First-Line Avastin Ups Survival in Advanced NSCLC

ASCO — A randomized phase II/III trial in more than 800 patients with previously untreated advanced nonsquamous non-small-cell lung cancer (NSCLC) has shown a clinically significant survival advantage for the addition of the angiogenesis inhibitor bevacizumab (Avastin) to the standard platinum-based chemotherapy regimen. Reporting the results of ECOG E4599 in a plenary session at the 41st Annual Meeting of the American Society of Clinical Oncology (abstract 4), lead investigator Alan B. Sandler, MD, commented, "This is the first randomized trial in the past 10 years to show a survival advantage in patients with untreated metastatic disease, and the first trial with a targeted agent that has shown a survival advantage in combination with chemotherapy."

Dr. Sandler, medical director of thoracic oncology, Vanderbilt-Ingram Cancer Center, Nashville, and associate professor of medicine, Vanderbilt University Medical Center, said that the addition of the angiogenesis inhibitor to a regimen of paclitaxel and carboplatin extended median survival beyond 1 year for the first time among patients with advanced nonsquamous NSCLC.

The study enrolled 878 patients with untreated stage IIIb or IV nonsquamous NSCLC; 14% had stage IIIb disease. Because data from an earlier phase II study of bevacizumab suggested that squamous cell NSCLC may confer increased risk for grade 5 hemoptysis, patients with a squamous histology were excluded from the trial, Dr. Sandler said. Patients were randomly assigned to receive either paclitaxel at 200 mg/m² and carboplatin to AUC 6 on day 1 every 3 weeks (n = 444) or the same regimen plus bevacizumab at 15 mg/kg on day 1 every 3 weeks (n = 434). All patients received six cycles of therapy, and those randomized to the chemotherapy plus bevacizumab arm were treated with bevacizumab until toxicity became intolerable or their cancer progressed.

At a median follow-up of 9.4 months, median survival time was 12.5 months for patients who received bevacizumab plus chemotherapy vs 10.2 months for patients who received standard chemotherapy alone (P = .0075). Progression-free survival time was 6.4 months with bevacizumab vs 4.5 months without it (P < .0001), and the overall response to therapy was 27% for those receiving bevacizumab vs 10% for patients receiving chemotherapy alone (P < .0001).

An intriguing finding in a subset analysis was that men treated with bevacizumab/chemotherapy survived longer than women randomized to this regimen, Dr. Sandler told ONI. "Although these data are not mature," he said, "it is possible that women who went off the trial may have been administered tyrosine kinase inhibitors as second-line or even third-line therapy, which may have been responsible for this survival difference."

The investigators will continue to collect retrospective data from the study correlating biomarkers such as VEGF, fibroblast growth factor (FGF), and cell-adhesion molecules with survival and response outcomes, he added.

Well-Tolerated Regimens

Patients tolerated both regimens well, Dr. Sandler reported, with hemoptysis, an adverse event of significant concern in similar trials, being seen in the current study in only 1.3% of patients (n = 5) receiving chemotherapy/bevacizumab. No patients in the chemotherapy-alone group developed hemoptysis. "Hemoptysis was not a major concern and was not clinically significant in this trial," Dr. Sandler commented. "In all likelihood, this is because we excluded patients with NSCLC who had a squamous histology."

Grade 4-5 neutropenia was noted in 16.4% of patients on chemotherapy alone vs 24% whose treatment included bevacizumab. Grade 3-4 thrombosis/embolism was seen in 3% vs 3.8% of patients, respectively, and hemorrhage was observed in 1.0% vs 4.1% of patients, respectively.

There were 11 treatment-related deaths in the study: 2 were in the chemotherapy-alone arm, and 9 were in the arm that included bevacizumab, with 5 of these 9 deaths occurring from hemoptysis. (No deaths from hemoptysis occurred with chemotherapy alone.)

Given the significant clinical improvements seen in this study, Dr. Sandler noted that the regimen is ECOG’s new treatment standard for this patient population. "This paclitaxel/carboplatin doublet in combination with bevacizumab will be the accepted standard of care for patients with nonsquamous NSCLC and ultimately other platinum-based doublets in combination with bevacizumab," he concluded.