Updates on Bosutinib Trials at ASH Demonstrate Durable Responses

Bosutinib (BOSULIF®), a dual inhibitor of Src and BCR-ABL, is considered a “third-generation” tyrosine kinase inhibitor (TKI) and is approved for the treatment of chronic myeloid leukemia (CML) in patients resistant to or intolerant of prior TKI therapy.¹ Updates on two clinical trials with bosutinib that provided additional data on long-term use of the drug were presented at the American Society for Hematology (ASH) Annual Meeting held in New Orleans in early December.

In the first study, adult patients with CML with imatinib resistance (n=196) or intolerance (n=90) were treated with bosutinib at the recommended starting dose of 500 mg/day.^1,2 Primary results of this phase 1/2 study were published in 2011 after a median 24.2 months of follow-up, at which point 53% of patients had achieved a major cytogenetic response (MCyR) and 41% had achieved complete cytogenic response (CCyR); overall survival (OS) at 2 years was higher among imatinib-intolerant patients (98%) than among imatinib-resistant patients (89%).³

Related: BOSULIF® (bosutinib) Drug Showcase

Data reflecting follow-up of more than 48 months were presented at ASH. Overall, 59% of patients achieved MCyR, including 49% who achieved CCyR. Although CCyR rates were similar in imatinib-resistant and imatinib-intolerant patients, only 22% of those with the T315I mutation achieved MCyR. The probability of maintaining MCyR at 4 years was 75% overall, and was higher among patients with intolerance (86%) than those who were resistant to the drug (69%). The cumulative incidence of on-treatment disease progression or death was 22% among imatinib-resistant patients and 10% among patients who were imatinib-intolerant. The cumulative incidence of on-treatment transformation to accelerated phase/blastic phase at 4 years was 4%. Overall, 60% of patients discontinued bosutinib, primarily due to adverse events (22%) and disease progression (18%). Of 40 deaths that occurred during the study, 24 were due to disease progression; most occurred in imatinib-resistant patients (n=22). Thrombocytopenia (25%) and neutropenia (17%) were the most frequent grade 3/4 hematologic events; 7% of patients experienced grade 3/4 cardiac events; and grade 3/4 diarrhea, vomiting, or rash occurred in 10% or less of patients.² No new or unexpected toxicities emerged throughout the study.

The second study evaluated bosutinib in 118 patients with chronic-phase CML (CML-CP) following treatment failure with imatinib plus dasatinib and/or nilotinib. The majority of patients were imatinib+dasatinib–resistant (n=38) or –intolerant (n=50); the remainder were imatinib+nilotinib–resistant (n=26), or resistant/intolerant to all three TKIs (n=4).⁴ Results, at a median 28.5-month follow-up, were previously published in 2012. At that time, 32% had achieved MCyR, including 24% with CCyR.⁵

The presentation at ASH provided a 36-month update, at which point 40% of patients had achieved MCyR, including 32% who achieved CCyR; 2-year OS was 84%. The probability of maintaining MCyR at 3 years was 65% and was higher among imatinib+dasatinib–intolerant (87%) and imatinib+nilotinib–resistant (75%) patients than among imatinib+dasatinib–resistant patients (25%).⁴ Among patients bearing the T315I mutation, 14% achieved MCyR. The cumulative incidence of on-treatment progression or death at 3 years was 25%; including 4% of patients with transformation to AP. Overall, 81% of patients discontinued treatment, primarily due to adverse events (25%), disease progression (21%), or inefficacy (19%). Grade 3/4 events included thrombocytopenia (26%), neutropenia (15%), and diarrhea (9%). Grade 3/4 cardiac events occurred in 8% of patients.⁴

These studies provide further evidence of the clinical value of bosutinib for patients exhibiting resistance to or intolerance of previous TKI therapy. Although durable cytologic responses were achieved in patients who previously had struggled with CML treatment, the T315I resistance mutation continues to be a barrier to effective therapy.

References

1. Keller-von Amsberg G, Schafhausen P. Bosutinib in the management of chronic myelogenous leukemia. Biologics. 2013;7:115-122.
2. Brümmendorf TH, Cortes JE, Khoury HJ, et al. Bosutinib as therapy for chronic phase chronic myeloid leukemia following resistance or intolerance to imatinib: 48-month update. Presented at the 55th Annual Meeting of the American Society of Hematology; December 8, 2013; New Orleans, LA. Abstract 2723.
3. Cortes JE, Kantarjian HM, Brümmerdorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118(17):4567-4576.
4. Cortes JE, Khoury HJ, Kantarjian HM, et al. Bosutinib as therapy for chronic phase chronic myeloid leukemia following failure with imatinib plus dasatinib and/or nilotinib: 36-month update. Presented at the 55th Annual Meeting of the American Society of Hematology; December 9, 2013; New Orleans, LA. Abstract 4025.
5. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119(15):3403-3412.