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The FDA has approved PF-06439535, a bevacizumab biosimilar, for the treatment of patients with metastatic colorectal cancer; unresectable, locally advanced, recurrent, or metastatic nonsquamous non–small cell lung cancer; recurrent glioblastoma; metastatic renal cell carcinoma; and persistent, recurrent, or metastatic cervical cancer.
The FDA has approved PF-06439535 (bevacizumab-bvzr; Zirabev), a bevacizumab (Avastin) biosimilar for the treatment of patients with metastatic carcinoma of the colon or rectum; 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
"Biosimilars like Zirabev can help increase access to impactful therapies, driving market competition that may ultimately lower costs and help address the diverse needs of patients living with cancer," Andy Schmeltz, Global President, Pfizer Oncology, the manufacturer of the biosimilar, stated in a press release. "We are proud to add Zirabev to our growing oncology portfolio for US patients living with a wide variety of tumor types."
The approval is based on findings from a comprehensive data package, which demonstrated biosimilarity of PF-06439535 to reference bevacizumab. This includes results from the REFLECTIONS B7391003 trial, which showed clinical equivalence and found no clinically meaningful differences between PF-06439535 and bevacizumab in patients with advanced non-squamous NSCLC.
"Zirabev represents a welcome addition to the treatment armamentarium in its approved indications, potentially providing physicians with a medicine that has a similar safety profile and efficacy as the reference product," Niels Reinmuth, MD, Department of Thoracic Oncology, Asklepios Lung Clinic, Munich-Gauting, Germany and lead study author of REFLECTIONS B7391003. "The FDA's approval of Zirabev may provide an important new option for the treatment of multiple forms of cancer."
Pfizer described PF-06439535 as a monoclonal antibody biosimilar of reference bevacizumab that works by inhibiting angiogenesis by specifically recognizing and binding to the VEGF protein. As part of the REFLECTIONS clinical trial program, PF-06439535 has been studied in nearly 400 patients to date.
The European Commission previously approved PF-06439535 in February 2019 for indications in colorectal, breast, lung, kidney, and cervical cancer. The approval was also based on data from the phase III REFLECTIONS B739-1003 trial. In the study, 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.