Bosutinib as Third-Line Treatment for Chronic Phase Chronic Myeloid Leukemia Following Failure of Second-Line Therapy with Dasatinib or Nilotinib
Authors: Khoury H. Jean , Kim Dong-Wook , Zaritskey Andrey , Gambacorti-Passerini Carlo , Hochhaus Andreas , Navarro Juan , Rapoport Aaron P. , Dorlhiac-Llacer Pedro Enrique , Zanichelli Maria , Kelly Virginia , Besson Nadine , McMullan Trevor , Kantarjian Hagop M. , Cortes Jorge E. 
Published: October 2019

Abstract
Abstract 892
Bosutinib (SKI-606) is an orally available, dual Src/Abl tyrosine kinase inhibitor (TKI) with minimal inhibitory activity against PDGFR or c-kit. This open-label, phase 1/2 study evaluated the safety and efficacy of bosutinib as third-line therapy in patients with Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML). Adults (aged ≥18 years) who had failed prior imatinib (IM) therapy and were resistant or intolerant to dasatinib (DAS; n = 35 and n = 51, respectively) or resistant to nilotinib (NIL; n = 28) received oral daily treatment with a starting dose of 500 mg bosutinib. Of the 118 patients enrolled, 46% were male, the median age was 56 years (range, 20–79 years), and the median time from CML diagnosis to start of bosutinib was 6.7 years (range, 0.6–19.2 years). The median daily dose of bosutinib was 446 mg (range, 140–563 mg). At week 24, 26% of patients achieved a major cytogenetic response (MCyR), including 13% with a complete cytogenetic response (CCyR; see Table). Cumulative response rates were 34% for MCyR and 22% for CCyR. The majority (81%) of patients who achieved a MCyR still retained their response as of the data snapshot date (median follow-up duration of 23 months). Comparable rates of response were observed across Bcr-Abl kinase domain mutations, except for the T315I mutation. The most frequently reported treatment-emergent adverse events (TEAEs; ≥20% of patients, all grades) were diarrhea (83%), nausea (45%), vomiting (36%), rash (26%), headache (25%), and fatigue (22%). The incidence of TEAEs was generally similar for DAS-resistant, DAS-intolerant, and NIL-resistant patients. Gastrointestinal events were predominantly grade 1/2, had an early onset, and usually subsided within the first 4 weeks of treatment. The only grade 3/4 TEAE reported in ≥5% of patients was diarrhea (8%). One grade 3 pleural effusion was observed in a patient with concomitant pneumonia and a history of recurrent pleural effusions on DAS. Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (23%), neutropenia (16%), and anemia (8%); all were usually transient. Other grade 3/4 laboratory abnormalities (≥5% of patients) included elevations of magnesium (12%), alanine transaminase (ALT; 7%), and lipase (5%). Grade 3/4 transaminase elevations were observed more frequently in NIL-resistant patients (ALT, 18% [grade 4, n = 1]; aspartate transaminase [AST], 11% [grade 4, n = 1]) compared with DAS-resistant/intolerant patients (ALT, 3–4%; AST, 0–3%). On-treatment QTcF interval prolongation was observed in 13 patients (11%), but was only grade 1/2 (≤500 msec) with a reported rate of arrhythmia of <1%. Adverse events led to treatment discontinuation in 27% of DAS-intolerant patients, 14% of DAS-resistant patients, and 11% of NIL-resistant patients; thrombocytopenia (4%), neutropenia (3%), and increased ALT (3%) were the only events resulting in discontinuation of >2 patients. In conclusion, bosutinib has an acceptable safety profile in patients with CP CML following failure of IM and DAS or NIL, with primarily low-grade and transient gastrointestinal TEAEs. Bosutinib also demonstrated clinical activity as a third-line therapy, with over one-third of patients achieving a MCyR. These results emphasize the therapeutic potential of bosutinib for CP CML patients with resistance or, particularly, intolerance to other second-generation TKI therapies.
Table 1: Table. IM failure + DAS resistant IM failure + DAS intolerant IM failure + NIL resistant Total Cytogenetic response at week 24, n (%)     Evaluablea 26 29 15 70     MCyR 5 (19) 9 (31) 4 (27) 18 (26)       CCyR 2 (8) 5 (17) 2 (13) 9 (13) Cytogenetic response(cumulative), n (%)     Evaluableb 32 38 21 91     MCyR 10 (31) 14 (37) 7 (33) 31 (34)       CCyR 3 (9) 13 (34) 4 (19) 20 (22) Patients retaining MCyR at time of latest data snapshot, n (%) 7 (70) 11 (79) 7 (100) 25 (81) Median follow-up time (range), months 12 (3–47) 27 (0.3–43) 7 (1–42) 23 (0.3–47) Median duration of MCyR (range), weeks 24 (6–64) 68 (7–124) 18 (6–185) 37 (6–185) a Evaluable patients had baseline and week 24 cytogenetic assessments. Patients who had experienced early progression or death before having a post-baseline assessment were also evaluable. b Evaluable patients had baseline and post-baseline cytogenetic assessments. Patients who had experienced early progression or death before having a post-baseline assessment were also evaluable.

Disclosures:
Khoury: BMS, Novartis: Honoraria. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gambacorti-Passerini:Pfizer Inc: Research Funding. Hochhaus:Novartis, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer Inc: Research Funding. Dorlhiac-Llacer:Novartis: Research Funding; BMS: Research Funding; Pfizer Inc: Research Funding. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment, Equity Ownership. McMullan:Pfizer Inc: Employment, Equity Ownership. Kantarjian:Pfizer, Novartis, BMS: Research Funding; Novartis: Consultancy. Cortes:Pfizer Inc: Consultancy, Research Funding.