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

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.