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The BYOND study evaluated the efficacy and safety of bosutinib 500 mg once daily in patients with chronic myeloid leukemia (CML) resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). These post-hoc analyses assessed the efficacy and safety of bosutinib by resistance or intolerance to prior TKIs (imatinib-resistant vs dasatinib/nilotinib-resistant vs TKI-intolerant), and cross-intolerance between bosutinib and prior TKIs (imatinib, dasatinib, nilotinib), in patients with Philadelphia chromosome-positive chronic phase CML. Data are reported after ≥3 years' follow-up. Of 156 patients with Philadelphia chromosome-positive chronic phase CML, 53 were imatinib-resistant, 29 dasatinib/nilotinib-resistant, and 74 intolerant to all prior TKIs; cumulative complete cytogenetic response rates at any time were 83.7%, 61.5%, and 86.8%, and cumulative major molecular response rates at any time were 72.9%, 40.7%, and 82.4%, respectively. Of 141, 95, and 79 patients who received prior imatinib, dasatinib, and nilotinib, 64 (45.4%), 71 (74.7%), and 60 (75.9%) discontinued the respective TKI due to intolerance; of these, 2 (3.1%), 5 (7.0%), and 0 had cross-intolerance with bosutinib. The response rates observed in TKI-resistant and TKI-intolerant patients, and low cross-intolerance between bosutinib and prior TKIs, further support bosutinib use for patients with Philadelphia chromosome-positive chronic phase CML resistant/intolerant to prior TKIs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02228382., Competing Interests: Declaration of Competing Interest B. Douglas Smith: honoraria for consulting to Agios, Celgene, Jazz Pharmaceuticals, Novartis and Pfizer, and received research support from Pfizer. Tim H. Brümmendorf: consultant for Janssen, Merck, Novartis, Pfizer, and Takeda, and received research support from Novartis and Pfizer. Gail J. Roboz: consultancy, advisory board or data and safety monitoring committee for AbbVie, Actinium, Agios, Amphivena, Argenx, Array Biopharma, Astex, Astellas, AstraZeneca, Bayer, Celgene, Celltrion, Daiichi Sankyo, Eisai, Epizyme, Helsinn, Janssen, Jasper Therapeutics, Jazz, MEI Pharma – IDMC Chair, Novartis, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda – IRC Chair, Trovagene. Received research support from Cellectis and Pfizer. Carlo Gambacorti-Passerini: provides consultancy to Bristol-Myers Squibb and received honoraria and research support from Pfizer. Aude Charbonnier: provides consultancy to Novartis and Pfizer; speaker’s bureau for Incyte; received research support from Pfizer. Andrea Viqueira, Eric Leip, Simon Purcell, and Erinn Goldman: employees of and have stock/stock options in Pfizer. Francis Giles: consultant to Actuate Therapeutics Inc, provides expert testimony to Novartis, and received research support from Pfizer. Thomas Ernst and Andreas Hochhaus: received research support from Bristol-Myers Squibb, Incyte, Novartis, and Pfizer. Gianantonio Rosti: received research support from Pfizer and served on the speaker bureau for Bristol-Myers Squibb, Incyte, Novartis, and Pfizer., (Copyright © 2024. Published by Elsevier Ltd.)

This analysis from the multicenter, open-label, phase 3 BFORE trial reports efficacy and safety of bosutinib in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) after five years' follow-up. Patients were randomized to 400-mg once-daily bosutinib (n = 268) or imatinib (n = 268; three untreated). At study completion, 59.7% of bosutinib- and 58.1% of imatinib-treated patients remained on study treatment. Median duration of treatment and time on study was 55 months in both groups. Cumulative major molecular response (MMR) rate by 5 years was higher with bosutinib versus imatinib (73.9% vs. 64.6%; odds ratio, 1.57 [95% CI, 1.08-2.28]), as were cumulative MR 4 (58.2% vs. 48.1%; 1.50 [1.07-2.12]) and MR 4.5 (47.4% vs. 36.6%; 1.57 [1.11-2.22]) rates. Superior MR with bosutinib versus imatinib was consistent across Sokal risk groups, with greatest benefit seen in patients with high risk. Treatment-emergent adverse events (TEAEs) were consistent with 12-month data. After 5 years of follow-up there was an increase in the incidence of cardiac, effusion, renal, and vascular TEAEs in bosutinib- and imatinib-treated patients, but overall, no new safety signals were identified. These final results support 400-mg once-daily bosutinib as standard-of-care in patients with newly diagnosed CP CML.This trial was registered at www.clinicaltrials.gov as #NCT02130557., (© 2022. The Author(s).)

Bosutinib has been investigated in multiple clinical trials globally, including Japan, for treatment of chronic myeloid leukemia (CML). A pooled analysis of seven Pfizer-sponsored clinical trials evaluated the safety of bosutinib in Japanese (n = 138) vs non-Japanese (n = 1210) patients with CML. First-line bosutinib was administered in 54.3% vs 41.4% of patients, and second-line or later bosutinib in the remainder. Median treatment duration was 1.4 vs 2.3 years, and median relative dose intensity 78.1% vs 90.0%. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100.0% vs 98.9% (grade ≥ 3: 81.9% vs 75.2%). In both groups, the most common TEAEs relevant to bosutinib were gastrointestinal (92.8% vs 84.7%), liver function (72.5% vs 34.8%), rash (63.8% vs 37.4%), and myelosuppression (55.1% vs 50.7%). TEAEs led to dose reduction in 65.2% vs 50.6%, dose interruption in 78.3% vs 68.8%, and permanent treatment discontinuation in 30.4% vs 25.4% of patients. The safety profile of bosutinib in Japanese patients was generally consistent with that in non-Japanese patients, despite a higher incidence of gastrointestinal, liver function, and rash events. TEAEs were largely manageable with dose modifications and supportive care in both groups. These data may help optimize TEAE management and outcomes in Japanese patients receiving bosutinib for CML. Trial registration ClinicalTrials.gov: NCT02130557, NCT03128411, NCT00574873, NCT00261846, NCT01903733, NCT00811070, NCT02228382., (© 2022. Japanese Society of Hematology.)

Bosutinib is approved in the United States, Europe, Japan, and other countries for treatment of newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML), and CML resistant/intolerant to prior therapy. In the phase 3 BFORE trial (Clinicaltrials.gov, NCT02130557), patients were randomized 1:1 to first-line bosutinib or imatinib 400 mg once daily. We examined efficacy, safety, and patient-reported outcomes of bosutinib vs imatinib and pharmacokinetics of bosutinib in the Asian (n = 33 vs 34) and non-Asian (n = 235 vs 234) subpopulations of BFORE followed for at least 24 months. At the data cutoff date, 72.7 vs 66.7% of Asian and 70.6 vs 66.4% of non-Asian patients remained on treatment. The major molecular response rate at 24 months favored bosutinib vs imatinib among Asian (63.6 vs 38.2%) and non-Asian (60.9 vs 52.6%) patients, as did the complete cytogenetic response rate by 24 months (86.7 vs 76.7%, 81.5 vs 76.3%). Treatment-emergent adverse events in both subpopulations were consistent with the primary BFORE results. Trough bosutinib concentration levels tended to be higher in Asian patients. Health-related quality of life was maintained after 12 months of bosutinib in both subpopulations. These results support bosutinib as a first-line treatment option in Asian patients with CP CML.

Objective: Bosutinib, nilotinib and dasatinib are approved for the treatment of patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). In the absence of head-to-head comparisons between second-generation tyrosine kinase inhibitors (TKIs), the objective of this study was to indirectly compare the efficacy of bosutinib with nilotinib and dasatinib in first-line (1L) CP-CML., Methods: Cross-trial heterogeneity in terms of patient baseline characteristics and imatinib dose escalation are difficult to adjust for in network meta-analyses and anchored matching-adjusted indirect treatment comparisons (MAICs). Therefore, an unanchored MAIC was performed using patient level data from bosutinib (BFORE trial) and published aggregated data from nilotinib (ENESTnd) and dasatinib (DASISION) trials. After matching, cytogenetic and molecular responses, and disease progression, after a minimum follow-up of 24 months were compared between nilotinib versus bosutinb and dasatinib versus bosutinib., Results: The comparison of nilotinib versus bosutinib resulted in no statistically significant differences for MMR at and by 24 months, MR4 by 24 months, MR4.5 at and by 24 months, CCyR by 24 months, and disease progression, however, a decreased odds of MR4 at 24 months in favor of bosutinib versus nilotinib was observed. The comparison of dasatinib versus bosutinib by 24 months resulted in no statistically significant differences for MMR, disease progression, and CCyR, however a decreased odds of MR4.5 in favor of bosutinib versus dasatinib was observed., Conclusions: Overall, in these analyses bosutinib demonstrates equivalent efficacy to nilotinib and dasatinib in the treatment of patients with newly diagnosed CP-CML.

Patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) can be effectively treated with tyrosine kinase inhibitors (TKIs) and achieve a lifespan similar to the general population. The success of TKIs, however, requires long-term and sometimes lifelong treatment; thus, patient-assessed health-related quality of life (HRQoL) has become an increasingly important parameter for treatment selection. Bosutinib is a TKI approved for CP CML in newly diagnosed adults and in those resistant or intolerant to prior therapy. In the Bosutinib Trial in First-Line Chronic Myelogenous Leukemia Treatment (BFORE), bosutinib demonstrated a significantly higher major molecular response rate compared with imatinib, with maintenance of HRQoL (measured by the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire), after 12 months of first-line treatment. We examined relationships between molecular response (MR) and HRQoL. MR values were represented by a log-reduction scale (MRLR; a continuous variable). A repeated-measures longitudinal model was used to estimate the relationships between MRLR as a predictor and each FACT-Leu domain as an outcome. Effect sizes were calculated to determine strength of effects and allow comparisons across domains. The majority of FACT-Leu domains (with the exception of social well-being and physical well-being) demonstrated a significant relationship with MRLR (p < 0.05). Our results showed variable impact of clinical improvement on different dimensions of HRQoL. For patients who achieved MR 5 , emotional well-being and leukemia-specific domains showed the greatest improvement, with medium differences in effect sizes, whereas social well-being and physical well-being had the weakest relationship with MR.