On June 28, 2019 Pfizer Inc. (NYSE:PFE) reported the United States (U.S.) Food and Drug Administration(FDA) has approved ZIRABEV (bevacizumab-bvzr), a biosimilar to Avastin (bevacizumab),1 for the treatment of five types of cancer: metastatic colorectal cancer; unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer (Press release, Pfizer, JUN 28, 2019, View Source [SID1234537325]).2

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"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 Oncology. "We are proud to add ZIRABEV to our growing oncology portfolio for U.S. patients living with a wide variety of tumor types."

The FDA approval was based on review of a comprehensive data package which demonstrated biosimilarity of ZIRABEV to the reference product. This includes results from the REFLECTIONS B7391003 clinical comparative study, which showed clinical equivalence and found no clinically meaningful differences between ZIRABEV and the reference product in patients with advanced non-squamous NSCLC.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," said Dr. Niels Reinmuth, Department of Thoracic Oncology, Asklepios Lung Clinic, Munich-Gauting, Germany and lead author of the REFLECTIONS B7391003 study.4 "The FDA’s approval of ZIRABEV may provide an important new option for the treatment of multiple forms of cancer."

Biosimilars have been a significant catalyst for change for the healthcare industry over the last decade, with the potential to create a more sustainable healthcare system. With more than 10 years of global in-market experience and six approved biosimilar products in the U.S., Pfizer is proud to be a leader and at the forefront of this vital healthcare segment. ZIRABEV is Pfizer’s second oncology monoclonal antibody (mAb) biosimilar to be approved by the FDA, following the FDA approval of TRAZIMERA (trastuzumab-qyyp) in March 2019.5 ZIRABEV was also approved for use in the European Union (EU) in February 2019 for the treatment of 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.6

About ZIRABEV (bevacizumab-bvzr)

ZIRABEV is a mAb biosimilar of the reference product, Avastin, which works by inhibiting the formation of new blood cells (angiogenesis) by specifically recognizing and binding to vascular endothelial growth factor (VEGF) protein. As part of the REFLECTIONS clinical trial program, ZIRABEV has been studied in nearly 400 patients to date.3,7,8,9

ZIRABEV IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Gastrointestinal Perforations and Fistulae. Serious and sometimes fatal gastrointestinal perforation occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. Non-GI fistulae (
Surgery and Wound Healing Complications. The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab-treated patients. Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days following surgery and until the wound is fully healed. Discontinue in patients who develop wound healing complications that require medical intervention or necrotizing fasciitis
Hemorrhage. Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding occurred up to 5-fold more frequently in patients receiving bevacizumab. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4% to 7%. Do not administer ZIRABEV to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood). Discontinue ZIRABEV in patients who develop grade 3–4 hemorrhage
Additional serious and sometimes fatal adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:
Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM). Discontinue in patients who develop a severe ATE.
Renal injury and proteinuria. Monitor proteinuria during ZIRABEV therapy. Patients with a 2+ or greater urine dipstick reading should undergo 24-hour urine collection. Withhold for proteinuria >2 grams per 24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome
Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
Nephrotic syndrome (
Additional serious adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:
Venous thromboembolism (grade ≥3, 11% seen in Study GOG-0240). Discontinue ZIRABEV in patients with a Grade 4 VTE, including pulmonary embolism
Hypertension (grade 3–4, 5%–18%). Monitor blood pressure during treatment and, for ZIRABEV associated hypertension, continue monitoring after discontinuation. Withhold for severe hypertension. Discontinue for hypertensive crisis or hypertensive encephalopathy
Posterior reversible encephalopathy syndrome (PRES) (
Congestive heart failure (CHF) (1%). Discontinue ZIRABEV in patients who develop CHF
Infusion-related reactions with the first dose of bevacizumab occurred in
Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with ZIRABEV
Pregnancy Warning

Based on the mechanism of action and animal studies, bevacizumab products may cause fetal harm
Advise female patients that bevacizumab products may cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy
Advise females of reproductive potential to use effective contraception during treatment with ZIRABEV and for 6 months after the last dose of ZIRABEV
Advise nursing women that breastfeeding is not recommended during treatment with ZIRABEV and for 6 months following their last dose of treatment
Bevacizumab products may impair fertility
Most Common Adverse Events

Across studies, the most common adverse reactions observed in bevacizumab patients at a rate >10% were:
Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis
Across all studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions
Indication-Specific Adverse Events

In first-line metastatic colorectal cancer (MCRC), the most common grade 3–4 events in Study 2107, which occurred at a (≥2%) higher incidence in the bevacizumab plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the bevacizumab plus FOLFOX4 vs FOLFOX4 groups, were fatigue (19% vs 13%), diarrhea (18% vs 13%), sensory neuropathy (17% vs 9%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), hypertension (9% vs 2%), abdominal pain (8% vs 5%), hemorrhage (5% vs 1%), other neurological (5% vs 3%), ileus (4% vs 1%), and headache (3% vs 0%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study
In non–small cell lung cancer (NSCLC), grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a (≥2%) higher incidence in bevacizumab-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thromboembolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
In recurrent glioblastoma (rGBM) Study EORTC 26101, 22% of patients discontinued treatment in the bevacizumab with lomustine arm due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving bevacizumab with lomustine, the adverse reaction profile was similar to that observed in other approved indications
In metastatic renal cell carcinoma (mRCC), the most common grade 3–5 adverse events in Study BO17705, occurring at a (≥2%) higher incidence in bevacizumab-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%, including hypertension and hypertensive crisis), and hemorrhage (3% vs 0.3%, including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma)
In persistent, recurrent, or metastatic cervical cancer, grade 3 or 4 adverse reactions in Study GOG-0240, occurring at a higher incidence (≥2%) in 218 patients receiving bevacizumab plus chemotherapy compared to 222 patients receiving chemotherapy alone, were abdominal pain (12% vs 10%), diarrhea (6% vs 3%), anal fistula (4% vs 0%), proctalgia (3% vs 0%), urinary tract infection (8% vs 6%), cellulitis (3% vs 0.5%), fatigue (14% vs 10%), hypertension (11% vs 0.5%), thrombosis (8% vs 3%), hypokalemia (7% vs 4%), hyponatremia (4% vs 1%), dehydration (4% vs 0.5%), neutropenia (8% vs 4%), lymphopenia (6% vs 3%), back pain (6% vs 3%), and pelvic pain (6% vs 1%)
INDICATIONS

Metastatic Colorectal Cancer

ZIRABEV, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer (mCRC).

ZIRABEV, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen.

Limitation of Use: ZIRABEV is not indicated for adjuvant treatment of colon cancer.

First-Line Non-Squamous Non-Small Cell Lung Cancer

ZIRABEV, in combination with carboplatin and paclitaxel, is indicated for the first line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer (NSCLC).

Recurrent Glioblastoma

ZIRABEV is indicated for the treatment of recurrent glioblastoma (GBM) in adults.

Metastatic Renal Cell Carcinoma

ZIRABEV, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC).

Persistent, Recurrent, or Metastatic Cervical Cancer

ZIRABEV, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.