BFORE Trial: Bosutinib Could Be a “Welcome” New Treatment Option for Chronic-Phase CML

Treatment with the dual SRC/ABL tyrosine kinase inhibitor bosutinib was associated with a higher major molecular response (MMR), deeper response, and shorter time to response, compared with imatinib, in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML), according to initial results from the BFORE trial presented at the 2017 ASCO Annual Meeting.

In the multicenter, open-label, phase III BFORE trial, Jorge E. Cortes, MD, professor at the MD Anderson Cancer Center at the University of Texas in Houston, and colleagues randomized 536 adult patients with CP-CML 1:1 to receive either bosutinib 400 mg once-daily or imatinib 400 mg once-daily (n=268 for each arm).

“Bosutinib has improved efficacy compared with imatinib,” Dr. Cortes said during his presentation. “The primary endpoint of MMR was met, as were other assessments of efficacy, such as earlier molecular response rates and fewer transformations [to accelerated-phase or blast-phase disease].”

Dr. Cortes 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), including Ph+ patients with typical BCR-ABL1 transcript types (e13a2 and/or e14a2), who had a 12-month follow-up visit by the time of data presentation.

At 12 months, 82 percent of patients in each group remained on treatment. The most common causes of treatment discontinuation were adverse events (AEs; such as liver toxicities and grade ≥3 gastrointestinal events) in each group: 14 percent in the bosutinib group and 9 percent in the imatinib group.

“There is a slightly higher percentage of patients who discontinued bosutinib for adverse events, whereas for imatinib, there is a higher percentage of patients who discontinued because of efficacy endpoints, including suboptimal response and progressive disease,” Dr. Cortes noted. Two patients in the imatinib group died before 12 months, while there were no deaths before 12 months in the bosutinib-treated group.

Of the remaining patients, the proportion who achieved MMR at 12 months (primary endpoint; defined as <0.1% BCR-ABL1 by real-time quantitative polymerase chain reaction assay) was greater in the bosutinib group, compared with the imatinib group: 47.2 percent versus 36.9 percent (odds ratio [OR] = 1.55; 95% CI 1.07-2.23; p=0.02).

The proportion of patients achieving complete cytogenetic response (CCyR) at 12 months (secondary endpoint) was also higher in the bosutinib group: 77.2 percent versus 66.4 percent (OR=1.74; 95% CI 1.16-2.61; p<0.01). “The CCyR rate was superior early on [at 3 months] and remained superior,” Dr. Cortes said, for a hazard ratio (HR) at 12 months of 1.38 (95% CI 1.13-1.69; p<0.001).

“We assessed molecular response every 3 months and, very early on, we started to see some imbalance in terms of MMR for bosutinib patients,” he said. “This became statistically significant and remained statistically significant at each of these monitoring time points during the first year.” The same relationship was true for deeper molecular responses, in favor of bosutinib:

  • MR4: 20.7% vs. 12.0% (p=0.01)
  • 5: 8.1% vs. 3.3% (p=0.02)

“Five patients met the definition for transformation to accelerated-phase CML based on basophilia, but they did so very early – within the first 2 weeks of treatment,” he noted. “So, they counted as disease transformation, but they continued on therapy because they became very stable. None of these patients has died or had progressive disease.”

The safety analysis, which included all 533 patients who received ≥1 dose of study drug (3 patients in the imatinib arm were randomized but never received treatment), revealed no new safety signals with either drug. However, bosutinib appeared to be associated with more frequent grade ≥3 AEs than imatinib, including diarrhea (7.8% vs. 0.8%), increased alanine aminotransferase levels (19% vs 1.5%), and increased aspartate aminotransferase levels (9.7% vs. 1.9%).

“The approved dose of bosutinib in the salvage setting was 500 mg daily, but we used 400 mg daily in an attempt to decrease the toxicity of bosutinib,” Dr. Cortes explained. “The results suggest that the lower dose improved the safety, with most of the adverse events being highly manageable.”

At the time of analysis, there were seven patient deaths: one in the bosutinib arm (second cancer) and six in the imatinib arm. Four of these (1 each of progressive disease, cardiovascular issues, pneumonia, and sepsis) occurred after imatinib treatment discontinuation, but within 28 days of the last dose.

“With these results, bosutinib could become a very welcome new treatment option for frontline CP-CML,” Dr. Cortes concluded. However, the current study was not powered to evaluate survival, and these results will need to be confirmed with longer-term follow-up.


Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib (BOS) versus imatinib (IM) for newly diagnosed chronic myeloid leukemia (CML): Initial results from the BFORE trial. Abstract #7002. Presented at the 2017 American Society of Clinical Oncology Annual Meeting, June 6, 2017; Chicago, Illinois.