Activity of Bosutinib by Baseline and Emergent Mutation Status in Philadelphia Chromosome–Positive Leukemia Patients with Resistance or Intolerance to Other Tyrosine Kinase Inhibitors
Authors: Khoury H. Jean , Cortes Jorge E , Gambacorti-Passerini Carlo , Kim Dong-Wook , Zaritskey Andrey , Hochhaus Andreas , Leip Eric , Besson Nadine , Kelly Virginia , Brümmendorf Tim H 
Published: October 2019

Abstract 110

Bosutinib is an orally active, Src/Abl tyrosine kinase inhibitor (TKI) that has demonstrated clinical activity and an acceptable safety profile in an open-label, phase 1/2 study of patients (pts) with Philadelphia chromosome–positive (Ph+) leukemia following resistance or intolerance to imatinib. Abl kinase domain mutations may affect drug binding and subsequent TKI efficacy. Responses to bosutinib by Bcr-Abl baseline mutation status and the emergence of mutations during bosutinib treatment in this phase 1/2 study are reported here.

A total of 570 pts in 3 cohorts received bosutinib: chronic phase chronic myeloid leukemia (CP CML) following prior imatinib only (CP2L cohort; n = 288); CP CML following prior imatinib plus dasatinib and/or nilotinib (CP3L cohort; n = 118); and advanced leukemia (ADV cohort: accelerated and blast phase CML and acute lymphoblastic leukemia; n = 164) following prior treatment with imatinib only or with other TKIs. For the CP2L, CP3L, and ADV cohorts, the respective median times since diagnosis were 3.6 y (range, 0.1–15.1 y), 6.5 y (range, 0.6–18.3 y), and 3.7 y (range, 0.1–22.1y). Per protocol, Bcr-Abl mutational status was evaluated at baseline (pre-dose) and at the end of treatment (EOT).

Mutations were assessed at baseline in 412 pts; of these, 79/212 (37%) CP2L pts, 39/83 (47%) CP3L pts, and 65/117 (56%) ADV pts had ≥1 baseline mutation, and 11 (5%), 9 (11%), and 7 (6%) pts, respectively, had ≥2 baseline mutations. The most common mutations were T315I (n = 31; prior to eligibility exclusion), F359C/I/S/V (n = 23), F317L (n = 21), G250E (n = 19), Y253F/H (n = 16), and M351T (n = 15). Rates of confirmed complete hematologic response (CHR) and major cytogenetic response (MCyR) were generally similar among chronic phase pts (CP2L, CP3L) with and without baseline mutations, although the presence of a mutation negatively impacted response rates in ADV pts (CHR, 17% vs 39%; MCyR, 24% vs 37%; see Table). CHR and/or MCyR were observed broadly across mutations, including those associated with dasatinib (F317L) or nilotinib (Y253F/H, E255K/V, and F359C/I/S/V) resistance, with the exception of the T315I mutation in all cohorts and the F317L and Y253H mutations in the ADV cohort (see Table).

Of the 140 pts who were assessed for emergent mutations at treatment completion, a new mutation was identified in 39 (28%) pts. Pts with a new mutation were more likely to have discontinued treatment due to PD/unsatisfactory response (UR; n = 34/39 [87%]) than those without a new mutation (n = 47/101 [47%]). The most common emergent mutations were T315I (n = 14) and V299L (n = 12), and nearly all pts who developed these mutations (93% and 100% of pts, respectively) discontinued treatment due to PD/UR. New mutations were more common in pts with ≥1 baseline mutation (n = 26) versus those without a baseline mutation (n = 13); of those pts, 21/26 (81%) and 13/13 (100%), respectively, discontinued treatment due to PD/UR. Eight pts discontinued treatment due to PD/UR within 6 months of starting bosutinib; all but 1 patient had a T315I or V299L mutation present at baseline or identified at treatment completion.

In conclusion, clinical activity to bosutinib was observed in CML pts across baseline Bcr-Abl kinase domain mutations, including those associated with resistance to other second-generation TKIs, except typically for T315I. These results support the observed benefit of bosutinib in pts with Ph+ leukemia following prior treatment with TKIs. Pts in whom new mutations were identified at treatment completion were more likely to have pre-existing mutations and to discontinue treatment due to PD/UR. The most common mutations to emerge during bosutinib therapy were T315I and V299L, some of which may have been present but not detected at baseline.Baseline mutation status, n/n evaluablea (%)IC50 fold increaseCP2L cohortCP3L cohortADV cohortCHRMCyRCHRMCyRCHRMCyRNo mutation120/133 (90)65/121 (54)34/44 (77)15/43 (35)19/49 (39)16/43 (37)≥1 mutation65/78 (83)44/78 (56)26/39 (67)11/35 (31)10/59 (17)13/55 (24)    Y253H0.52/22/25/64/61/72/7    F359V0.98/94/90/21/20/20/1    Y253F1.01/10/10000    F317L2.44/43/44/81/70/90/6    F359I2.41/11/12/22/20/21/2    G250E4.35/63/53/60/54/62/7    E255V5.52/21/21/10/10/41/3    E255K9.50/22/30/10/10/41/3    V299L26.1001/20/200    T315I45.42/92/92/70/60/131/13    F359CNA002/21/20/10/1    F359SNA1/11/1001/10/1NA, not available.aTreated pts with adequate baseline response assessment.

Disclosures:

Cortes: Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Gambacorti-Passerini:Pfizer Inc: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria; Biodiversity: Honoraria. Kim:Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Hochhaus:Pfizer Inc: Research Funding; BMS: Research Funding; Novartis: Research Funding; Ariad: Research Funding. Leip:Pfizer Inc: Employment. Besson:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment. Brümmendorf:Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria.