Asciminib Shows High Efficacy and Favorable Tolerability at 80 Mg Once Daily and 40 Mg Twice Daily in Patients with Chronic Phase Chronic Myelogenous Leukemia Previously Treated with 2 or More Tyrosine Kinase Inhibitors: Primary Analysis from the ASC4OPT Study

Introduction: Asciminib, a BCR::ABL1 inhibitor intentionally designed to Specifically Target the ABL Myristoyl Pocket (STAMP), has been approved for the treatment of adult patients (pts) with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs). A once daily (QD) regimen is likely to improve quality of life and increase treatment adherence. Pharmacokinetic modelling showed 40 mg twice daily (BID) and 80 mg QD regimens had similar and substantial efficacyin pts with CML-CP without the T315I mutation; both schedules have been recommended as standard doses. Here, we present the primary results from the ASC4OPT (NCT04948333) trial, assessing safety and efficacy of once and twice daily schedules for asciminib (80 mg total daily dose) in pretreated adult pts with CML-CP. Methods: ASC4OPT is an international, multi-center, non-comparative phase 3b study in adults with CML-CP without the T315I mutation and previously treated with ≥2 TKIs. Eligible pts were in treatment failure or warning categories according to ELN 2020, or intolerant to their most recent TKI and not in major molecular response (MMR, BCR::ABL1IS ≤0.1%). Pts intolerant to their most recent TKI and in MMR at baseline were also enrolled and analyzed separately. Pts were randomized 1:1 to receive asciminib 40 mg BID or 80 mg QD, fasting. In pts not achieving MMR at 48 weeks or losing response after week 48 and up to week 108, asciminib dose could be escalated to 200 mg QD at investigator's discretion. The primary endpoint was MMR rate at week 48; pts who discontinued earlier were considered as non-responders at week 48. Secondary endpoints included time to MMR, deep molecular response (MR4 [BCR::ABL1IS ≤0.01%] and MR4.5 [BCR::ABL1IS ≤0.0032%]), BCR::ABL1IS ≤1%, and complete cytogenetic response (CCyR) rates, and safety for pts not in MMR at baseline. For pts in MMR at baseline, MMR rate at week 48 was assessed separately. Results: Overall, 169 pts were randomized to asciminib 40 mg BID (n=85) or 80 mg QD (n=84); 1 pt in the 40 mg BID arm was not treated. Median age was 55 years (range, 18‒86) and 62.1% pts were male. Overall, 49.7%, 29.6%, and 20.1% of pts had received 2, 3, or ≥4 prior lines of therapy, respectively; 28.4% of pts had discontinued their most recent TKI due to intolerance. After a median follow-up of 17.5 months, treatment was ongoing for 136 pts (80.5%); 5.9% had discontinued treatment due to adverse events (AEs, 6 pts on 40 mg BID and 4 pts on 80 mg QD) and 4.1% due to unsatisfactory therapeutic effect (4 pts on 40 mg BID and 3 pts on 80 mg QD). The overall MMR rate at week 48 was 38.5% (65/169; 95% CI: 31.1%‒46.2%); 42.4% (36/85; 95% CI: 31.7%‒53.6%) in the 40 mg BID arm and 34.5% (29/84; 95% CI: 24.5%‒45.7%) in the 80 mg QD arm. Median time to MMR was 59.3 weeks and 72.1 weeks for pts on asciminib 40 mg BID and 80 mg QD, respectively. CCyR rates (including pts in MMR without bone marrow assessment) at week 48 were 58.8% and 54.8% for pts on asciminib 40 mg BID and 80 mg QD, respectively. BCR::ABL1IS ≤1% was achieved at week 48 in 64.7% and 59.5% pts on 40 mg BID and 80 mg QD, respectively. MR4 and MR4.5 rates at week 48 were 20.0% and 11.8% for pts on 40 mg BID, and 13.1% and 8.3% for pts on 80 mg QD, respectively. Overall, 89.3% of pts experienced any-grade AEs and 29.8% of pts experienced Grade ≥3 AEs (90.5% and 25.0% on 40 mg BID, and 88.1% and 34.5% on 80 mg QD, respectively). The most common AEs for all pts were thrombocytopenia (15.5%), arthralgia (13.7%), COVID-19 (11.9%), leukopenia (11.3%), and pruritus (10.1%). AEs led to treatment discontinuation in 6.0% of pts and to dose reduction or interruption in 30.4% of pts. One on-treatment death was reported on the 80 mg QD arm (cerebrovascular accident). Among pts already in MMR at baseline, 28/30 pts (93.3%; 14/14 [100%] on 40 mg BID and 14/16 [87.5%] on 80 mg QD) remained in MMR at week 48. Two pts on 80 mg QD discontinued treatment due to AEs. Conclusions: Asciminib at both 40 mg BID and 80 mg QD doses is efficacious and shows favorable tolerability in pts with CML-CP previously treated with ≥2 TKIs. MMR rates in ASC4OPT were numerically higher than in ASCEMBL (NCT03106779, 29.0% for asciminib 40 mg BID at week 48). An analysis will be conducted to investigate numerical differences between the schedules and in comparison to the ASCEMBL study. Results complement those of the ASCEMBL study to support asciminib as a standard of care in non-optimally treated pts with CML.

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