FDA Grants Pembrolizumab Priority Review for TMB-High Tumors
April 07, 2020 04:24pm
By Lisa Astor
The FDA has approved Zirabev, a biosimilar to bevacizumab for 5 indications. Zirabev has been approved for the treatment of patients with metastatic colorectal cancer; unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer; recurrent glioblastoma; metastatic renal cell carcinoma; and persistent, recurrent or metastatic cervical cancer.
The FDA has approved Zirabev (bevacizumab-bvzr; PF-06439535), a biosimilar to bevacizumab (Avastin) for 5 indications.1
Zirabev has been approved for the treatment of:
“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,” said Andy Schmeltz, global president, Pfizer Oncologythe company developing the biosimilar, in a statement. “We are proud to add Zirabev to our growing oncology portfolio for U.S. patients living with a wide variety of tumor types.”
The approval was based on a comprehensive data package, including results from the REFLECTIONS B7391003 comparative clinical study, that established the biosimilarity of Zirabev to the reference product.
The double-blind, randomized, global REFLECTIONS B7391003 study investigated the efficacy, safety, and immunogenicity of Zirabev in comparison with reference bevacizumab from the EU. The biosimilar and reference product were compared in combination with paclitaxel and carboplatin in patients with newly diagnosed advanced nonsquamous NSCLC.2
Patients were treated with either Zirabev (n = 358) or bevacizumab-EU (n = 361) plus chemotherapy on day 1 of each cycle of 3 weeks for 4 to 6 cycles followed by single-agent Zirabev or bevacizumab-EU until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by week 19, which was to be confirmed by week 25. Secondary endpoints included safety, progression-free survival (PFS) rate at 1 year, overall survival (OS) rate at 1 year, duration of response, pharmacokinetics, and immunogenicity.
The median age of patients in the study was 61 years, and a majority of patients were male (65%) and had stage IV disease at diagnosis (76%).
In both arms, patients received a median of 10 cycles of Zirabev (range, 1-32) or bevacizumab-EU (range, 1-30) and 6 cycles of both paclitaxel and carboplatin.
The ORR in patients who received Zirabev was 45.3% (95% CI, 40.01%-50.57%) and was 44.6% (95% CI, 39.40%-49.89%) in patients who received bevacizumab-EU. The relative risk of ORR was 1.015 (90% CI, 0.886-1.163), which was within the FDA pre-specified equivalence margin of 0.73 to 1.37.
The median PFS with Zirabev was 9.0 months (95% CI, 7.6-9.7) and 7.7 months (95% CI, 7.6-8.5) with bevacizumab-EU. The 1-year PFS rate was 30.8% (95% CI, 24.6%-37.2%) with Zirabev and with the reference product the PFS rate was 29.3% (95% CI, 23.5%-35.3%) at 12 months.
With Zirabev, the median OS was 18.4 months (95% CI, 16.2-not evaluable [NE]) and was 17.8 months (95% CI, 15.9-NE) with bevacizumab-EU. The OS rates at 1 year were 65.2% (95% CI, 59.0%-70.7%) and 66.4% (95% CI, 59.9%-72.0%) with Zirabev and bevacizumab-EU, respectively.
The frequency of treatment-emergent adverse events (AEs) were similar between the 2 arms (96.6% with Zirabev vs 96.1% with bevacizumab-EU). Hypertension was the most frequent AE of special interest of grade ≥3 and occurred slightly more often in the Zirabev arm than in the reference product arm. Other AEs of special interest included cardiac disorders, bleeding/hemorrhage, venous thromboembolic events, proteinuria, arterial thromboembolic events, congestive heart failure, and gastrointestinal perforation (all under 5%), with no clinically meaningful differences between the 2 arms.
The proportion of patients with grade 5 serious AEs was 5.3% in the Zirabev arm versus 5.9% in the bevacizumab-EU arm.
Treatment discontinuation occurred in an equal amount of patients in both arms (73.3% with Zirabev vs 73.2% with bevacizumab-EU). The reason for discontinuation was progression or relapse in 43.0% of patients in the Zirabev arm and 47.5% in the reference product arm.
The incidence of post-treatment anti-drug antibodies was low and similar between the 2 treatment arms. Treatment-related anti-drug antibodies were also not considered to be associated with infusion-related reactions.
These results confirmed biosimilarity in line with previous studies of Zirabev in comparison with bevacizumab.3
“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, PhD, of the Department of Thoracic Oncology, Asklepios Lung Clinic, Munich-Gauting, Germany, and lead author of the REFLECTIONS B7391003 study, said in a statement. “The FDA’s approval of Zirabev may provide an important new option for the treatment of multiple forms of cancer.”
In line with bevacizumab’s label, the FDA label for Zirabev includes warnings and precautions for serious and sometimes fatal gastrointestinal perforation, wound healing and surgical complications, sever or fatal hemorrhage, and potential fetal harm for women who are pregnant.
Zirabev was also approved for use in the European Union in February 2019 for the treatment of patients with metastatic carcinoma of the colon or rectum; metastatic breast cancer; unresectable advanced, metastatic, or recurrent NSCLC; advanced and/or metastatic RCC; and persistent, recurrent or metastatic carcinoma of the cervix