Optimizing Dose of Bosutinib to Minimize Adverse Events While Maintaining Efficacy in Patients with Newly Diagnosed Chronic Myelogenous Leukemia

Introduction: Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor that has demonstrated efficacy and a manageable safety profile in adult patients with chronic phase (CP) chronic myeloid leukemia (CML). A previous clinical trial (BELA), using a starting dose of 500 mg/day bosutinib, failed to meet its primary efficacy endpoint, primarily because of early discontinuation due to adverse events. Therefore, a new trial, BFORE, was recently conducted using a reduced starting dose of 400 mg/day. This analysis integrated results of these phase 3 trials in order to quantitatively assess the impact of reducing the starting bosutinib dose from 500 mg/day to 400 mg/day on safety and efficacy outcomes in adults with newly diagnosed CP CML.

Methods: Oral bosutinib (400 or 500 mg/day) was administered to patients with newly diagnosed CP CML in 2 completed phase 3 trials. Patients with evaluable pharmacokinetic (PK) and pharmacodynamic data were included in the analysis. Bosutinib exposures were derived from a two-compartment PK model with first-order absorption and an absorption lag time. Exposure-response (E-R) analysis was conducted for the primary efficacy endpoint of major molecular response (MMR) assessed at 48 weeks using logistic regression. Safety endpoints were analyzed using ordered logistic regression to identify correlations between bosutinib exposures and ordered adverse event (AE) severity grades. Based on the incidence and clinical relevance of the AEs following treatment with bosutinib, 8 prespecified safety outcomes were included: diarrhea, nausea, vomiting, rash, elevated alanine and aspartate aminotransferase (ALT and AST), thrombocytopenia, and neutropenia. AEs were assessed at the first occurrence of the highest AE grade within the first year of treatment for each patient.

Results: A total of 512 patients were included in the E-R analysis of MMR. The rate of MMR at 48 weeks for the bosutinib arm was 47.2% for a starting dose of 400 mg/day (BFORE) and 38.0% for a starting dose of 500 mg/day (BELA), suggesting that a lower dose did not compromise efficacy. Since the endpoint was defined at 48 weeks, time on treatment was included to account for the lack of MMR responses due to earlier trial discontinuation; hence the E-R analysis was only able to predict MMR at 48 weeks. Trough bosutinib plasma concentrations and time on bosutinib treatment were significant predictors (both P <0.05) of the probability of achieving MMR, with days on treatment having a larger impact than plasma concentrations (Figure 1, Table 1).

The incidence of AEs associated with permanent discontinuation from bosutinib treatment was 14.2% for a starting dose of 400 mg/day (BFORE) and 21.0% for a starting dose of 500 mg/day (BELA). An E-R relationship between bosutinib exposures and time to event was identified for incidence of grade>0 diarrhea, nausea, and vomiting. Higher bosutinib exposure increased the probability of moving from one grade to the next higher one, while increased time to event decreased the probability of moving up from one grade to the next. For incidence of grade>0 rash, elevated ALT, and elevated AST, patients had a higher probability of an AE grade with increasing bosutinib exposures. In contrast, the incidence of grade>0 thrombocytopenia and neutropenia decreased with increasing bosutinib exposures.

Conclusions: Both bosutinib exposure and time on bosutinib treatment were significant predictors of MMR, but time on treatment appeared to play a larger role in efficacy. This suggests that staying on treatment may be more important than receiving a higher dose of bosutinib. The incidence of AEs appeared to correlate with bosutinib exposure; higher bosutinib exposure was associated with a greater probability of an AE earlier on treatment for diarrhea, nausea, and vomiting, and at any time on treatment for rash, elevated ALT, and elevated AST. When comparing the 2 bosutinib starting doses, the incidence of AEs associated with permanent discontinuation suggests that the lower dose of bosutinib used in the BFORE trial (400 mg/day) did not compromise efficacy but decreased the probability of patients discontinuing due to AEs.

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