Real-world data comparison of asciminib 40 mg twice daily vs. 80 mg once daily in chronic myeloid leukemia patients Free

Introduction:

Asciminib (ASC) is a first-in-class Specifically Targeting the ABL Myristoyl Pocket (STAMP) inhibitor that binds to the ABL myristoyl pocket. In Canada, it is approved for adults with Philadelphia chromosome–positive chronic-phase chronic myeloid leukemia (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs) since 2022. Both 40 mg twice daily (BID) and 80 mg once daily (QD) regimens demonstrate equivalent pharmacokinetics thus suggesting similar efficacies in patients (pts) without the T315I mutation. Early data from the ASC4OPT trial suggested both schedules are similarly effective and well-tolerated.

Objective:

To compare molecular response rates and safety profile of ASC 80 mg QD versus 40 mg BID from real-world experience in CML-CP pts previously exposed to ≥2 TKIs.

Methods:

We conducted a retrospective, single-center study in 51 CML pts treated with ASC as 3^rd line therapy or beyond at single center. The dose, either 40mg BID or 80mg QD, was determined by physicians' discretion and/or pts'preference. Endpoints included dose modification rates, failure-free survival (FFS), and event-free survival (EFS) at 2 years. Treatment failure was defined as loss of molecular response with 2 log reduction (MR2), transformation to accelerated or blast phase (AP/BP), or death. FFS was defined as the time from ASC initiation to treatment failure, while EFS included both failure and treatment discontinuation due to adverse events (AEs). Major molecular response (MMR; BCR::ABL1 <0.1%IS) at weeks 12 and 24 was also assessed. Achievement of MR2 (BCR::ABL1 <1%IS) and MR4 (BCR::ABL1 <0.01%IS) were also evaluated.

Results:

Fifty-one pts were included (median age 61 years; range 31–83; 45% female). One pt (2%) received ASC as second-line therapy; most received it as third line (69%), while 30% received it as fourth line or beyond. ASC was initiated due to intolerance (61%) or resistance (39%) to prior TKIs. At baseline, 31% had BCR::ABL1 >10% IS; all were in chronic phase.

Twenty-seven pts (53%) received ASC 40 mg BID and 24 (47%), 80 mg QD. Baseline characteristics were comparable between the 2 groups. Dose modifications occurred more frequently in the BID cohort (70% vs. 25%; p=0.001), with similar rates of dose reduction due to AEs (30% BID, 25% QD). Among those who required dose reduction, the majority in both groups were reduced to 40 mg once daily; additional strategies such as reductions to 20 mg QD or intermittent dosing (every other day or alternating doses) were also utilized (7 BID, 6 QD). Grade ≥3 AEs included thrombocytopenia (n=3), musculoskeletal pain (n=3), cardiac events (n=2) (QTc prolongation, premature ventricular contractions), and symptomatic pancreatitis (n=1).

Among pts who underwent dose escalation due to suboptimal response (n=6 (22%), all initially on 40 mg BID), 3 pts (5.9%) stopped ASC therapy due to lack of molecular response (2 from QD group, 1 from the BID group). One pt progressed to AP. An additional 5 BID pts who achieved MMR were switched to QD dosing per physician/pt preference. No escalations occurred in the QD group.

With a median follow-up duration of 729 days (range 112-2016), the 2-year FFS rate was 96% (95% CI [74–99%]) for BID and 91% [69–98%] for QD (HR 2.46; p=0.463). The 2-year EFS rate was 84% [62–94%] and 82% [58–93%], respectively (HR 1.27; p=0.73). At 24 weeks, MR2 rates were 84% [60–97%] for BID vs. 83% [52–98%] for QD (HR 0.77; p=0.44); MMR rates were 75% [48–89%] vs. 75% [43–95%] (HR 1.03; p=0.08); and MR4 rates were 83% [59–96%] vs. 46% [17–77%] (HR 0.53; p=0.147).

Conclusions:

In this real-world analysis, both ASC 40 mg BID and 80 mg QD demonstrated similar response rates and favorable AE profiles in CML-CP pts previously treated with ≥2 TKIs, with the limitation of a relatively small sample size. Overall efficacy was well maintained. The QD regimen was associated with fewer dose escalations and discontinuation rate, supporting its convenience and potentially advantageous dosing strategy in clinical practice.