The newest data presented from the BELA (Bosutinib Efficacy and Safety in Chronic Myeloid Leukemia) trial show a superior cumulative complete cytogenetic response rate (CCyR) for bosutinib versus the standard-of-care agent, imatinib, when used as frontline treatment for patients with chronic myeloid leukemia (CML), with 87% and 81% response rates, respectively, at 24 months.
“Given these results, bosutinib may soon offer a new therapeutic option for patients with newly diagnosed chronic-phase CML,” said lead investigator Jorge E. Cortes, MD, of the University of Texas M.D. Anderson Cancer Center, Houston.
The way was not always so clear for bosutinib, the most clinically advanced, investigational second-generation tyrosine kinase inhibitor in the pipeline. The initial report of the pivotal BELA trial was a sensation for the wrong reason; the trial failed to meet its primary end point.
The reason that the 12-month data (presented in 2010) fell short of expectations was not for the drug’s lack of efficacy, but because of a conflict between the planned intent-to-treat (ITT) analysis, and because the trial was conducted in more than 100 locations, where some clinicians failed to proactively manage treatment-related adverse events. This suboptimal care led to an inordinate number of patient discontinuations, thereby driving down the otherwise encouraging treatment response rates. This critical issue has been addressed, and results at 24 months have improved significantly.
BELA Trial at 24 Months
The BELA trial was designed to look at the use of bosutinib versus imatinib in 502 patients with treatment-naïve, chronic-phase CML. The study’s primary end point was CCyR at 12 months, with secondary end points including major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. The planned follow-up period for BELA is 8 years.
At 24 months, the initial ITT analysis for CCyR indicated that the response to both drugs was nearly identical: 79% for bosutinib and 80% for imatinib. However, when patients who discontinued unnecessarily were excluded from the calculation, the cumulative CCyR was 87% for bosutinib versus 81% for imatinib.
Further analysis showed a complete response rate plus MMR of 67% for bosutinib versus 52% for imatinib, Dr Cortes reported.
Although median PFS and OS have not yet been reached, at 24 months bosutinib has a lower rate of treatment failure: 4% versus 13% for imatinib.
Regarding adverse events, as expected (and now effectively managed), individuals in the bosutinib cohort had more grade 3/4 diarrhea, whereas patients in the imatinib arm had more edema and myalgia. Hematologic events were more common in the imatinib treatment arm, especially for neutropenia (24% vs 10% for bosutinib).
New Drug Application
On January 27, 2011, the US Food and Drug Administration accepted a new drug application for bosutinib for a standard review as a treatment option for patients with previously treated Philadelphia chromosome–positive CML; the drug was submitted for approval in Europe late last year. n