On October 11, 2006, the U.S. Food and Drug Administration granted approval for a labeling extension for bevacizumab (Avastin, Genentech, Inc.), administered in combination with carboplatin and paclitaxel, for the initial systemic treatment of patients with unresectable, locally advanced, recurrent, or metastatic, non-squamous, non-small cell lung cancer. This recommendation is based on the demonstration of a statistically significant improvement in overall survival (OS) in patients receiving Avastin with carboplatin and paclitaxel compared to those receiving carboplatin and paclitaxel alone.
The primary trial (E4599) supporting this approval was a randomized, active controlled, open label, multi-center clinical trial evaluating Avastin plus carboplatin and paclitaxel (n=434) versus carboplatin and paclitaxel alone (n=444). Patients with squamous histology, mixed cell tumors with predominant squamous cell histology, central nervous system metastases, gross hemoptysis (≥1/2 tsp red blood), or unstable angina and those receiving therapeutic anticoagulation were excluded from the trial. Patients with squamous cell histology were excluded based on four patients with life-threatening or fatal hemoptysis among 13 patients with squamous cell histology enrolled in a randomized, active-control, Phase 2 study (AVF0757g) who received chemotherapy with Avastin.
Among the 878 randomized patients, the median age was 63, 46% were female, no patients had received prior chemotherapy, 76% had Stage IV disease, 12% had Stage IIIB disease with malignant pleural effusion, 11% had recurrent disease, and 40% had an ECOG performance status of 0.
OS, the primary endpoint, was significantly longer in patients receiving Avastin in combination with paclitaxel and carboplatin as compared to those receiving paclitaxel and carboplatin alone (median OS 12.3 vs 10.3 mos; hazard ratio 0.80, p=0.013 stratified log rank test). Although a consistent effect was observed across most subgroups, in an exploratory analysis, evidence of a survival benefit was not observed in women. (HR 0.99; 95% CI 0.79, 1.25).
In E4599, data collection was limited to NCI-CTC grade 3-5 adverse events. Severe and life-threatening adverse events occurring more frequently in patients receiving Avastin and chemotherapy were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), thrombosis/embolism (5% vs 3%), pneumonitis or pulmonary infiltrate (5% vs 3%), infection with grade 3 or 4 neutropenia (5% vs 2%), febrile neutropenia (5% vs 2%), hyponatremia (4% vs 1%), proteinuria (3% vs 0), and headache (3% vs 0.5%). Fatal, treatment-related adverse events in patients receiving Avastin were pulmonary hemorrhage (2.3% vs. 0.5%), gastrointestinal hemorrhage, CNS infarction, gastrointestinal perforation, myocardial infarction, and neutropenic sepsis.
The most serious, and sometimes fatal, Avastin toxicities are gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, congestive heart failure, and neutropenic sepsis. The most common adverse events in patients receiving Avastin are asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available in Drugs@FDA.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by phone at 1-800-FDA-1088, by facsimile 1-800-FDA-0178, by mail, or by using the Form 3500