Abstract
BACKGROUND: The BELA and BFORE trials compared bosutinib starting doses of 500 mg once daily (QD) and 400 mg QD, respectively, with imatinib in adults with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML). The B1871048 trial evaluated bosutinib 400 mg QD in Japanese patients with newly diagnosed CP-CML. AIM: This analysis assessed the impact of a lower bosutinib starting dose on key efficacy and safety outcomes. MATERIALS & METHODS: A pharmacokinetic model was used to estimate metrics of bosutinib exposure, and logistic regression was used to investigate relationships with efficacy (cumulative major molecular response [MMR] and cumulative complete cytogenetic response [CCyR]) and safety outcomes (eight prespecified adverse events). RESULTS: Totals of 573 and 574 patients were included in the efficacy and safety endpoint analyses, respectively. Cumulative MMR and CCyR were similar across studies. Log(C(trough) ) and log(C(avg) ) were significant predictors of MMR and CCyR, and the probability of achieving MMR or CCyR increased 1.3-fold or 2.7-fold for every 1 unit increase in log(C(trough) ) or log(C(avg) ), respectively. An exposure-response relationship was identified between time-to-event and risk of diarrhea, nausea, and vomiting. Significant relationships were also observed between time-to-event and log(C(avg) ), C(trough) , and C(avg) with diarrhea, nausea, and vomiting, respectively. DISCUSSION: A bosutinib exposure-response relationship with safety and efficacy was observed. CONCLUSION: Compared with 500 mg QD, a bosutinib starting dose of 400 mg QD improved tolerability in some patients with newly diagnosed CP-CML without compromising efficacy. CLINICALTRIALS: gov identifiers: NCT00574873; NCT02130557; NCT03128411.