In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication

In September 4, 2012, bosutinib (Bosulif) was approved for the treatment of chronic phase, accelerated phase, or blast phase Philadelphia chromosome–positive chronic myelogenous leukemia (CML) in adult patients with resistance or intolerance to prior therapy.^1,2 (For information on investigational first-line use of bosutinib in CML, see 'Related Links' sidebar.)

Approval was based on results of a single-arm, open-label, multicenter trial in 546 patients with chronic phase (n = 406), accelerated phase, or blast phase CML (n = 140 for accelerated and blast phase) previously treated with at least one prior tyrosine kinase inhibitor.² All patients had received prior imatinib (Gleevec) therapy; 73% were imatinib-resistant and 27% were imatinib-intolerant. Fifty-three percent of patients were male, 65% were Caucasian, and 20% were aged 65 years or older. The T315I imatinib resistance mutation has also been found to confer resistance to bosutinib; after 396 patients had been enrolled in the trial, those known to harbor the T315I mutation were excluded.

In total, 503 patients were evaluable for efficacy. Among evaluable patients with chronic phase CML (n = 374), 266 received prior treatment with only imatinib and 108 received prior treatment with imatinib followed by either dasatinib (Sprycel) and/or nilotinib (Tasigna). All 129 evaluable patients with advanced phase CML (accelerated phase = 69, blast phase =60) were previously treated with at least imatinib.

Median durations of bosutinib treatment were 22 months in patients with chronic phase CML previously treated with one tyrosine kinase inhibitor (imatinib), 8 months in patients with chronic phase CML previously treated with imatinib and at least one additional tyrosine kinase inhibitor, 10 months in patients with accelerated phase CML previously treated with at least imatinib, and 3 months in patients with blast phase CML previously treated with at least imatinib.

Among patients with chronic phase CML who received prior therapy with imatinib alone, 34% achieved a major cytogenetic response at week 24; of 53% of those achieving a major cytogenetic response at any time during the trial, 53% had that response last at least 18 months. Among the chronic phase CML patients who received prior therapy with imatinib and at least one other tyrosine kinase inhibitor, 27% achieved a major cytogenetic response at week 24; of 32% who achieved a major cytogenetic response at any time, 51% of those had that response last at least 9 months.

Among patients with accelerated phase CML, 30% achieved a complete hematologic response and 55% achieved an overall hematologic response by week 48. Among patients with blast phase CML, 15% achieved a complete hematologic response and 28% achieved an overall hematologic response by week 48.

How It Works

Bosutinib inhibits the Bcr-Abl tyrosine kinase that promotes CML. It is also an inhibitor of Src-family kinases (including Src, Lyn, and Hck), which have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development.

Bosutinib has been show to inhibit 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, with no inhibition of T315I and V299L mutant cells being observed. Bosutinib treatment reduced the size of CML tumors in mice compared with controls and inhibited growth of murine myeloid tumors expressing several imatinib-resistant forms of Bcr-Abl.

How It Is Given

The recommended dose of bosutinib is 500 mg orally once daily with food, with treatment continuing until disease progression or intolerance. An increase to 600 mg/d can be considered in patients who do not reach complete hematologic response by week 8 or complete cytogenetic response by week 12 and who have not had grade 3 or higher adverse reactions. Treatment interruption until recovery and dose reduction are recommended for elevated liver transaminases (> 5 times upper limit of normal), diarrhea of grade 3 or 4, neutropenia (< 1,000 × 10⁶/L), and thrombocytopenia (< 50,000 × 10⁶/L).

The recommended dose of bosutinib in patients with mild, moderate, or severe hepatic toxicity is 200 mg/d. Strong or moderate CYP3A inhibitors (eg, thalidomide [Thalomid], itraconazole, clarithromycin) and/or P-glycoprotein inhibitors (eg, voriconazole) increase bosutinib exposure and strong or moderate CYP3A inducers reduce bosutinib exposure; concomitant use of these agents with bosutinib should be avoided. Bosutinib doses of 300 mg/d or lower have not been evaluated.

Safety Profile

Safety data are from the 546 patients enrolled in the single-arm trial. Serious adverse reactions included anaphylactic shock, myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity, and rash.

Among the 406 patients with chronic phase CML, the most common adverse events of any grade (> 20%) were diarrhea (84%), nausea (46%), abdominal pain (40%), thrombocytopenia (40%), vomiting (37%), rash (34%), fatigue (26%), anemia (23%), and pyrexia (22%). The most common grade 3 or 4 adverse events (> 5%) were thrombocytopenia (26%), neutropenia (11%), diarrhea (9%), anemia (9%), rash (8%), and increased ALT (7%). The most common grade 3 or 4 laboratory abnormalities (> 5%) were thrombocytopenia (25%), neutropenia (18%), anemia (13%), increased ALT (10%), increased lipase (8%), and low phosphorus.

Among the 140 patients with advanced phase CML, the most common adverse events of any grade were diarrhea (76%), nausea (47%), vomiting (42%), thrombocytopenia (42%), anemia (37%), pyrexia (36%), rash (35%), abdominal pain (29%), and cough (21%). The most common grade 3 or 4 adverse events were thrombocytopenia (37%), anemia (26%), neutropenia (18%), and dyspnea (6%). The most common grade 3 or 4 laboratory abnormalities were thrombocytopenia (57%), neutropenia (37%), anemia (35%), low phosphorus (7%), and increased ALT (6%).

Bosutinib carries warnings/precautions for gastrointestinal toxicity, myelosuppression, hepatic toxicity, fluid retention, and embryo-fetal toxicity.

Cost

The cost of bosutinib is expected to be approximately $8,000 per month. ■

References

1. U.S. Food and Drug Administration. Approved drugs. Bosutinib tablets. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm318203.htm. Accessed September 13, 2012.

2. BOSULIF® (bosutinib) tablets prescribing information. Pfizer, Inc, September 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf. Accessed September 13, 2012.