Bevacizumab Advanced Melanoma (BEAM) Was a Positive Trial

Abstract

TO THE EDITOR: Bevacizumab Advanced Melanoma (BEAM) by Kim et al was a randomized phase II trial. Cannistra clarified the differences between a phase III trial and a randomized phase II trial in 2009. “Unlike the randomized phase III study, the type I error of a randomized phase II trial is typically high, in the range of 10% to 20%, to keep patient numbers reasonable . . . The typical goal of performing a randomized comparison phase II trial is not to obtain definitive efficacy information, but to identify promising experimental regimens that have a high likelihood of success in the phase III setting.” The BEAM trial showed improvements in response rates, progression-free survival, and overall survival at all time points, with a similar degree of improvement to that seen in other solid tumors in which bevacizumab was added to chemotherapy. The hazard rate for improvement in overall survival at the last time point, 0.79, is the same rate of improvement seen with bevacizumab with the same chemotherapy that led the US Food and Drug Administration to approve bevacizumab for lung cancer. The BEAM trial produced strong evidence that a phase III trial would likely be successful. The statistical design for the BEAM trial was written in 2007, and the desire to keep the patient numbers reasonable together with the desire to use a more traditional type one error of 5% probably led to the hypothesis that the experimental arm would have a 50% improvement in progression-free survival, from 4 to 6 months, despite the fact that rate of improvement has almost never been reported with the addition of bevacizumab to chemotherapy. Because the statistical design of the trial was too ambitious in both the hypothesized improvement and the type one error (P value) sought, “the study did not meet the primary objective.” Our interpretation of the results of the BEAM might be moot if the results of a phase III trial were expected soon. Although there was enthusiasm among both the trial investigators and Genentech personnel in July 2009 for quickly starting a phase III trial, the merger of Genentech into Roche that year led to a change in corporate priorities away from a phase III trial in melanoma. Now with the approval of ipilimumab and vemurafenib, a first-line trial of chemotherapy with bevacizumab would be neither appropriate nor feasible. The BEAM trial was positive, and it will remain our best evidence of the efficacy of antiangiogenic therapy in metastatic melanoma for the near future. Other antivascular endothelial growth factor–targeted agents are being studied for melanoma, and we hope to soon see both phase II and phase III trials of bevacizumab with the new agents that are now our first-line therapy for metastatic melanoma.