BERLIN — The addition of bevacizumab to chemotherapy failed to significantly improve progression-free or overall survival in previously untreated advanced melanoma in the phase II BEAM trial.
Median progression-free survival was 5.6 months for bevacizumab (Avastin) plus carboplatin and paclitaxel-based chemotherapy, and 4.2 months for chemotherapy alone. Despite a hazard ratio of 0.78, the difference was not statistically significant (P = .14), Dr. Steven O'Day reported at a joint congress of the European Cancer Organization and the European Society for Medical Oncology.
Overall survival was widely reported before the congress as having been significantly increased by 4 months with bevacizumab, but an unplanned post hoc analysis performed just before the formal data presentation showed that the survival benefit had narrowed and had taken the statistical advantage with it.
Median overall survival went from 12.3 months in the bevacizumab arm and 8.6 months in the chemotherapy arm at a median follow-up of 13 months in the initial analysis (HR, 0.67; P = .04) to 12.3 months and 9.2 months, respectively, at a median follow-up of 18 months in the post hoc analysis (HR, 0.79; P = .19).
Response rates also favored bevacizumab over chemotherapy (25.5% vs. 16.4%), but were not significantly different (P =.16) in the Roche Pharmaceuticals–sponsored study.
Although the revised data sent stock analysts and journalists scrambling, the findings are still cause for optimism in a disease with few treatment options and a 5-year survival of less than 5%, according to Dr. O'Day, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.
“I am optimistic because strong trends of improvement were seen across all efficacy parameters” (progression-free survival, overall survival, and response), he said in an interview. “This was a randomized, phase II with 2:1 randomization, so it wasn't powered for overall survival to be significantly different. I'm also optimistic because even the worse prognosis patients with M1c disease and elevated [lactate dehydrogenase] seemed to benefit from this treatment.”
Based on the current data, Roche plans to go forward with a larger, randomized phase III trial that is adequately powered to detect a significant survival benefit, he said.
BEAM (A Study of Bevacizumab With Carboplatin and Paclitaxel Chemotherapy for the First-Line Treatment of Patients With Metastatic Melanoma) included 214 patients (mean age, 60 years) with stage IV M1a/b, M1c disease, of which 73% was M1c disease and 54% of M1c patients had abnormal lactate dehydrogenase levels. Patients received chemotherapy with or without bevacizumab 15 mg/kg administered intravenously on day 1 every 3 weeks.
Bevacizumab, an anti–vascular endothelial growth factor (VEGF)–specific inhibitor, was evaluated because melanoma is a very vascular tumor, and elevated VEGF levels correlate with tumor progression and worse prognosis. The addition of bevacizumab to chemotherapy has improved outcomes in other cancers, including metastatic colorectal cancer and non–small cell lung cancer.
No new safety events were observed in the trial. Grade 3/4 treatment-related adverse events that occurred with 2% or more increased incidence in the bevacizumab arm included febrile neutropenia, neutropenia, peripheral neuropathy, pulmonary embolism, hypertension, anorexia, and musculoskeletal pain. There were two deaths in the bevacizumab arm and none in the chemotherapy arm, Dr. O'Day said.
He has served an advisory/consultant role and received research funds from Genentech Inc. and Roche for clinical trials.