Safety and efficacy of bosutinib in patients with AP and BP CML and ph+ ALL following resistance/intolerance to imatinib and other TKIs: Update from study SKI-200.

Abstract

6509 Background: Bosutinib (SKI-606) is an oral Src/Abl kinase inhibitor currently evaluated in a phase I/II study in Ph+ leukemia patients (pts) with resistance/intolerance to imatinib. Methods: Advanced leukemia pts received 500 mg daily of bosutinib. Results: 134 pts were enrolled (63 accelerated phase [AP], 48 blast phase [BP], 23 ALL), median age was 50 yrs, 40% female and median follow-up 8.3 months. Prior therapy besides imatinib included interferon (43 pts), dasatinib (45 pts), nilotinib (16 pts) and stem cell transplant (12 pts). Nonhematologic treatment-related adverse events (AEs) occurring in ≥10% of pts were diarrhea (67%), vomiting (40%), nausea (37%), rash (20%), fatigue (10%). Grade 3/4 AEs of any causality occurring in ≥5% of pts were: diarrhea (6%), pneumonia (6%), elevated ALT (6%), vomiting (5%), dyspnoea (5%). Grade 3/4 hematologic abnormalities of any causality were anemia (37%), neutropenia (46%), thrombocytopenia (65%). 27 pts required dose-reductions and median daily dose was 477 mg. Overall efficacy analysis is presented in Table. Among 66 pts with baseline sequencing analysis, 16 distinct Bcr-Abl mutations were found in 40 pts. CHR and MCyR were achieved in 50% and 47% of evaluable pts with mutations, and in 47% and 54% of evaluable pts without mutations, respectively. 9/10 pts with T315I were resistant to bosutinib. Conclusions: Bosutinib is effective and well tolerated in advanced leukemia pts, with primarily transient low-grade gastrointestinal AEs. Clinical responses are achieved across a wide range of mutations, except with T315I. Diagnosis at time of bosutinib start AP N (%) BP N (%) ALL N (%) Hematologic response Evaluable* 33 22 4 Overall 21 (64) 7 (32) 1 (25) Complete 20 (61) 7 (32) 1 (25) Cytogenetic response Evaluable* 27 21 2 Major 13 (48) 11 (52) 2 (100) Complete 9 (33) 6 (29) 2 (100) Molecular response Evaluable* 26 25 13 Major 4 (15) 7 (28) 6 (46) Complete 1 (4) 3 (12) 3 (23) Progression-free survival (ITT) n=56 n=45 n=23 Median, Kaplan-Meier estimate, 95% C.I. 11.6 7.8 2.7 Range (months) (8.4, 20.1) (4.0, 8.8) (1.3, 4.2) * Pts without CHR, CCyR or CMR at baseline, and with ≥1 post-baseline assessment for respective response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Wyeth Pfizer Pfizer