL-1402O or reference bevacizumab in combination with carboplatin and paclitaxel in patients with stage IV non-squamous non-small cell lung cancer. Bevacizumab (as MYL-1402O or reference bevacizumab) 15 mg/kg was administered intravenously in 3-week cycles [5]. BEV bevacizumab, CI confidence interval, RD risk difference

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Therapeutic equivalence of MYL-1402O to reference bevacizumab was demonstrated at week 18 analysis in the intent-to-treat population (primary efficacy analysis; Fig. 1). Overall response rates were similar between the MYL-1402O and reference bevacizumab treatment arms, and both EMA and FDA requirements for equivalence were met. The 95% confidence intervals of the risk difference were contained within the predefined equivalence margin of ± 12.5% (EMA requirement), and the 90% confidence intervals of the ratio of the overall response rate fell within the predefined equivalence margin of 0.73–1.36 (FDA requirement) [5].

Analyses at week 42 supported the therapeutic equivalence of MYL-1402O to reference bevacizumab [5]. The disease control rate in the MYL-1402O treatment arm was congruent with the rate in the bevacizumab treatment arm (Fig. 1). No significant differences between the MYL-1402O and reference bevacizumab arms were reported in median progression-free survival (7.6 months vs 9.0 months) and overall survival [OS] (70.0% vs 75.4%) rates; median OS was not reached in both treatment arms. The duration of response was consistent between treatment arms (7.7 vs 6.9 months) [5]. Data beyond week 42 indicated the OS in the MYL-1402O and reference bevacizumab arms was 71.9 and 77.3 weeks [4].

4 Tolerability and Safety

The safety and tolerability profile of MYL-1402O was similar to reference bevacizumab during a phase III trial in patients with stage IV non-squamous NSCLC. In total, 664 patients were analysed in the safety set, including 335 patients in the MYL-1402O treatment arm. In the MYL-1402O and reference bevacizumab treatment arms, treatment-related adverse events (TRAEs) were reported in 35.8% vs 35.0% of patients, serious TRAEs were reported in 5.1% vs 6.7% of patients, TRAEs leading to treatment discontinuation in 3.9% vs 4.0% of patients and TRAEs leading to death in 2.1% and 1.2% of patients. The most commonly reported TRAEs with an incidence ≥ 5% of patients were anaemia (6.6% vs 6.7%), thrombocytopenia (6.3% vs 5.5%) and diarrhoea (6.0% vs 3.6%) [4].

The incidence of adverse events of special interest (AESI) were generally similar between the MYL-1402O and reference bevacizumab treatment arms. The incidence of any-grade AESI at week 18 (i.e. when patients received combination therapy with MYL-1402O or reference bevacizumab and chemotherapy) in the MYL-1402O and reference bevacizumab treatment arms was 16.1% vs 20.1%; hypertension (3.6% vs 3.3%) and epistaxis (1.5% vs 5.2%) were the only AESI with an incidence ≥ 3% in any treatment arm. Grade ≥ 3 AESI were reported in 6.9% vs 7.0% of patients. At week 42 (i.e. when patients received monotherapy with MYL-1402O or reference bevacizumab), the incidence of any-grade (10.5% vs 8.0%) and grade ≥ 3 AESI (2.0% vs 2.5%) were consistent between treatment arms [4].

5 Immunogenicity

The immunogenicity of MYL-1402O was comparable to reference bevacizumab (Table 2). During a phase III trial in patients with stage IV non-squamous NSCLC, the incidence of treatment-emergent anti-drug antibodies (ADAs) was similar between the MYL-1402O and reference bevacizumab treatment arms (Table 2) [5]. In healthy male subjects, the majority (≥ 89%) of patients in the MYL-1402O, EU- and US-sourced reference bevacizumab treatment arms tested positive for ADAs on day 15. A similar decrease in ADA-positive subjects over time was observed across the trial arms [3]. Furthermore, in an analysis of the total trial population, higher levels of ADAs did not appear to have clinically significant effects on the pharmacokinetics of bevacizumab in healthy male subjects (Table 2) [3].

6 Conclusion

MYL-1402O is a bevacizumab biosimilar with similar physicochemical and functional properties to the reference product (Table 2). Based on the efficacy, tolerability and safety characteristics in clinical data available from patients with non-squamous NSCLC (Table 2), MYL-1402O (as Abevmy®) has been approved in the EU for all indications for which reference bevacizumab is approved (Table 1).