Asciminib (ASC) Once-Daily (QD) Dosing Demonstrates Comparable Tolerability and Efficacy to Twice-Daily (BID) Dosing: Results from the ASC in Monotherapy 4 CML (AIM4CML) Study in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

BACKGROUND: ASC is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL1 Myristoyl Pocket, distinguishing it from other approved treatments that target the ATP binding site. In the phase III ASCEMBL trial (NCT03106779) ASC 40 mg BID was well tolerated and demonstrated superior efficacy vs bosutinib 500 mg QD in pts previously treated with ≥2 TKIs, with major molecular response (MMR; BCR::ABL1^IS ≤0.1%) rates of 25.5% vs 13.2% at wk 24 and 37.6% vs 15.8% at wk 96. We present an interim analysis of the primary endpoint of the AIM4CML trial (NCT04666259), which was initiated to assess the safety, efficacy, and QD dosing of ASC in a similar population of pts with CML-CP.

METHODS: This is a multicenter, phase IIIb, open-label study of ASC in pts with CML-CP without the T315I mutation after ≥2 prior TKIs and pts with the T315I mutation after ≥1 prior TKI. Adults aged ≥18 years with CML-CP who had treatment failure with or intolerance of the most recent TKI were eligible. Pts without the T315I mutation were randomized to receive ASC 40 mg BID (cohort A) or 80 mg QD (cohort B). Results for pts with the T315I mutation who received ASC 200 mg BID (cohort C) will not be presented for this analysis. The primary endpoints include adverse events (AEs) and serious AEs by wk 24 in cohorts A and B, with additional safety and efficacy secondary endpoints. This study was not powered to detect statistical differences between cohorts. End of study is when the last pt completes 72 wks of treatment or discontinues prematurely.

RESULTS: The numbers of enrolled pts in cohorts A, B, and C were 26, 27, and 3, respectively. This interim analysis included 42 pts randomized to cohort A (n=22) or cohort B (n=20), who reached 24 wks after cycle 1 day 1 of treatment by February 17, 2023. Most baseline characteristics in cohorts A and B were comparable, but median time since initial diagnosis and median baseline BCR::ABL1^IS levels were longer and higher, respectively in cohort B (Table). Median duration of exposure was 23.1 (range, 2.7-72.3) wks in cohort A and 24.1 (range, 1.3-71.0) wks in cohort B. Prior to wk 24, treatment was discontinued in 7 and 4 pts in cohorts A and B, respectively. Reasons for discontinuation included physician decision (cohort A, n=4; cohort B, n=2), AEs (cohort A, n=2; cohort B, n=1), or pt decision (cohort A, n=1; cohort B, n=1). At the time of this interim analysis, discontinuation due to treatment failure was reported only in cohort B in 2 pts that discontinued due to physician decision.

Cohorts A and B had comparable all-grade, grade 3, and grade 4 AEs. Treatment-emergent all-grade AEs occurring in ≥20% in cohorts A and B were fatigue (32% and 25%), headache (27% and 20%), abdominal pain (27% and 15%), rash (23% and 5%), dyspnea (23% and 10%), nausea (14% and 30%), hypertension (14% and 20%), cough (18% and 20%), and arthralgia (9% and 20%). While many pts had AEs requiring additional therapy, few had serious AEs, and similar numbers of pts in cohorts A and B had AEs leading to dose adjustments/interruptions and treatment discontinuation (Figure). One pt in cohort B had a fatal AE due to sepsis that was not attributed to study treatment. This trial is ongoing; data for the wk 24 primary endpoint for all enrolled pts will be available at the time of presentation.

Pts with ≥1 molecular response assessment by wks 4, 12, and 24 were 18, 19, and 20 in cohort A, respectively, and 17, 17, and 18 in cohort B, respectively. The proportions of pts who maintained or achieved BCR::ABL1^IS ≤1% by wks 4, 12, and 24 were higher in cohort B with 52.9%, 76.5%, and 88.9%, respectively than in cohort A with 50.0%, 63.2%, and 65.0%, respectively, likely due to higher baseline BCR::ABL1^IS levels in cohort B (Table). MMR rates by wks 4, 12, and 24 were 33.3%, 42.1%, and 45.0% in cohort A and 23.5%, 47.1%, and 61.1% in cohort B, respectively. Deep molecular response (MR⁴; BCR::ABL1^IS ≤0.01%) rates by wks 4, 12, and 24 were 27.8%, 31.6%, and 30.0% in cohort A and 5.9%, 11.8%, and 27.8% in cohort B, respectively.

CONCLUSIONS: This interim analysis of the AIM4CML trial further demonstrates the tolerability and efficacy of ASC and is among the first clinical reports on QD dosing of ASC in pts with CML-CP. Safety was comparable between the 80-mg QD and 40-mg BID doses, with both demonstrating safety profiles consistent with prior reports. Pts receiving ASC at both doses achieved and maintained molecular responses, which deepened over time. These results support the flexibility of QD dosing with ASC.