Asciminib, a tyrosine kinase inhibitor (TKI), offers a flexible dosing strategy for patients with chronic myeloid leukemia (CML). New data support the use of an 80 mg once-daily (q.d.) regimen as an alternative to the approved 40 mg twice-daily (b.i.d.) regimen for chronic phase (CP) CML patients without the T315I mutation. This finding, derived from population pharmacokinetic (PopPK) and exposure-response (ER) analyses, aims to improve patient compliance without compromising efficacy or safety.
The analysis, which integrated data from the dose-finding and ASCEMBL studies, demonstrated comparable efficacy between the 80 mg q.d. and 40 mg b.i.d. regimens. Predicted major molecular response (MMR) rates were similar between the two regimens, aligning with clinical data from the ASCEMBL study, where asciminib 40 mg b.i.d. showed a superior benefit/risk profile compared to bosutinib 500 mg q.d. The study's findings support approvals in the United States, ACCESS countries (UK, Australia, Singapore, Switzerland), and South Korea.
Rationale for Once-Daily Dosing
The rationale behind exploring the 80 mg q.d. regimen stems from the challenges associated with twice-daily dosing, which can impact patient adherence. Studies have shown that patients on once-daily regimens exhibit higher adherence rates compared to those on twice-daily regimens. Given that asciminib should be administered under fasting conditions, a more convenient once-daily regimen could further enhance treatment compliance.
Safety Profile
Exposure-response analyses indicated no correlation between increased asciminib exposure and a higher probability of safety events. This suggests that the safety profiles of the 80 mg q.d. and 40 mg b.i.d. regimens are comparable. Even with a 60% increase in maximum drug concentration (Cmax) observed with the 80 mg q.d. regimen, the overall safety profile remained consistent.
Dosing for T315I-Mutated CML
The analysis also supports the use of asciminib at 200 mg b.i.d. for CML-CP patients harboring the T315I mutation. This dosing regimen was selected based on preclinical findings and clinical data from the dose-finding study. Asciminib's activity against the T315I mutation, a common resistance mutation in later-line CML-CP, makes it a valuable treatment option for this patient population. Simulations based on the time-course of BCR::ABL1IS over two years demonstrated that a dose of 200 mg b.i.d. was effective and adequate in this heavily pretreated patient population with limited treatment options.
Model-Informed Drug Development
Model-informed drug development (MIDD) played a crucial role in assessing and justifying the comparability of the 80 mg q.d. and 40 mg b.i.d. dosing regimens. By integrating data across different dose regimens and studies, MIDD provided a strong rationale for the similar efficacy between the two regimens, ultimately supporting the approval of both dosing regimens in several countries.
Clinical Implications
These findings provide clinicians with additional flexibility in prescribing asciminib, potentially improving patient adherence and outcomes. The availability of both 40 mg b.i.d. and 80 mg q.d. regimens allows for a more patient-centric approach to CML treatment. The 200 mg b.i.d. regimen remains a critical option for patients with the T315I mutation, addressing a significant unmet need in this population.
