An Ongoing Phase 3 Study of Bosutinib (SKI-606) Versus Imatinib In Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Abstract

208 Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor (TKI), with minimal inhibitory activity against PDGFR or c-kit. In a phase 2 study, bosutinib demonstrated activity in patients with Philadelphia chromosome–positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) in the second- and third-line treatment settings (Cortes JE, et al. ASCO 2010, Abstract #6502; Khoury JH, et al. ASCO 2010, Abstract #6514), as well as in patients with advanced Ph+ leukemias (Gambacorti-Passerini C, et al. ASCO 2010, Abstract #6509) following resistance or intolerance to imatinib and other TKIs. The current randomized, open-label, phase 3 study compared the activity and safety of bosutinib with that of imatinib in newly diagnosed patients with CP CML. The study enrolled adults aged 318 years with cytogenetic diagnosis of Ph+ CP CML within 6 months, adequate hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomized to daily oral treatment with 500 mg bosutinib or 400 mg imatinib. Adverse events were graded using the National Cancer Institute Common Terminology Criteria, version 3.0. The primary efficacy endpoint was the rate of complete cytogenetic response (CCyR) at 1 year; the rates of hematologic response, molecular response, and progression and transformation to accelerated or blast phase were also evaluated. The study randomized 502 patients: 56.6% male, median age of 48 years (range, 18–91 years), and median time since diagnosis of 0.7 months (range, -0.3-7.9 months; the range minimum is negative due to CML diagnosis during the study screening period, and the range maximum is >6 months because of 1 patient considered a major protocol violator). The median duration of treatment was 11.1 months (range, 0.03–24.8 months). At Week 48 (approximately 11 months), 71.5% and 74.8% of patients (both treatment arms combined) were in CCyR and complete hematologic response (CHR), respectively. During the study, 81.4% of patients achieved a CCyR at or before Week 48, with a median time to CCyR of 24 weeks; 82.6% of patients achieved a CHR, with a median time to CHR of 8 weeks; and 40.6% of patients achieved a major molecular response (MMR), with a median time to MMR of 49 to 61 weeks for the 2 treatment arms. For the combined treatment arms, common treatment-emergent adverse events included diarrhea (43.7%), nausea (32.3%), vomiting (22.0%), rash (16.8%), pyrexia (11.6%), and fatigue (11.0%). The only grade 33 treatment-emergent adverse event observed in 32% of patients was diarrhea (5.2%), which was usually limited to the first weeks of treatment. Grade 33 hematologic laboratory abnormalities included neutropenia (14.2%), thrombocytopenia (12.4%), and anemia (5.8%). Other grade 33 laboratory abnormalities (35% of patients) included alanine aminotransferase elevation (11.6%), phosphatemia (7.6%), and aspartate aminotransferase elevation (6.4%). Overall, 22.2% patients discontinued therapy; adverse events led to discontinuation or death in 12.8% of patients, and 4.2% of patients discontinued due to disease progression. The high combined percentage of patients achieving MMR, CCyR, and CHR and the relatively low incidence of generally manageable grade 33 events observed suggest good efficacy and an overall favorable safety profile. Data for individual treatment arms will be unblinded by the end of August 2010, and will be presented at the meeting. Disclosures: Gambacorti-Passerini: Pfizer Inc: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; BMS, Pfizer: Research Funding. Brummendorf:Pfizer Inc: Membership on an entity's Board of Directors or advisory committees. Griskevicius:Pfizer Inc: Research Funding. Goh:Novartis and Janssen Ciliag: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Cortes:Pfizer Inc: Consultancy, Research Funding.

Tyrosine kinase inhibitors as a first‐line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed‐treatment comparison

“…A total of 365 potentially relevant references were identified by the electronic search, of which a total of six trials, reported in 20 published papers and conference abstracts, met the inclusion criteria and were pooled in meta-analysis. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Figure 1 depicts the results of the search strategy and study selection.…”

“…Both trials had a maximum follow-up period of 5 years. Four publica-tions and abstracts reported on bosutinib versus imatinib in newly diagnosed CML patients, referred to as BELA, [28][29][30][31] with a median reported follow-up period of 19 months; the trial is still ongoing. Two conference abstracts reported on ponatinib versus imatinib in newly diagnosed CML patients, referred to as EPIC 32,33 ; EPIC was terminated early after a median of 3 months and a follow-up time of 5 months, due to the observation of vascular events in long-term follow-up of phase II trial evaluating ponatinib 37 ; therefore, data of this study were not included in the pooled MTC, but a direct comparison was conducted comparing ponatinib to imatinib.…”

Chronic myeloid leukemia 2011: Successes, challenges, and strategies—Proceedings of the 5th annual BCR‐ABL1 positive and BCR‐ABL1 negative myeloproliferative neoplasms workshop

“…The preliminary results from a frontline randomized Phase 3 study comparing the activity and toxicity of imatinib were presented at the 52nd ASH meeting [10]. The study enrolled 502 newly diagnosed patients with CML‐CP.…”

“…In this regard, the use of second‐generation TKIs (i.e., nilotinib, dasatinib, bosutinib) as frontline therapy has led to an increase in the number of patients capable of achieving CCyR during the first year of therapy. The activity of these agents as frontline therapy for patients with CML‐CP has been tested in a series of ongoing randomized, multicenter: nilotinib (ENESTnd), dasatinib (DASISION and Intergroup Trial SO325), and bosutinib [8–10].…”

ASH 2010 meeting report—Top 10 clinically oriented abstracts in chronic myeloid leukemia

“…Bosutinib, a dual Src/ABL TKI, displayed activity in patients previously treated with imatinib [14–16]. In the BELA (Bosutinib Efficacy and Safety in Chronic Myeloid Leukemia) study, patients with newly diagnosed CML‐CP were randomized to bosutinib 500 mg daily ( n = 250) or imatinib 400 mg daily ( n = 252).…”