Bosutinib appears to be an appropriate new frontline treatment option for CML

Madrid, June 2017 – First results from the BEFORE trial¹ comparing bosutinib to imatinib in a first-line setting demonstrate that the study met its primary endpoint with a significantly higher 12-months MMR rate for bosutinib versus imatinib.

Bosutinib is a second generation TKI targeting BCR-ABL and SCR family kinases. It is indicated for adult patients with previously treated Ph+ CML when imatinib, nilotinib and dasatinib are not appropriate due to resistance, or intolerance.

In a first-line setting, the BELA trial² with newly diagnosed CML patients in chronic phase, has previously showed improved efficacy on a molecular level in favour of bosutinib versus imatinib, however it failed to meet the primary endpoint defined as 12-month complete cytogenetic response (CCyR) rate.

“The objective of this ongoing, open-label, Phase III BEFORE study is to further assess the efficacy and safety of bosutinib versus imatinib for first-line treatment of CP-CML now using a modified dose of 400 mg bosutinib compared to 500 mg used in the BELA study”, explained Dr Tim Brümmendorf during his presentation at the 22nd EHA congress.

536 patients with newly diagnosed CP-CML were randomized to bosutinib 400mg once daily, or 400mg imatinib once daily. After ≥12 months of follow-up, 78.0% of bosutinib and 73.2% of imatinib patients remain on treatment with median treatment durations of 14.1 months and 13.8 months, respectively.

The primary endpoint of this study was defined as MMR rate at 12 months. “The major molecular response rate at 12 months was in favour of bosutinib with 47.2% versus 36.9% of imatinib”, summarised Dr Brümmendorf outlining the primary results of the study. “We could also see a higher MMR rate in all Sokal risk groups.”

The MMR rate at 12 months was significantly higher with bosutinib versus imatinib in the modified intention to treat (ITT) population (47.2% vs 36.9%; P=0.02) as well as in the ITT population of all randomized patients (46.6% vs 36.2%; P<0.02). According to Brümmendorf, the time to response was faster with bosutinib versus imatinib (hazard ratio=1.34 based on cumulative incidence; P<0.02). “We have also tried to identify factors predictive of MMR at 12 months but could only identify a low Sokal risk score as a significant predictor” said Dr Brümmendorf.

The rate of CCyR by 12 months was also significantly higher with bosutinib versus imatinib (77.2% vs 66.4%; P<0.008), with time to CCyR shorter for bosutinib (hazard ratio=1.38; P≤0.001).

4 patients on bosutinib and 6 patients on imatinib progressed to blast phase during treatment. According to Brümmendorf, 5 of these patients (3 bosutinib and 2 imatinib) met the accelerated phase criteria within 2 weeks based on basophil count and all 5 continued on study drug including 4 patients who achieved MMR.

The safety data was consistent with known profiles. Discontinuation due to drug-related AE’s occurred with 12.7% of bosutinib patients and 8.7% of imatinib. Gastrointestinal events and transaminase elevations were more common on bosutinib treatment. “Diarrhoea was the most common side effect in all grades, but only led to treatment discontinuation in two cases” explained Brümmendorf.

In conclusion, the BEFORE trial met its primary endpoint with a significantly higher 12-month MMR rate for bosutinib versus imatinib and these responses occurred earlier with bosutinib. Bosutinib was associated with a higher incidence of GI events and transaminase elevations. Results indicate that the lower bosutinib dose (400mg) is associated with better tolerability and improved outcomes. The primary results from this study suggest that bosutinib is an important treatment option for patients with newly diagnosed CP CML.

1. Bosutinib vs. imatinib for newly diagnosed chronic myeloid leukemia. Initial results from the before trial, abstract presented by
   T. Brümmendorf during the 22nd Congress of the European Hematology Association (EHA), June 22-25, 2017 in Madrid, Spain.
2. Bosutinib versus imatinib in newly diagnosed chronic phase chronic myeloid leukemia: results from the BELA trial.
   Cortes JE et al. J Clin Oncol, October 2012

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