Exposure-response analysis of asciminib efficacy and safety in patients with chronic myelogenous leukemia in chronic phase.

Abstract

Objective This study aimed to evaluate the relationships between asciminib pharmacokinetics with efficacy in first line (1 L) and safety in 1 L and third line (3 L) patients with Philadelphia-positive chronic myeloid leukemia in chronic phase. Methods The key primary efficacy endpoint in ASC4FIRST (1 L, phase 3), the week-48 major molecular response (MMR), versus asciminib exposure relationship were evaluated using linear regression model; the same model was applied to assess safety endpoints vs. exposure in ASC4FIRST, ASCEMBL (3 L, phase 3) and first-in-human (3 L, phase 1) trials based on abnormal laboratory data, vital signs and adverse events. Results The probability of week-48 MMR in ASC4FIRST versus exposure (averaged daily AUC and Cmin) in 1 L was 70–80% for the second through fourth quartile AUC0−24 h and Cmin where majority of patients had relative dose intensity > 75%; the MMR rate in the first quartile exposure metrics was 45%. Of all safety endpoints in 1 L, the only statistically significant positive relationship with exposure was the worsening event for grade ≥ 3 lipase increase but event probabilities were low (5.8%-11.2%). Line of therapy was investigated as a covariate for all safety endpoints; newly diagnosed patients had a lower probability of all safety events occurring than in pretreated patients. Conclusion Treatment compliance optimizes the efficacy of asciminib in newly diagnosed patients. Safety incidences associated with asciminib were low. The 80 mg once-daily regimen provides an optimal benefit-risk profile in newly diagnosed patients. Similar efficacy is expected from the 40 mg twice-daily regimen in the same population