Jorge E. Cortes, MD

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. 

Study Details 

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%. 

Adverse Events 

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. 

REFERENCE 

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).