Clinical Activity of Bosutinib by Mutational Status In Patients with Previously Treated Philadelphia Chromosome–positive Leukemias.
Authors: Gambacorti-Passerini Carlo , Khoury H. Jean , Pinczowski Helio , Masszi Tamas , Kim Dong-Wook , Zanichelli Maria , Martinelli Giovanni , Kelly Virginia , Besson Nadine , McMullan Trevor , Brummendorf Tim H. , Cortes Jorge E. 
Published: October 2019

Abstract 3434

Bosutinib (SKI-606) is a dual Src/Abl tyrosine kinase inhibitor (TKI) with minimal inhibitory activity against PDGFR or c-kit. Previous reports of this open-label, phase 1/2 study have demonstrated the efficacy and safety of oral daily treatment with 500 mg bosutinib in adult patients with Philadelphia chromosome–positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) following resistance or intolerance to imatinib (second-line setting; Cortes JE, et al. ASCO 2010. Abstract #6502) and dasatinib or nilotinib (third-line setting; Khoury HJ, et al. ASCO 2010. Abstract #6514), or with Ph+ advanced leukemias (ie, accelerated or blast phase CML, acute lymphocytic leukemia) following imatinib failure in the second- and third-line settings (Gambacorti-Passerini C, et al. ASCO 2010. Abstract #6509). Failure of therapy with imatinib and other TKIs may result from mutations in the Abl kinase domain that affect drug binding. Therefore, the current analysis compared the rates of hematologic and cytogenetic responses to 500 mg bosutinib in patients with and without Bcr-Abl kinase domain mutations. Of the 570 patients treated, 53% were male and the median age was 53 years (range, 18–91). Median duration of follow-up was 24.1 months (range, 0.6–53.8) for patients with CP CML in the second-line setting, 22.6 months (range, 0.3–47.3) for patients with CP CML in the third-line setting, and 12.1 months (range, <0.1-45.5) for patients with advanced leukemias. Among the 222 (39%) patients with baseline sequencing analyses across all study cohorts, 119 (54%) patients had 27 unique Bcr-Abl mutations (Table). Patients with and without mutations had similar rates of complete hematologic response (CHR; 78% vs 82%, respectively) and major cytogenetic response (MCyR; 56% vs 53%, respectively). Comparable rates of response to bosutinib were observed across P-loop and non–P -loop Bcr-Abl kinase domain mutations, except for the T315I mutation. In particular, although a small number of patients was evaluable for individual mutations, hematologic and cytogenetic responses were observed with mutations such as F317L, F359V/I/C, and E255K/V, which are commonly associated with resistance following sequential treatment with multiple TKI therapies. Although response rates among patients with the T315I mutation were lower, 2 of 6 (33%) evaluable patients achieved a CHR and 1 of 7 (14%) patients achieved a MCyR. Among patients with mutations, the rate of CHR was higher for those with CP CML in the second-line (95%) and third-line (83%) settings than for those with advanced leukemias (46%). The rate of MCyR was highest among patients with CP CML in the second-line setting (73%). In conclusion, bosutinib was associated with substantial clinical activity in multiple patient populations independent of the presence or absence of Bcr-Abl kinase domain mutations and across all types of mutations, with the exception of the T315I mutation.

Response n/n evaluablea (%) Bcr-Abl kinase domain mutation type n CHR MCyR Overall population     Any mutation 119 35/45 (78) 44/79 (56)         P-loop 35 9/11 (82) 12/21 (57)             L248V 5 2/2 (100) 2/4 (50)             G250E 11 2/2 (100) 3/5 (60)             Y253F 1 1/1 (100) 0/1             Y253H 9 2/3 (67) 4/6 (67)             E255K 6 2/3 (67) 2/4 (50)             E255V 3 0 1/1 (100)         Non–P-loop 84 26/34 (76) 32/58 (55)             M244V 6 3/3 (100) 3/5 (60)             K263E 1 0 1/1 (100)             L273M 1 1/1 (100) 1/1 (100)             V299L 1 0 0             F311L 1 0 1/1 (100)             T315I 19 2/6 (33) 1/7 (14)             F317L 16 4/5 (80) 4/11 (36)             G321R 1 1/1 (100) 0             N331S 1 0 1/1 (100)             M351T 11 3/4 (75) 6/9 (67)             E355G 1 1/1 (100) 1/1 (100)             E355G/M244V 1 1/1 (100) 0/1             F359C 3 0 1/2 (50)             F359I 4 3/3 (100) 3/3 (100)             F359V 8 6/6 (100) 4/7 (57)             L384P 1 0/1 0/1             H396P 2 1/1 (100) 2/2 (100)             H396R 1 0 0             I432T 1 0 0/1             E453K 1 0 1/1 (100)             F486S 3 0/1 2/3 (67)     No mutation 103 42/51 (82) 38/72 (53) Second-line CP CML population     Any mutation 46 19/20 (95) 29/40 (73) Third-line CP CML population     Any mutation 26 10/12 (83) 5/17(29) Advanced leukemia population     Any mutation 47 6/13 (46) 10/22 (45) a Evaluable patients had a baseline and post-baseline hematologic or cytogenetic assessments, respectively. Patients who had experienced early progression or death before having a post-baseline assessment were also evaluable.

Disclosures:

Gambacorti-Passerini: Pfizer Inc: Research Funding. Khoury:BMS, Novartis: Honoraria. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinelli:BMS: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; GlaxoSmithKline: Honoraria. Kelly:Pfizer: Employment, Equity Ownership. Besson:Pfizer: Employment, Equity Ownership. McMullan:Pfizer: Employment, Equity Ownership. Brummendorf:Pfizer: Membership on an entity's Board of Directors or advisory committees. Cortes:Pfizer Inc: Consultancy, Research Funding.