IN THE PHASE III BFORE trial reported in the Journal of Clinical Oncology by Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center, and colleagues, the SRC/ABL kinase inhibitor bosutinib (Bosulif) improved response rates vs imatinib in the first-line treatment of patients with Philadelphia chromosome (Ph)-positive chronic-phase chronic myeloid leukemia (CML) with typical BCR-ABL 1 transcript types.1 Bosutinib is already approved for the treatment of adults with Ph-positive CML resistant to or intolerant of prior therapy.
IN THE ONGOING open-label trial, 536 patients with newly diagnosed Ph-positive CML from 151 sites in 26 countries were randomized between July 2014 and August 2015 to receive 400 mg once daily of bosutinib (n = 268)—although the standard dose is 500 mg for bosutinib—or 400 mg of imatinib (n = 268). Randomization was stratified by Sokal risk group and geographic region. The primary endpoint was major molecular response (MMR) at 12 months in the modified intent-to-treat population, with the primary analysis including only patients with typical BCR-ABL 1 transcript types (e13a2 or e14a2); this population consisted of 246 patients in the bosutinib group and 241 patients in the imatinib group. Patients with Ph-negative/BCR-ABL1–positive status and those with unknown Ph status or atypical BCR-ABL1 transcript types were excluded from the primary analysis. At data cutoff, all patients had a minimum follow-up of 12 months. The study is ongoing and is expected to last approximately 5 years per patient.
For the bosutinib vs imatinib groups in the modified intent-to-treat population: the median age was 52 vs 53 years (19% vs 17% ≥ 65 years); 58% vs 56% were male; 78% vs 77% were white and 12% vs 12% were Asian; prior hydroxyurea or anagrelide had been received by 53% vs 55%; the median duration from diagnosis was 23 vs 26 days; Sokal risk group was low for 38% vs 39%, intermediate for 41% vs 39%, and high for 21% vs 21%; Eastern Cooperative Oncology Group performance status was 0 (71% vs 71%) or 1 in all patients; 5.7% vs 3.3% had extramedullary disease; and 11.4% vs 12.0% had a history of cardiac disease, and 6.1% vs 6.6% had a history of cardiac procedures.
“Results indicate bosutinib may be an effective first-line treatment for chronic-phase chronic myeloid leukemia.”— Jorge E. Cortes, MD, and colleagues
Tweet this quote
Major Molecular Response Rates
THE MAJOR MOLECULAR response rate at 12 months was 47.2% in the bosutinib group vs 36.9% in the imatinib group (odds ratio = 1.55, P = .02), and the complete cytogenetic response rate at 12 months was 77.2% vs 66.4% (odds ratio = 1.74, P = .0075). Major molecular response rates were higher in the bosutinib group at 3 months (4.1% vs 1.7%), 6 months (35.0% vs 18.3%), and 9 months (42.3% vs 29.5%); the cumulative incidence function of major molecular response rate was higher with bosutinib (hazard ratio [HR] = 1.34, P = .0173), indicating a shorter time to response with bosutinib. The cumulative incidence function for complete cytogenetic response was also greater in the bosutinib group (HR = 1.38, P < .001). The major molecular response rates at 12 months were 34.0% vs 16.7% among patients with high Sokal risk scores, 44.9% vs 39.1% among those with intermediate Sokal risk scores, and 58.1% vs 46.3% among those with low Sokal risk scores. Dose escalation due to suboptimal response occurred in 17.2% vs 27.5% of patients. In the total patient population, major molecular response rates at 12 months were 46.6% vs 36.2% (odds ratio = 1.57, P = .0126). Disease progression to blast phase occurred in 1.6% vs 2.5% of patients. Overall survival at 12 months was 99.6% vs 97.9%.
THE MOST COMMON adverse events of any grade were diarrhea (70%), nausea (35%), thrombocytopenia (35%), increased alanine transaminase (ALT; 31%), and increased aspartate transaminase (AST; 23%) in the bosutinib group and nausea (39%), diarrhea (34%), muscle spasms (26%), and neutropenia (21%) in the imatinib group. Grade ≥ 3 adverse events occurred in 56% vs 43% of patients, with the most common (> 10% of patients) being ALT increase (19%) and thrombocytopenia (14%) in the bosutinib group and neutropenia (12%) in the imatinib group. Cardiac events occurred in 5.2% vs 5.3% of patients, and peripheral vascular events occurred in 1.5% vs 1.1%.
Adverse events led to dose interruptions in 56% vs 36% of patients, dose reductions in 35% vs 17%, and treatment discontinuation in 14% vs 11%; the most common causes of treatment discontinuation in the bosutinib group were ALT increase (4.9%) and AST increase (2.2%).
The investigators concluded: “Patients who received bosutinib had significantly higher rates of [major molecular response] and complete cytogenetic response and achieved responses faster than those who received imatinib. Consistent with the known safety profile, [gastrointestinal] events and transaminase elevations were more common with bosutinib. Results indicate bosutinib may be an effective first-line treatment for chronic-phase chronic myeloid leukemia.” ■
DISCLOSURE: The study was supported by Avillion under a collaborative development agreement with Pfizer and grants from the National Cancer Institute. For full disclosures of the study authors, visit www.jco.ascopubs.org.
1. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al: Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: Results from the randomized BFORE trial. J Clin Oncol. November 1, 2017 (early release online).
Error loading Partial View script (file: ~/Views/MacroPartials/TAP Article Portrait Widget.cshtml)
BOSUTINIB ( BOSULIF) is the latest tyrosine kinase inhibitor that has shown a superior molecular response profile when compared with imatinib.1,2 An orally available dual SRC/ABL1 inhibitor, the drug ...