Bosulif Granted Priority Review in CML

Bosulif (bosutinib) was granted a priority review to a supplemental new drug application (sNDA) by the Food and Drug Administration (FDA) for use in the first-line treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

Mace Rothenberg, MD

Bosulif (bosutinib) was granted a priority review to a supplemental new drug application (sNDA) by the Food and Drug Administration (FDA) for use in the first-line treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). The agency is scheduled to make a final decision by December 2017.

According to Pfizer and Avillion, the co-developers of the tyrosine kinase inhibitor (TKI), the European Medicines Agency (EMA) is also reviewing an application for use of Bosulif in the same patient population.

The FDA and EMA applications are based on data from the phase 3 BFORE trial, in which Bosulif was associated with a significantly higher rate of major molecular response at 12 months compared with imatinib (47.2 percent vs 36.9 percent), in patients with newly diagnosed Ph+ CML.

“As physicians gained experience with Bosulif, they have come to appreciate its favorable risk-benefit profile in patients with Ph-positive CML who no longer responded to or could not tolerate prior TKI therapy,” Mace Rothenberg, M.D., Chief Development Officer, Oncology, Pfizer Global Product Development, said in a press release. “At the 400-mg dose, we believe that the BFORE study demonstrates a similarly favorable risk-benefit in previously untreated patients with Ph-positive CML.”

In the multicenter, multinational, open-label BFORE trial, patients with newly diagnosed chronic phase CML were randomly assigned to 400 mg once daily of Bosulif (268 patients) or 400 mg once daily of imatinib (265 patients). Investigators lowered the Bosulif dose from 500 mg daily that was used in a previous study in an attempt to reduce toxicity.

Efficacy was assessed in a modified intent-to-treat population of 487 Ph+ patients, 246 in the Bosulif group and 241 in the imatinib group. The safety analysis included all patients treated.

The arms were well balanced. Median age was 52 years in the Bosulif arm (range, 18-84) and 53 years in the imatinib arm (range, 19-84). Roughly 20 percent of patients in the both arms were in the Sokal high-risk group. In both groups, all patients had an ECOG performance score of 0 or 1.

At three months, after achieving BCR-ACL transcript levels of less than 10 percent, early response was significantly superior for Bosulif (75 percent vs 57 percent).

Complete cytogenetic response (CCyR) by 12 months was also statistically significant in favor of Bosulif (77.2 percent vs 66.4 percent). Cumulative incidence of CCyR was also superior in the Bosulif group.

At 12 months, 82 percent of patients in both groups completed the full course of treatment and 18 percent in both groups discontinued within 12 months. In the Bosulif arm, 13 percent discontinued due to treatment-related adverse events compared with 9 percent in the imatinib arm.

More patients in the Bosulif arm experienced treatment-related dose interruptions (55 percent vs 36 percent) and reductions (35 percent vs 17 percent). Median dose intensity was 392 mg per day with Bosulif and 400 mg per day with imatinib.

All-grade diarrhea (70 percent vs 34 percent) and grade 3 or higher diarrhea (8 percent vs 1 percent) were significantly higher with Bosulif. Patients in the experimental arm were also much more likely to experience all-grade liver toxicity (40 percent vs 14 percent) and grade 3 or higher liver toxicity (24 percent vs 4 percent).

Bosulif is currently indicated in the United States for the treatment of adult patients with Ph+ CML who have resistance or intolerance to prior therapy. In Europe, Bosulif has conditional marketing authorization for the treatment of adult patients with Ph+ CML previously treated with one or more TKIs and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.