Abstract

Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of Philadelphia chromosome-positive CML in adults resistant or intolerant to prior therapy. This analysis evaluated the efficacy of first-line bosutinib versus imatinib in the BFORE study (NCT02130557) by 3-month BCR-ABL1 transcripts ≤10% versus >10% and examined baseline and on-treatment characteristics as predictors of time to major molecular response (MMR).

Methods: In this ongoing, multinational, phase 3, open-label study, 536 patients were randomized 1:1 to bosutinib 400 mg or imatinib 400 mg once daily. The present analysis is based on ≥12 months of follow-up. Baseline and on-treatment time-dependent covariates were analyzed using a proportional subdistribution hazards model predicting time to initial MMR. No adjustment for multiple comparisons was made.

Results: The intent-to-treat (ITT) population included 268 patients in the bosutinib arm and 268 patients (including 3 untreated patients) in the imatinib arm. Among evaluable patients (≥3000 ABL1 analyzed) at 3 months in the ITT population, more patients in the bosutinib arm than in the imatinib arm had BCR-ABL1 transcripts ≤10% (80.6% of 248 patients vs 60.5% of 253 patients; P <0.0001). The MMR rate at 12 months was higher in evaluable patients who had transcripts ≤10% versus >10% at 3 months with bosutinib (117 [58.5%] vs 7 [14.6%], P <0.0001) and with imatinib (83 [54.2%] vs 14 [14.0%], P <0.0001). The cumulative MMR rates were also higher in evaluable patients with transcripts ≤10% with bosutinib (138 [69.0%] vs 12 [25%]; P <0.0001) and with imatinib (100 [65.4%] vs 30 [30.0%]; P <0.0001). In the ITT population, transcripts ≤10% (vs >10% or not evaluable) at 3 months was a predictor of time to MMR in both arms (Table; bosutinib: hazard ratio [HR]=6.44, P <0.0001; imatinib: HR=3.69, P <0.0001). The only other predictor of time to MMR among the covariates examined was not having a bosutinib dose reduction to 300 mg due to an adverse event.

Conclusion: BOS treatment was associated with a higher number of patients presenting transcripts ≤10% at 3 months than those treated with IMA. Patients with transcripts ≤10% at 3 months had higher rates of 12-month MMR and achieved response faster than those with transcripts >10%. These findings suggest that the transcript level at 3 months may be a predictor of response to first-line bosutinib and imatinib.

Disclosures

Hochhaus: Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger: BMS: Consultancy, Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Gilead: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Research Funding. Mauro: Bristol-Myers Squibb: Consultancy. Chuah: Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria; Avillion: Honoraria. Kim: Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria. le Coutre: BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Incyte: Honoraria; ARIAD: Honoraria. García Gutiérrez: Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Reilly: Avillion LLP: Employment. Jeynes-Ellis: Avillion LLP: Employment, Equity Ownership. Crescenzo: Pfizer: Employment, Equity Ownership. Leip: Pfizer: Employment, Equity Ownership. Bardy-Bouxin: Pfizer: Employment, Equity Ownership. Brümmendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes: ARIAD: Consultancy, Research Funding; Teva: Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.