In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On December 19, 2017, bosutinib (Bosulif) was granted accelerated approval for the treatment of newly diagnosed chronic-phase Philadelphia chromosome–positive chronic myeloid leukemia (CML).1,2
Supporting Efficacy Data
APPROVAL WAS BASED on findings in an open-label phase III trial (BFORE) in which 536 patients were randomized to receive oral bosutinib at 400 mg once daily (n = 268) or oral imatinib at 400 mg once daily (n = 268).2,3 They included 487 patients with Philadelphia chromosome–positive CML harboring b2a2 or b3a2 transcripts at baseline and baseline BCR-ABL copies > 0 (modified intent-to-treat population), of whom 246 were randomized to receive bosutinib and 241, imatinib.
The chief efficacy outcome measure was major molecular response at 12 months in the modified intent-to-treat population, defined as ≤ 0.1% BCR-ABL ratio (corresponding to ≥ 3 log reduction from standardized baseline) with a minimum of 3,000 ABL transcripts as assessed by a central laboratory. In the modified intent-to-treat population, patients had a median age of 53 years (19% ≥ 65 years), 57% were male, and 77% were white.
Major molecular response at 12 months was 47.2% in the bosutinib group vs 36.9% in the imatinib group (P = .0200). Complete cytogenetic response by month 12 was achieved in 77.2% vs 66.4% (P = .0075). After a minimum of 12 months of follow-up, 77.6% vs 72.4% of patients were still receiving treatment.
How It Works
BOSUTINIB IS a tyrosine kinase inhibitor that inhibits the BCR-ABL kinase, which promotes CML. It also inhibits Src-family kinases including Src, Lyn, and Hck. Bosutinib was found to inhibit 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines, with no inhibition found for T315I- and V299L-mutant cells.
How It Is Used
THE RECOMMENDED DOSE of bosutinib in newly diagnosed chronic-phase Philadelphia chromosome–positive CML is 400 mg once daily with food until disease progression or intolerance. The recommended starting dose is 300 mg daily in patients with a creatinine clearance of 30 to 50 mL/min and 200 mg daily in those with a creatinine clearance < 30 mL/min. The recommended starting dose is 200 mg daily in patients with mild, moderate, or severe hepatic impairment.
In studies conducted in adult Philadelphia chromosome–positive CML patients, dose escalation by increments of 100 mg once daily to a maximum of 600 mg once daily was permitted in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response and who did not have grade ≥ 3 adverse events at the recommended starting dosage.
Treatment should be withheld for elevations in liver transaminases to > 5 × upper limit of normal (ULN) and can be restarted at 400 mg once daily upon recovery to ≤ 2.5 × ULN; treatment should be discontinued if recovery takes > 4 weeks. Treatment should be discontinued for transaminase elevations ≥ 3 × ULN concurrently with bilirubin elevation > 2 × ULN and alkaline phosphatase < 2 × ULN.
Treatment should be withheld for grade 3 or 4 diarrhea and can be resumed at 400 mg upon recovery to grade ≤ 1. For other clinically significant moderate or severe nonhematologic toxicity, treatment should be withheld until the toxicity has resolved, with resumption at a dose reduced by 100 mg being considered; the dose may then be increased to the starting dose if clinically appropriate. The efficacy of doses < 300 mg/d has not been established.
For hematologic toxicity, treatment should be withheld for an absolute neutrophil count < 1,000 × 106/L or platelets < 50,000 × 106/L until levels increase above these thresholds. Treatment can be resumed at the same dose if recovery occurs within 2 weeks and at a dose reduced by 100 mg if recovery takes > 2 weeks. If cytopenia recurs, the dose should be reduced by an additional 100 mg when restarting treatment after recovery.
Concomitant use of bosutinib with strong CYP3A inhibitors (eg, ketoconazole, itraconazole, clarithromycin), moderate CYP3A inhibitors (eg, erythromycin, fluconazole, diltiazem), or strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin) should be avoided. Short-acting antacids or H2 blockers should be used as an alternative to proton pump inhibitors.
IN THE TOTAL population of the phase III trial, the most common adverse events of any grade in the bosutinib group were diarrhea (70% vs 34% in imatinib group), nausea (35% vs 38%), thrombocytopenia (35% vs 20%), rash (34% vs 21%), increased alanine transaminase (ALT) levels (31% vs 6%), abdominal pain (25% vs 15%), and increased aspartate transaminase (AST) levels (23% vs 6%). The most common grade 3 or 4 adverse events in the bosutinib group were increased ALT levels (19% vs 2%), thrombocytopenia (14% vs 6%), increased AST levels (10% vs 2%), increased lipase levels (10% vs 5%), and diarrhea (8% vs < 1%).
Serious adverse events in trials of bosutinib have included anaphylactic shock, myelosuppression, diarrhea, fluid retention, hepatotoxicity, and rash. On-treatment declines in estimated glomerular filtration rate have been observed in patients treated with bosutinib.
Bosutinib carries warnings/precautions for gastrointestinal toxicity, myelosuppression, hepatic toxicity, fluid retention, renal toxicity, and embryofetal toxicity. Blood counts should be monitored. Liver enzymes should be monitored at least monthly for the first 3 months of treatment and as needed. Renal function should be monitored at baseline and during therapy.
Bosutinib is contraindicated in patients with hypersensitivity to the agent. Women should be advised not to breastfeed during treatment. ■
1. U.S. Food and Drug Administration: FDA grants accelerated approval to bosutinib for treatment of newly-diagnosed Ph+ CML. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm589856.htm. Accessed February 21, 2018.
2. Bosulif (bosutinib) tablets prescribing information, December 2017, Pfizer Inc. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/203341s009lbl.pdf. Accessed February 21, 2018.
3. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al: Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: Results from the randomized BFORE trial. J Clin Oncol 36:231-237, 2017.