Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib

Abstract

Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinib-intolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

Figure 1

Disposition of patients. A total of 288 patients were enrolled in part 2, including 200 imatinib-resistant patients and 88 imatinib-intolerant patients. *AEs leading to withdrawal in 2 or more imatinib-resistant patients included thrombocytopenia (n = 6), aspartate aminotransferase elevation (n = 4), alanine aminotransferase elevation (n = 3), diarrhea (n = 3), neutropenia (n = 2), anemia (n = 2), leukopenia (n = 2), and vomiting (n = 2). AEs leading to withdrawal in 2 or more imatinib-intolerant patients included thrombocytopenia (n = 8), diarrhea (n = 3), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 2), dyspnea (n = 2), neutropenia (n = 2), pancytopenia (n = 2), and rash (n = 2).

Figure 2

Duration of CHR and MCyR with bosutinib treatment. Duration of CHR (A) and MCyR (B) were determined by the evaluable population; patients entering the study in CCyR were excluded. As of the data cutoff, 77% of the evaluable patients who achieved a CHR still retained their response (124/172 [72%] imatinib-resistant and 65/75 [87%] imatinib-intolerant patients), with a median duration of CHR not reached. Of the evaluable patients who achieved a MCyR, 78% still retained their MCyR as of the data cutoff (73/101 [72%] imatinib-resistant and 36/39 [92%] imatinib-intolerant patients), with the median duration of MCyR not reached.

Figure 3

CHR and MCyR by Bcr-Abl mutation status at baseline. Mutations indicated as “unknown” included abnormalities not associated with known mutations (eg, nucleotide insertions or deletions, alternate splicing).

Figure 4

PFS and overall survival with bosutinib treatment. PFS (A) and overall survival (B) are shown for chronic phase imatinib-resistant or -intolerant patients treated with bosutinib (all-treated population) at a median follow-up of 24.2 months.

Figure 5

Mean plasma concentration vs time profiles after oral administration of bosutinib 500 mg on days 1 and 15.