ASC4OPT 96-week results: Asciminib once or twice daily continues to be highly efficacious and demonstrates favorable safety in patients with chronic myeloid leukemia and suboptimal response, resistance or intolerance to two or more tyrosine kinase in

Abstract Introduction: The primary results of the ASC4OPT study (NCT04948333), assessing asciminib 40 mg twice daily (BID) and 80 mg once daily (QD) in pretreated patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP), showed high efficacy and a favorable safety profile for both dosing regimens. Here we present longer-term results from ASC4OPT. Methods: This Phase 3b, international, non-comparative study in adults with CML-CP without the T315I mutation and previously treated with ≥2 tyrosine kinase inhibitors (TKIs) enrolled two different cohorts. The main cohort included pts not in major molecular response (MMR; treatment failure/warning categories as per European LeukemiaNet [ELN] 2020 or intolerant to their most recent TKI). Dose escalation to 200 mg QD was permitted for pts who did not achieve MMR at Week 48 or lost response between Weeks 48‒108. An exploratory cohort of pts intolerant to their most recent TKI and in MMR at baseline was also enrolled and analyzed separately. All pts were randomized 1:1 to each dosing regimen. The primary endpoint was MMR rate at Week 48 for pts in the main cohort; response rates were assessed separately for the exploratory cohort. Pt-reported outcomes were assessed with the MD Anderson Symptom Inventory (MDASI)-CML questionnaire. Results: 169 pts were recruited to the main cohort. At data cutoff (11 February 2025, after the last pt completed their Week 96 visit), treatment was ongoing for 55.0% of pts, 18.3% had reached the end of the study at Week 144 and 26.0% had discontinued treatment; reasons for discontinuation included adverse events (AEs, 7.7%) and unsatisfactory therapeutic effect (5.3%). Four pts in the main cohort had a T315I mutation at baseline, which was detected after treatment start; these pts were excluded from efficacy analyses. MMR rates increased at Week 96 vs Week 48 (43.6% vs 39.4% overall; 45.8% vs 43.4% on 40 mg BID and 41.5% vs 35.4% on 80 mg QD, respectively). Deep molecular response (DMR) rates were maintained at Week 96 vs Week 48 (overall, MR4: 17.0% vs 17.0%; MR4.5: 10.9% vs 10.3%, respectively). Overall, 94.0% and 37.5% of pts in the main cohort experienced any-grade and Grade ≥3 AEs, respectively (94.0% and 32.1% on 40 mg BID, and 94.0% and 42.9% on 80 mg QD, respectively). The most frequent AEs included thrombocytopenia (16.7%), arthralgias (16.1%), COVID-19 and fatigue (13.1% each). AEs leading to discontinuation were reported in 7.1% of pts (40 mg BID, 8.3%; 80 mg QD, 6.0%). Forty pts (23.7%) in the main cohort had their asciminib dose escalated to 200 mg QD (40 mg BID, n=16; 80 mg QD, n=24); at data cutoff, 60.0% remained on treatment and 27.5% had reached the end of the study at Week 144. Among the 5 pts who discontinued treatment, the most common reason for discontinuation was disease progression/loss of response (n=2). At Week 96, 17.5% of these pts were in MMR. Among pts in the exploratory cohort (n=30), treatment was ongoing for 53.3%, 33.3% had reached the end of the study at Week 144 and 13.3% had discontinued treatment by data cutoff. Reasons for treatment discontinuation included AEs (n=2), physician decision and pt decision (n=1 each). At Week 96, 86.7% of pts maintained MMR (vs 93.3% at Week 48); 2 pts had discontinued treatment due to AEs (both on 80 mg QD) before Week 24 and were counted as non-responders. One more pt achieved MR4 in Week 96 vs Week 48 (7/14 at both timepoints on 40 mg BID; 9/16 vs 8/16 on 80 mg QD, respectively). MDASI-CML Symptom and Interference Total scores decreased slightly and quickly at Weeks 4‒12, denoting some improvement in main cohort pts' symptoms and reduced interference with their daily life activities; scores then stabilized. Similar results were observed for pts in the exploratory cohort, although with slightly larger reductions in scores. Two deaths were reported overall, assessed as not treatment related: one on treatment (in the 80 mg QD arm, main cohort, due to stroke) and one that occurred >30 days after the last treatment (in the 40 mg BID arm, exploratory cohort, due to hypoxemic respiratory failure). Conclusions: The 96-week results from the ASC4OPT study further strengthen asciminib as a standard of care for pretreated pts with CML-CP, regardless of dosing regimen, including those who are intolerant to previous TKIs: a considerable proportion of these pts maintained or deepened their response regardless of asciminib regimen.