Justification for Asciminib Dosing in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (Ph+ CML-CP) with and without the T315I Mutation

Abstract

Introduction: Asciminib (ASC), a first-in-class BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP), is approved by the FDA for adult patients (pts) with Ph+ CML-CP previously treated with ≥2 tyrosine kinase inhibitors (TKIs) and for pts with the T315I mutation. Approval was based on the results of the pivotal phase III ASCEMBL trial (NCT03106779), where ASC 40 mg twice daily (BID) demonstrated superior efficacy and better safety and tolerability vs bosutinib 500 mg once daily (QD), and an ongoing phase I study (NCT02081378), which evaluates ASC in doses of 20‒200 mg BID and 10‒200 mg BID in pts with and without the T315I mutation, respectively; doses of 80‒200 QD are also evaluated. Population pharmacokinetics (PopPK) has previously shown that total systemic exposure of ASC over 24 h was comparable between 80 mg QD and 40 mg BID (AUC0-24h 12,646 vs 12,638 ng*h/mL) and exposure-response (ER) models have quantified the longitudinal effect of ASC on BCR:ABL1IS levels. Here, we illustrate the similarity in efficacy and safety of ASC at 80 mg QD and 40 mg BID in pts with Ph+ CML-CP without the T315I mutation, and further support the ASC 200 mg BID dose in pts with the T315I mutation. Methods: Two ER-efficacy analyses, assessing the association between ASC exposure and efficacy endpoint were performed: 1) for pts without the T315I mutation on either 40 mg BID or 80 mg QD, and 2) for pts with the T315I mutation. The efficacy endpoint was based on longitudinal BCR::ABL1IS and summarized as major molecular response (MMR) rates at weeks (wks) 24 and 48. The ER-safety analysis assessed the association between ASC exposure and the probability of safety event based on laboratory abnormalities, vital signs for hypertension and adverse events (AEs) of fatigue/asthenia at any time during treatment. Results: Similar efficacy was predicted for ASC 80 mg QD vs 40 mg BID in pts without the T315I mutation (predicted MMR rate [mean ± SE] at Wk 24: 24.8 ± 4.2% vs 27.6 ± 4.5%; Wk 48: 30.6 ± 4.7% vs 32.3 ± 4.8%, respectively); rates were similar to those observed in ASCEMBL. Predicted efficacy did not differ significantly between the two regimens regardless of the different ASC minimum and maximum plasma concentrations. Stratified time-course simulations using both 80 mg QD and 40 mg BID regimens showed clinically relevant decreases in BCR::ABL1IS levels regardless of regimen, baseline (BL) BCR::ABL1IS levels or number of prior TKIs received. Predicted BCR::ABL1IS values continued to decrease after 48 wks of treatment for all BL BCR::ABL1IS levels. In pts with the T315I mutation, a dose of 200 mg BID was the most efficacious, as BCR::ABL1IS decreases were more likely than with lower dose regimens. The ER-safety analysis showed that increasing ASC exposure was not associated with increased probability of experiencing fatigue/asthenia or hypertension, the most common AEs reported in clinical trials. Additionally, there was no clinically relevant association between ASC exposure at doses up to 200 mg BID and risk of laboratory abnormalities, including amylase increase and lipase increase (any grade and Grade ≥3); ALT increase, AST increase and bilirubin increase (Grade ≥2); platelet decrease, neutrophil decrease and hemoglobin decrease (Grade ≥3); and triglyceride increase (any grade). Conclusions: Both the ASC 80 mg QD and 40 mg BID regimens demonstrated substantial efficacy in pts with Ph+ CML-CP without the T315I mutation, regardless of BL BCR::ABL1IS levels or number of prior TKIs received. While ASC showed efficacy across subgroups, pts who are heavily pre-treated and those with high BL BCR::ABL1IS levels may benefit from continuous, long-term ASC treatment as BCR::ABL1IS was predicted to decrease beyond 48 wks of treatment. The 80 mg QD dose regimen is likely to support better treatment adherence, potentially improving benefit from therapy. For pts with the T315I mutation, modelling validated the 200 mg BID dose as both effective and safe. ASC had a similar safety profile across all dose regimens evaluated (up to 200 mg BID), with ER-safety analyses suggesting that increased exposure had no clinically relevant association with increased risk of assessed toxicities. More data on asciminib at the 80 mg QD dose in both first and later lines will be available from ongoing clinical trials: ASC4FIRST (NCT04971226), AIM4CML (NCT04666259), ASC4OPT (NCT04948333). Sponsor: Novartis.