Results from the phase III BFORE trial suggest that treatment with the second-generation tyrosine kinase inhibitor bosutinib is associated with higher rates of cytogenetic and molecular responses than imatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML), according to a report published in the Journal of Clinical Oncology. Jorge E. Cortes, MD, from the MD Anderson Cancer Center at the University of Texas in Houston, and co-authors also reported that responses occurred earlier than in imatinib-treated patients.
In the multicenter, open-label trial, the researchers randomized 536 adult patients with CP-CML 1:1 to receive bosutinib 400 mg once-daily or imatinib 400 mg once-daily (n=268 in each arm). Patients were excluded from the trial if they received prior CML treatment, had central nervous system involvement, or had a history of significant cardiac disease.
In the study, the authors presented results from a modified intent-to-treat population of 246 bosutinib-treated patients (median age = 52 years; range = 18-84 years) and 241 imatinib-treated patients (median age = 53 years; range = 19-84 years) with Philadelphia chromosome-positive patients with typical BCR-ABL1 transcript types (e13a2 and/or e14a2).
Patients were treated with a median dose intensity of 392 mg once-daily (range = 39-557 mg) in the bosutinib group and 400 mg once-daily (range = 189-679 mg) in the imatinib group. Median duration on study treatment was 15.6 and 15.3 months (ranges not provided), respectively.
At 12 months of follow-up, 219 (81.7%) bosutinib-treated patients and 218 (82.3%) imatinib-treated patients were still receiving treatment. Treatment discontinuations were most often related to adverse events (AEs), and discontinuation due to AEs appeared to be more common in the bosutinib group (12.7% and 8.7%, respectively). However, a higher percentage of imatinib-treated patients discontinued for not achieving pre-specified efficacy endpoints (7.5% and 2.2%; p value not reported).
At 12 months, the rate of major molecular response (MMR; primary endpoint; defined as <0.1% BCR-ABL1 by real-time quantitative polymerase chain reaction assay) was significantly higher in the bosutinib-treated group than in the imatinib-treated group: 47.2 percent versus 36.9 percent (odds ratio [OR] = 1.55; 95% CI 1.07-2.23; p=0.02).
The authors assessed molecular response every three months. Three months after treatment initiation, the incidence of MMR was higher in the bosutinib group: 4.1 percent versus 1.7 percent (hazard ratio = 1.34; 95% CI 1.06-1.69; p=0.017).
The relationship remained statistically significant through the first year of treatment, even for deeper molecular responses:
- MR4 (defined as a BCR-ABL1:ABL1 ratio consistently <0.01%): 20.7% for bosutinib vs. 12.0% for imatinib (p=0.01)
- MR5 (defined as a BCR-ABL1:ABL1 ratio consistently <0.001%): 8.1% vs. 3.3% (p=0.02)
Rates of complete cytogenetic response (CCyR) were similarly higher in the bosutinib group (77.2% vs. 66.4%; OR=1.74; 95% CI 1.16-2.61; p=0.008).
Four patients (1.6%) receiving bosutinib and six patients (2.5%) receiving imatinib experienced disease progression to accelerated-phase or blast-phase CML. Five patients met the definition for transformation to accelerated-phase CML based on basophilia, but they did so within the first two weeks of treatment, the authors noted. All continued to receive the study drug, and four achieved MMR.
The 12-month estimated survival rate was 99.6 percent with bosutinib and 97.9 percent with imatinib. Seven patients died during study follow-up (1 bosutinib-treated patient and 6 imatinib-treated patients). “Four of these deaths (all in the imatinib group) occurred within 28 days of last dose (disease progression, cardiovascular failure/cerebrovascular accident, pneumonia, and septicemia),” the authors reported.
In the safety analysis, which included all 533 patients who received at least one dose of study drug, the authors found that “AEs were consistent with the known safety profiles of both drugs, [and] the percentage of patients reporting one or more treatment-related AEs was similar with bosutinib and imatinib (98.1% and 97.0%, respectively).”
The most common all-grade AEs (≥20%) in each group were diarrhea (70.1% with bosutinib and 33.6% with imatinib), nausea (35.1% and 38.5%), and thrombocytopenia (35.1% and 19.6%).
Grade ≥3 AEs were more common in bosutinib-treated patients (56.3%) than in imatinib-treated patients (43.6%). With bosutinib, the most common grade ≥3 AEs were increases in alanine aminotransferase (19.0%) and thrombocytopenia (13.8%); with imatinib, neutropenia (12.1%) was the most common grade ≥3 AEs.
“Cardiovascular events occurred in 3.0 percent of patients receiving bosutinib and 0.4 percent of patients receiving imatinib,” the researchers reported, including 2.2 percent and 0.4 percent, respectively, during the first year of therapy. However, there were no deaths due to cardiovascular toxicity.
“These results suggest that bosutinib can be an important alternative for patients with previously untreated CP-CML,” the authors concluded.
The study is limited by the use of MMR and CCyR as endpoints, and it was not powered to evaluate survival. Follow-up was short, and it is not known whether endpoints continued to differ at later time points. The authors added that longer follow-up is also needed to better assess and understand the incidence of cardiovascular events reported in this study.
The BFORE trial was sponsored by Pfizer, the manufacturer of bosutinib.
The authors report financial relationships with Pfizer and Novartis.
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. 2017 November 1. [Epub ahead of print]