ROCKVILLE, Maryland—Avastin (bevacizumab, Genentech) has gained Food and Drug Administration (FDA) approval in combination with carboplatin(Drug information on carboplatin) and paclitaxel(Drug information on paclitaxel) for the first-line treatment of unresectable, locally advanced, recurrent, or metastatic non-squamous-cell, non-small-cell lung cancer (NSCLC), which accounts for about three-quarters of newly diagnosed cases in the United States. The agency acted after reviewing findings from a pivotal phase III study that found the Avastin/chemotherapy combination increased overall survival by 25%, compared with the two chemotherapeutic agents alone.
“Bevacizumab, in combination with chemotherapy, is the first therapy in 10 years to improve on standard first-line treatment for advanced lung cancer, and the first FDA-approved therapy ever to extend survival for these patients beyond one year in a large, randomized clinical trial,” said Alan Sandler, MD, director of Medical Thoracic Oncology at Vanderbilt- Ingram Cancer Center. “With this survival benefit, bevacizumab(Drug information on bevacizumab) represents an important therapy for many advanced lung cancer patients fighting this difficult disease.”
Dr. Sandler served as the lead investigator for the phase III trial, designated E4599, which was led by the Eastern Cooperative Oncology Group (ECOG).
Avastin is an antiangiogenic, recombinant, humanized monoclonal IgG1 antibody that inhibits the biologic activity of human vascular endothelial growth factor. As a result, tumors apparently cannot acquire the new blood vessels required for them to grow. FDA initially approved Avastin in combination with intravenous fluorouracil(Drug information on fluorouracil) (5-FU) in February 2004 for the first-line treatment of metastatic colorectal cancer. In June of this year, the drug received approval in combination with 5-FU as a second-line treatment in the same disease.
Genentech supported its pivotal study—E4599, a randomized, activecontrolled, open-label, multicenter trial—with data from a smaller randomized, dose-ranging, active-controlled phase II study. E4599 researchers enrolled 878 patients without prior chemotherapy and randomized them 1:1 to receive six 21-day cycles of paclitaxel 200 mg/m2 and carboplatin to AUC 6 (PC) on day 1 or PC plus 15 mg/kg of Avastin on day 1. When patients in the Avastintreated arm completed or discontinued chemotherapy, they continued to receive Avastin alone until disease progression or unacceptable toxicity. Duration of survival served as the primary outcome.
Median overall survival was a statistically significant 12.3 months in the Avastin plus PC arm vs 10.3 months in the PC-alone group (HR 0.80, P = .013). One-year survival was 51% in the Avastin-treated patients vs 44% in the PC-alone arm. Investigators reported that the Avastin-treated patients had longer progression-free survival, compared with PC alone, but their assessments were not independently verified. Exploratory analyses of subgroups found Avastin had less overall survival impact in women, patients age 65 and older, and in those with 5% or greater weight loss at accrual.
The most common side effects associated with Avastin included weakness, abdominal pain, headache, diarrhea, and vomiting. The grade 3 to 5 adverse events observed in E4599 were neutropenia, fatigue, hypertension, infection, and hemorrhage. Clinical experience with Avastin has revealed two different hemorrhage patterns. One is minor, most commonly NCI-CTC grade 1 epistaxis. The second causes serious, sometimes fatal bleeding.