PF415 EFFICACY AND SAFETY FOLLOWING DOSE REDUCTION OF BOSUTINIB IN PREVIOUSLY TREATED PATIENTS WITH CHRONIC MYELOID LEUKEMIA: ANALYSIS OF THE PHASE 4 BYOND TRIAL
Authors: Brümmendorf T.H. , Giles F. , Gambacorti‐Passerini C. , Roboz G.J. , Le Coutre P. , Hjorth‐Hansen H. , Stenke L. , Cervantes F. , Rousselot P. , Viqueira A. , Bardy‐Bouxin N. , Leip E. , Leone J.M. , Steegmann J.L. , Cortes J.E. , Hochhaus A. 
Published: June 2019

Background:Bosutinib (BOS) is approved in patients (pts) with Philadelphia chromosome‐positive (Ph+) chronic myeloid leukemia (CML) who are newly diagnosed (400 mg once daily [QD]) or resistant or intolerant to prior treatment (tx; 500 mg QD). Some pts require dose interruptions/reductions to manage the occurrence of adverse events (AEs).Aims:Evaluate efficacy and safety of BOS before and after dose reductions in pretreated pts with Ph+ chronic phase (CP) CML.Methods:BYOND is an ongoing, single‐arm, open‐label phase 4 study of BOS in pts resistant or intolerant to prior tyrosine kinase inhibitors (TKIs). Dose reduction to 400, 300 or 200 mg QD was allowed for management of tx‐related AEs.Results:Pts with Ph+ CP CML (N = 156) were categorized as resistant to ≥1 prior TKI (n = 83; 53.2%) or intolerant to all prior TKIs (73; 46.8%); data cutoff: 1 y after last enrolled pt. Overall, median (range) tx duration was 23.7 (0.2–42.2) mo and median (range) dose intensity was 313.1 (79.7–560.6) mg/d. In resistant and intolerant pts, median (range) tx duration was similar: 23.4 (0.2–42.2) and 25.3 (0.4–41.9) mo, respectively. 37.3% resistant and 63.0% intolerant pts experienced dose reductions to 300 or 200 mg QD. This resulted in higher median dose intensity in resistant vs intolerant pts: 405.9 (125.0–560.6) vs 292.0 (79.7–500.0) mg/d. 153 pts started at 500 mg QD or reduced to a lower dose, ≥1 dose reduction to 400, 300 and 200 mg QD, respectively, was seen in 42 (27.5%), 39 (25.5%) and 38 (24.8%) and median (range) tx duration was 27.6 (0.4–42.2), 11.1 (0.8–41.3) and 24.0 (0.9–41.9) mo. Of 34 pts who remained on 500 mg QD without dose reduction, median (range) tx duration was 23.5 (0.2–41.4) mo; 21 (61.8%) had complete cytogenetic response; 19 (55.9%) had major molecular response (MMR). Among pts who dose‐reduced, most had a newly attained or maintained response, few pts lost a previously attained response (Table). Of 10 pts with baseline mutations, 7 (70.0%) received 400 or 500 mg QD; 3 (30.0%) achieved at least MMR. Across all time points up to 2 y, a high proportion (>65%) of resistant pts still receiving tx were on 400 or 500 mg QD while ∼20% of intolerant pts still receiving tx were on 500 mg QD. Tx was discontinued in 17 (50.0%), 12 (28.6%), 24 (61.5%) and 15 (39.5%) pts without dose reduction, ≥1 dose reduction to 400, 300 and 200 mg QD, respectively, including: 4 (11.8%), 7 (16.7%), 17 (43.6%), 11 (28.9%) due to AEs; and 5 (14.7%), 0, 2 (5.1%), 1 (2.6%) due to insufficient clinical response. Most common AEs overall (N = 156) leading to dose reduction were diarrhea (26.3%), increased alanine (ALT; 13.5%) and aspartate (10.3%) aminotransferase. Most common (≥20%) AEs before dose reduction to each dose were diarrhea, nausea, vomiting, increased ALT and headache; tolerability improved after dose reduction—most common AEs decreased by >10%, except increased ALT.Summary/Conclusion:BOS dose reduction in pts with CP CML with resistance or intolerance to prior TKIs improved tolerability. Resistant pts were generally treated with higher doses of BOS than intolerant pts. Individualized tx allowed pts to remain on BOS while maintaining efficacy. The 500 mg QD dose of BOS should be used if tolerated, while lower doses should be reserved for when tx tolerability is a concern. Temporary BOS dose reduction is an important strategy to manage AEs; nevertheless, given the limited amount of data available, dose adjustments in intolerant and particularly in resistant pts should be made with caution and based on individual pt and disease characteristics.image