Safety and efficacy of bosutinib (SKI-606) in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) following resistance or intolerance to imatinib (IM).

Abstract

6502 Background: Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor, with minimal inhibitory activity against PDGFR or c-kit. Methods: A phase I/II study to investigate the efficacy and safety of bosutinib in pts with CP CML who failed treatment with IM is ongoing. Results: We report preliminary data for 299 pts, 72% IM-resistant, 28% IM-intolerant, with a median follow-up from start of bosutinib of 16.5 mos (0.56-43.8). Prior therapy besides IM, included interferon (91 pts) and stem cell transplant (8 pts). The most common adverse events were gastrointestinal (nausea, vomiting, diarrhea), usually grade 1-2, manageable, improving spontaneously after 3-4 weeks. Grade 3-4 nonhematologic toxicities (>5% of pts) were rash (9%) and diarrhea (8%). The most common grade 3-4 hematologic abnormalities were: thrombocytopenia (23%), neutropenia (14%), and anemia (9%). Other common grade 3-4 laboratory abnormalities included hypermagnesemia (11%) and increased ALT (10%). 56 (19%) pts were discontinued due to toxicity. Of 132 pts evaluable for hematological response, 103 (78%) had complete response (CHR). 111/192 (58%) evaluable pts achieved a major cytogenetic response (MCyR), 89 (46%) of which were complete. Of 156 pts evaluable for molecular response, 76 (49%) achieved a major molecular response, 47 (30%) of which were complete. 20 different mutations were found at baseline in 45/99 (45%) pts tested. CHR occurred in 78% of pts with mutations and in 89% of pts with no mutations; MCyR occurred in 60% and 54% of pts in these groups, respectively. Conclusions: Bosutinib is an active agent for pts with CP CML who failed prior imatinib, including pts with a wide variety of Bcr-Abl mutations. Bosutinib demonstrated a favorable toxicity profile with minimal hematologic toxicity. IM resistant N (%) IM intolerant N (%) Hematologic response Evaluable* 94 38 Complete 72 (77) 31 (82) Cytogenetic response Evaluable* 144 48 Major 79 (55) 32 (67) Complete 62 (43) 27 (56) Molecular response Evaluable* 113 43 Major 55 (49) 21 (49) Complete 31 (27) 16 (37) * 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 Bristol-Myers Squibb, Novartis, Pfizer, Wyeth Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Novartis, Pfizer, Wyeth