Combes, Francois Pierre, Li, Ying Fei, Sy, Sherwin, Lorenzo, Sebastien, Dasgupta, Kohinoor, Kapoor, Shruti, Hoch, Matthias and Ho, Yu-Yun (2024) Dose Justification for Asciminib in Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia With and Without the T315I Mutation. Clinical Pharmacokinetics, 63 (9). pp. 1301-1312. ISSN 39243304

Abstract

Purpose: 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 demonstrate the 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 mutation.
Patients and Methods: Data were collected from 199 patients in the Phase 1 (NCT02081378; 10−200 mg b.i.d. or 10−400 mg q.d.) and 154 patients in the Phase 3 (NCT03106779; 40 mg b.i.d.) studies. Evaluations were based on population pharmacokinetics (PopPK) and exposure-response (efficacy/safety) analyses.
Results: The PopPK analysis showed comparable exposure (area under the curve, AUC0-24h) 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 revealed similar predicted 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: A daily dose of 80 mg asciminib (40 mg b.i.d. or 80 mg q.d.) demonstrated substantial efficacy with well-tolerated safety in patients with CML-CP without T315I mutation, while 200 mg b.i.d. asciminib was appropriate for patients with T315I mutation.

Item Type:	Article
Date Deposited:	19 Oct 2024 00:45
Last Modified:	19 Oct 2024 00:45
URI:	https://oak.novartis.com/id/eprint/50025