Page 63 - Haematologica August 2018

Long-term second-line bosutinib for CP CML
Several TKIs are approved for treatment of newly diag- nosed chronic phase (CP) CML, each associated with a distinct safety profile. First-line TKI therapies include ima- tinib3 and the second-generation TKIs, nilotinib,4 dasa- tinib,5 and, most recently, bosutinib.6 Although response rates are high with TKI therapy, patients develop treat- ment resistance or experience intolerable toxicities.7,8 Determining the most appropriate therapy following treatment failure is critical to achieve optimal outcomes and prevent disease progression. Second- and third-line treatment decisions are based on the prior therapy, the reason for failure (primary or secondary resistance, intol- erance), BCR-ABL1 mutation status, comorbidities, and prior toxicities.8,9
Bosutinib was initially approved in 2012 for the treat- ment of patients with Ph+ CP, accelerated-phase (AP), or blast-phase (BP) CML resistant or intolerant to prior TKI therapy.6 This approval was based primarily on the results of a pivotal phase I/II trial of bosutinib in CP CML patients following failure of imatinib.10 Results of a preliminary analysis approximately 15 months after the last enrolled patient demonstrated potent activity with second-line bosutinib across a spectrum of BCR-ABL1 mutations and a toxicity profile distinct from those of other TKIs.10 The durability of response was confirmed with subsequent analyses 24 and 48 months after the last enrolled patient.11,12 The final results presented here from the phase I/II trial of bosutinib for imatinib-resistant or imatinib- intolerant CP CML are assessed after at least five years from the time the last patient was enrolled.
Methods
Study design and patients
This phase I/II, open-label, multicenter study was initiated in January 2006; the design has been described previously.10,12 Part 1 (dose-escalation phase) determined the recommended Part 2 starting dose of bosutinib 500 mg/day; in Part 2, the efficacy, safety, and tolerability of bosutinib were evaluated. Patients without a complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12 were allowed to receive bosutinib 600 mg/day unless treatment-relat- ed grade ≥3 adverse events (AEs) occurred. Patients continued bosutinib treatment until disease progression (PD), death, unac- ceptable toxicity, or withdrawal of consent.
The protocol was approved by central or institutional review boards for each site and was conducted in accordance with Good Clinical Practice principles and the Declaration of Helsinki.
Eligible patients were aged 18 years or over with a confirmed diagnosis of Ph+ CP CML resistant to full-dose imatinib (IM-R; ≥600 mg/day) or intolerant to any dose of imatinib (IM-I). Additional eligibility criteria are provided in the Online Supplementary Methods.
Safety and efficacy analyses
Cytogenetic response was assessed as previously described10 and defined as newly-achieved on study or maintained from baseline for four weeks or more (earliest time point for assess- ment). Evaluable patients received at least one dose and had a valid baseline assessment for the respective end point. Molecular response data were assessed at a central laboratory; however, the International Scale (IS) was not used. Patients from sites in China, India, Russia, and South Africa were not assessed for
molecular response due to logistical constraints. For the purpose of this study, responders for major molecular response (MMR) had a ≥3-log reduction from standardized baseline, a detectable BCR-ABL1 transcript at baseline or postbaseline, and must have maintained or attained a CCyR. Duration of response (date of first response until confirmed response loss or PD/death) was evaluated through 30 days after last dose using the Kaplan- Meier method; patients without events were censored at their last assessment visit. See the Online Supplementary Methods for further details of the statistical methods used for this report.
Disease progression was assessed as described previously.10 Time to PD or death, and time to on-treatment transformation to AP/BP CML, were evaluated through 30 days after the last bosutinib dose using cumulative incidence adjusting for the competing risk of treatment discontinuation without an event; patients without events were censored at their last assessment visit. Progression-free survival (PFS; time to PD or death within 30 days of last bosutinib dose) was analyzed for prognostic fac- tors. Overall survival (OS) was evaluated using the Kaplan-Meier method; patients still alive were censored at the last known date on which they were alive.
Per protocol, patients were followed for OS for up to two years after discontinuation of study treatment; analysis of fol- low up and OS includes data from patients enrolled in an ongo- ing extension study (clinicaltrials.gov identifier: 01903733). Safety was assessed in patients who received at least one bosutinib dose; AEs were reported at each visit up to 30 days after last dose and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v.3.0. Treatment-emergent AEs (TEAEs) were assessed overall and by year of first occurrence.
Results
Patients and treatment
A total of 284 patients with CP CML (IM-R, n=195; IM- I, n=89) were enrolled and treated with second-line bosu- tinib (Online Supplementary Table S1). The study was closed as of August, 2015; patients still on study were offered enrollment on an extension study. As for the final database lock for this study (2nd October 2015), the time from the last second-line patient’s first dose was 60 months or more. The median (range) duration of OS fol- low up was 54.8 (0.6-96.3) months, and the median treat- ment duration was 25.6 (0.2-96.3) months (Table 1). At year 2, 153 (54%) patients were receiving bosutinib and at year 5, 115 (40%; IM-R, n=81 and IM-I, n=34) patients still remained on bosutinib treatment (1 year=48 weeks). Discontinuation from treatment was most common with- in the first two years, with 131 (46%) patients discontinu- ing by the end of year 2, and 38 (13%) patients discontin- uing treatment in years 3 through 5 (Online Supplementary Table S2). The most common primary reasons for discon- tinuation from treatment through year 5 were lack of effi- cacy [categorized by the investigator separately as PD and unsatisfactory response; n=47 (17%) and n=21 (7%), respectively], AE [n=64 (23%)], and patient request [n=19 (7%)]. The most common reasons for discontinuation from treatment in years 3 through 5 were PD and unsatis- factory response in year 3, AE and PD in year 4, and unsat- isfactory response and death in year 5. Overall, younger patients (aged <65 years vs. ≥65 years) were less likely to permanently discontinue treatment because of AE (21% vs. 32%), patient request (7% vs. 14%), or death (1% vs.
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