General Information

Bosulif (bosutinib) is a tyrosine kinase inhibitor. Tyrosine kinases a subclass of protein kinase. Tyrosine kinases function as an on or off switch in many cellular functions. They can become mutated and cause unregulated growth of the cell, which is a necessary step for the development of cancer. Bosutinib inhibits the Bcr-Abl kinase that promotes CML amd also inhibits the Src-family kinases.

Bosulif is specifically indicated for:

Newly-diagnosed chronic phase Ph+ chronic myelogenous leukemia (CML).

Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy

Bosulif is supplied as a tablet for oral administration. The recommended dosing is as follows:

Newly-diagnosed chronic phase Ph+ CML: 400 mg orally once daily with food.

Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy: 500 mg orally once daily with food.

Consider dose escalation by increments of 100 mg once daily to a maximum of 600 mg daily in patients who do not reach complete hematologic, cytogenetic, or molecular response and do not have Grade 3 or greater adverse reactions.

Mechanism of Action

Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. In mice, treatment with bosutinib reduced the size of CML tumors relative to controls and inhibited growth of murine myeloid tumors expressing several imatinib-resistant forms of Bcr-Abl.

Clinical Trial Results

The FDA approval of Bosulif was based on a phase I/II single arm, open-label, multicenter trial in in patients with imatinib-resistant or -intolerant CML. Subjects were enrolled in separate cohorts for chronic, accelerated, and blast phase disease previously treated with one prior TKI (imatinib) or more than one TKI (imatinib followed by dasatinib and/or nilotinib). The protocol was amended to exclude subjects with a known history of the T315I mutation after 396 subjects were enrolled in the trial. A total of 546 subjects were treated with Bosulif 500 mg once daily. Of the 546 treated subjects, 503 were considered evaluable for efficacy. Median duration of Bosulif treatment was 22 months in patients with CP CML previously treated with one TKI (imatinib), 8 months in patients with CP CML previously treated with imatinib and at least 1 additional TKI, 10 months in patients with AP CML previously treated with at least imatinib, and 3 months in patients with BP CML previously treated with at least imatinib. The efficacy endpoints for patients with CP CML previously treated with one prior TKI (imatinib) were the rate of attaining MCyR at week 24 and the duration of MCyR. The efficacy endpoints for patients with CP CML previously treated with both imatinib and at least 1 additional TKI were the cumulative rate of attaining MCyR by week 24 and the duration of MCyR. The efficacy endpoints for patients with previously treated AP and BP CML were confirmed complete hematologic response (CHR) and overall hematologic response (OHR). The results are as follows:

Efficacy Results in Patients with Ph+ CP CML with Resistance to or Intolerance to Imatinib:

Prior Treatment with Imatinib Only:

Week 24 MCyR: 90%

Prior Treatment with Imatinib and Dasatinib or Nilotinib:

Week 24 MCyR: 29%.

Efficacy Results in Patients with Accelerated Phase and Blast Phase CML Previously Treated with at Least Imatinib:

AP CML:

CHR by Week 48: 21%; OHR by Week 48: 31%

BP CML:

CHR by Week 48: 9%; OHR by Week 48: 17%. Of the 69 evaluable subjects with AP CML, 4 had confirmed disease transformation to BP while on Bosulif treatment.