Andreas Penk, MD
The European Commission has approved PF-06439535 (Zirabev), a bevacizumab (Avastin) biosimilar for the treatment of patients with metastatic carcinoma of the colon or rectum, metastatic breast cancer, unresectable advanced, metastatic, or recurrent non–small cell lung cancer (NSCLC), advanced and/or metastatic renal cell cancer, and persistent recurrent or metastatic carcinoma of the cervix.1
“We are proud that Zirabev was approved today as our second oncology biosimilar in Europe,” said Andreas Penk, MD, regional president of oncology international developed markets at Pfizer, the developer of the biosimilar. “This milestone reflects our ongoing commitment to biosimilars as we continue to bring high-quality medicines to market that may help generate cost savings for cancer care.”
The approval is based on data from a comprehensive submission package, which evidenced the biosimilarity between PF-06439535 and reference bevacizumab. The package included data from the phase III REFLECTIONS B739-03 trial (NCT02364999), a comparative clinical research study in which investigators assessed the safety and efficacy of the biosimilar in combination with paclitaxel and carboplatin for the first-line treatment of patients with advanced or metastatic nonsquamous NSCLC.
For the trial, 719 eligible patients were randomized 1:1 to receive either the biosimilar or reference bevacizumab sourced from the European Union (EU) plus paclitaxel and carboplatin on day 1 of every 3-week cycle followed by PF-06439535 (n = 358) or bevacizumab-EU (n = 361) blinded monotherapy as a maintenance treatment until progressive disease or unacceptable toxicity. Investigators set out to compare the objective response rate (ORR) by week 19 between the 2 arms.
Results presented at the 2018 Annual ASCO Meeting showed that the relative risk of ORR was 1.015, and the 90% confidence interval (0.886-1.163) was contained within the therapeutic equivalence margin of 0.73 to 1.37 prespecified by the FDA.2
The trial’s secondary endpoints served to further support the similarity between the 2 products.
Regarding safety, the rate of adverse events (AEs) was 14.6% in the PF-06439535 arm and 10.9% in the bevacizumab-EU arm. The rate of death was 4.8% and 5.3%, respectively. Investigators did not identify any significant differences between the 2 arms with arterial thromboembolic (TE) events/venous TE events, bleeding events, hypertension, gastrointestinal perforation, and proteinuria.
Investigators also compared the pharmacokinetics between the 2 agents to determine similarity in a previous phase I trial. In the double-blind trial, 102 healthy males between the ages of 21 and 55 were randomized 1:1:1 to receive either a single 5 mg/kg intravenous dose of the biosimilar, bevacizumab-EU, or bevacizumab sourced from the United States.
For 71 days, investigators conducted pharmacokinetic assessments; they also performed added safety and immunogenicity assessments up until day 100 of the trial. In order to achieve pharmacokinetic similarity, the 90% CIs for the test-to-reference ratios of the maximum serum concentration (C max), area under the serum concentration-time curve from 0 to infinity (AUC0-∞), and from 0 to time of last quantifiable concentration (AUC0-t), had to be within a bioequivalence acceptance window of 80.00 to 125.00.
Results showed similar pharmacokinetic properties across all 3 agents evaluated, with the 90% confidence interval for ratios of C max, AUC0-∞, and AUC0-t all within the acceptance window.3
Two patients treated with the biosimilar tested positive for antidrug antibodies, as well as 1 patient who received bevacizumab-EU and 2 patients who received bevacizumab-US. None of these patients tested positive for neutralizing antibodies.
Treatment-related AEs were observed in 15.2% of those who received the biosimilar compared with 25.7% and 18.2% in those who were given bevacizumab-EU and bevacizumab-US, respectively.
Overall, investigators concluded that the biosimilar showed pharmacokinetic similarity to both reference products, as well as comparable safety profiles, with no significant safety signals observed.
The European Commission’s decision to approve the biosimilar follows a positive recommendation from the agency’s Committee for Medicinal Products for Human Use in December 2018. PF-06439535 has also been filed for regulatory approval by the FDA.
- Pfizer receives European Approval for ZIRABEV (bevacizumab), a biosimilar to Avastin. Pfizer. Published February 19, 2019. https://on.pfizer.com/2BMbr8d. Accessed February 19, 2019.
- Socinski MA, Von Pawel J, Kasahara K, et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non–small cell lung cancer. J Clin Oncol. 2018;36(suppl 15, abstr 109). doi: 10.1200/JCO.2018,36,15_suppl.109.
- Knight B, Rassam D, Liao S, et al. A phase I pharmacokinetics study comparing PF-06439535 (a potential biosimilar) with bevacizumab in healthy male volunteers. Cancer Chemother Pharmacol. 2016;77(4):839-46. doi: 10.1007/s00280-016-3001-2.