Dose Justification for Asciminib in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia with and Without the T315I Mutation

Abstract

Background and objective: Asciminib is approved in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥ 2 prior tyrosine kinase inhibitors. Here, we aimed to demonstrate similarity in efficacy/safety of asciminib 80 mg once daily (q.d.) versus 40 mg twice daily (b.i.d.) in patients with CML-CP without T315I mutation and support the use of the 200-mg b.i.d. dosage in patients harboring T315I, using model-informed drug development.

Methods: Data were collected from 199 patients in the phase I (NCT02081378; 10-200 mg b.i.d. or 10-400 mg q.d.) and 154 patients in the phase III (NCT03106779; 40 mg b.i.d.) studies. Evaluations were based on population pharmacokinetics (PopPK) and exposure-response (efficacy/safety) analyses.

Results: PopPK showed comparable exposure (area under the curve, AUC_0-24h) for 40 mg b.i.d. and 80 mg q.d. (12,638 vs 12,646 ng*h/mL); average maximum and minimum plasma concentrations for 80 mg q.d. were 1.61- and 0.72-fold those of 40 mg b.i.d., respectively. Exposure-response analyses predicted similar major molecular response rates for 40 mg b.i.d. and 80 mg q.d. (Week 24: 27.6% vs 24.8%; Week 48: 32.3% vs 30.6%). Results also established adequacy of 200 mg b.i.d. in patients with T315I mutation (Week 24: 20.7%; Week 48: 23.7%), along with a similar safety profile for all dose regimens.

Conclusions: Similarity between 40 mg b.i.d. and 80 mg q.d. regimens was investigated, demonstrating similar and substantial efficacy with well-tolerated safety in patients without T315I mutation. The 200-mg b.i.d. dose was deemed safe and effective for patients with T315I mutation.

Fig. 1

Simulated time-course of log₁₀-transformed BCR::ABL1^IS for asciminib 40 mg b.i.d. and 80 mg q.d. in patients not harboring the T315I mutation: all patients (a) and patients stratified by number of prior TKIs and baseline BCR::ABL1^IS levels (b). The black line represents the median over the 100 replicates of the 50th percentile of BCR::ABL1^IS. The darker shaded area represents the median of 25th and 75th percentiles of BCR::ABL1^IS, and the lighter shaded area is the median of 10th and 90th percentiles of BCR::ABL1^IS. b.i.d. twice daily, q.d. once daily, TKI tyrosine kinase inhibitor

Fig. 2

Simulated time-course of log₁₀-transformed BCR::ABL1^IS for asciminib 40 mg b.i.d., 80 mg q.d., 120 mg b.i.d., 160 mg b.i.d., or 200 mg b.i.d. in patients (with any number of prior TKI treatments) harboring the T315I mutation. The black line represents the median over the 100 replicates of the 50th percentile of BCR::ABL1^IS. The darker shaded area represents the median of 25th and 75th percentiles of BCR::ABL1^IS and the lighter shaded area is the median of 10th and 90th percentiles of BCR::ABL1^IS. b.i.d. twice daily, q.d. once daily, TKI tyrosine kinase inhibitor

Fig. 3

Regression coefficient estimates of repeated-measures logistic regression model for asciminib exposure metrics versus laboratory events, vital signs (hypertension) and AEs of fatigue/asthenia. AE adverse event, AUC area under the concentration–time curve, CI confidence interval, C_max maximum plasma concentration, C_min minimum plasma concentration

Fig. 4

Scatterplot, regression line (red), and 90% CI (blue shaded area) of change from baseline QTcF versus plasma asciminib concentration. Data are from 239 patients from the dose-finding study (patients with CML and Ph+ acute lymphoblastic leukemia). Each circle represents a data point (PK sample with time-matched QTc assessment) any time post-asciminib dose. Vertical lines represent median C_max for 40 mg b.i.d., 80 mg q.d., 200 mg b.i.d. and HCRE. Scatterplot includes only the matched ECG records. The model was QTcF change from baseline = concentration + baseline QTcF are fixed effects, and patient is a random effect. b.i.d. twice daily, CI confidence interval, C_max maximum plasma concentration, HCRE highest clinically relevant exposure, PK pharmacokinetic, q.d. once daily, QTcF QT interval corrected using the Fridericia method, TKI tyrosine kinase inhibitor