Efficacy and Safety of Bosutinib (SKI-606) among Patients with Chronic Phase Ph+ Chronic Myelogenous Leukemia (CML).

Bosutinib (SKI-606), an orally bioavailable dual Src/Abl inhibitor, shows inhibitory activity against Bcr-Abl 200 times more potent than imatinib, but has minimal inhibitory activity against platelet-derived growth factor receptor (PDGFR) or c-kit. In addition, it inhibits a wide variety of Bcr-Abl kinase domain mutants, except T315I. A phase I study in CML identified the phase II dose as 500 mg daily and showed evidence of clinical efficacy. We thus initiated the phase II portion of the study to investigate efficacy and safety of bosutinib in patients (pts) with chronic phase Ph+ CML who had failed imatinib therapy. We report preliminary data for 98 pts, median duration of treatment 5.1 mos (range 0.03–16.7 mos). Median age 56 yrs (range 18–86 yrs), 48% male. Prior therapy included interferon (40 pts), imatinib (98 pts), dasatinib (13 pts), nilotinib (4 pts), stem cell transplant (6 pts). Among pts who failed imatinib (with no other tyrosine kinase inhibitor), 57 were imatinib resistant, 21 pts were intolerant. Of 23 resistant pts evaluable for hematological response, 17 (74%) had complete hematological response (CHR). Of 36 evaluable imatinib-resistant pts, 15 (42%) achieved major cytogenetic response (MCyR) including 12 (33%) with complete cytogenetic response (CCyR). Among imatinib intolerant pts, 4 (57%) achieved MCyR and 3 (43%) CCyR; 5/6 (83%) pts evaluable for hematologic response achieved CHR. Among 8 pts who had previously received nilotinib or dasatinib, 3 (38%) achieved CHR, 2 (25%) MCyR. Among imatinib-resistant pts, median time to MCyR was 47.3 wks. Of 40 imatinib-resistant pts evaluable for molecular response, 13 (33%) achieved major molecular response, 6 (15%) of which were complete. Of 72 pts with samples tested for mutations, 19 different mutations were found in 27 pts (38%). CHR occurred in 4/5 pts with P-loop mutations and 14/17 with non-P-loop mutations; MCyR occurred in 1/4 pts and 8/19 pts, respectively. Treatment was generally well tolerated. Gr 3–4 hematologic laboratory abnormalities included thrombocytopenia in 9 pts (9%), neutropenia in 8 pts (8%), anemia in 1 pt (1%). The most common adverse events were gastrointestinal (nausea, vomiting, diarrhea) but these were usually gr 1–2, manageable and transient, reducing in frequency and severity after the first 3–4 wks of therapy. Gr 3–4 non-hematologic toxicity occurring in >5% of pts were diarrhea (n=6, 6%), increased ALT (n=6, 6%), rash (n=9, 9%). In most instances these events resolved with medical management and dose reduction allowing for continuation of therapy. 10 pts reported grade 1/2 edema. 1 pt had both pleural and pericardial effusions and 1 had pleural effusion, all gr 1/2 and considered unrelated to treatment. A single pt had gr 3 possibly related pleural effusion with concomitant pneumonia and pre-treatment history of recurrent pleural effusions. We conclude that bosutinib is effective in imatinib-resistant pts with chronic CML across a range of mutations and after the failure of other TKIs. The relative specificity without significant c-kit or PDGFR inhibition distinguishes bosutinib from other TKIs and may be responsible for the relatively favorable toxicity profile with only a small numbers of pts experiencing hematologic toxicity or pleural effusions/edema.