High rates of deep molecular response (DMR) in patients (pts) with chronic myeloid leukemia in chronic Phase (CML-CP) who have not achieved dmr after ≥1 year of prior imatinib (IMA) in the asciminib (ASC) monotherapy arm of the Phase 2 ASC4MORE study

Abstract

Abstract Introduction As treatment (tx) for CML is often lifelong, goals include good quality of life (QOL) and tx-free remission (TFR). Among pts receiving frontline (1L) IMA, only 31% to 37% achieve MR4.5 by 5 years and TFR eligibility is 11% and 30% by 5 and 10 years, respectively. Thus, there is a need for efficacious, safe and tolerable tx options. ASC is the first BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP). In the phase 2 ASC2ESCALATE study (NCT05384587), second-line ASC demonstrated high molecular response rates and a favorable safety profile, consistent with established ASC data across tx lines. The ASC4MORE study (NCT03578367) initially compared ASC 40 or 60 mg once daily (QD) add-on to IMA 400 mg QD vs continued IMA 400 mg QD vs switch to nilotinib (NIL) 300 mg twice daily in pts with CML-CP not achieving MR4 with ≥1 year of 1L IMA. Primary results at wk 48 showed more pts in ASC 40- and 60-mg QD add-on arms (19.0% and 28.6%, respectively) achieved MR4.5 than with continued IMA (0.0%) or switch to NIL (4.8%). An ASC monotherapy arm was added to assess if the combination of ASC and IMA was necessary to improve DMR rates, or if similar responses could be achieved with ASC alone. We report wk 48 results in pts who switched to ASC monotherapy after not achieving MR4 after ≥1 year of IMA. Methods Pts (aged ≥18 years) with CML-CP who received 1L IMA ≥300 mg QD for ≥1 year with baseline BCR::ABL1IS >.01% to ≤1%, with no previous MR4confirmed by 2 consecutive tests and no history of tx failure per ELN 2013 criteria, received ASC monotherapy at 80 mg QD. The primary endpoint was achievement of MR4.5 at wk 48. A secondary endpoint was achievement of MR4.5 by wk 48. Exploratory endpoints assessed changes from baseline (BL) in EORTC QLQ-C30 scores/individual scales, including improvement (increase of >5 in functional scales and global health status/QOL or decrease of >5 in symptom/item scores) and no change (increase or decrease of ≤5). Results A total of 20 pts were enrolled. Median (range) age was 52.0 (39.0-80.0) years, and 60.0% of pts were male. At BL, all 20 pts had BCR::ABL1IS ≤1%; 12 had major molecular response. By cutoff (Feb 26, 2025), 19 pts (95.0%) completed tx; 1 discontinued due to a serious adverse event (SAE) of grade ≥3 edematous pancreatitis (onset at day 226, ongoing at data cutoff) and had BCR::ABL1IS >.01% to ≤.1% at discontinuation. At wk 48, 7 pts (35.0%; 90% CI, 17.7%-55.8%) were in MR4.5. By wk 48, 8 pts (40.0%; 90% CI, 21.7%-60.6%) achieved MR4.5. In pts who achieved MR4.5, the median (range) time to MR4.5 was 24.3 (8-61) wk. Median (range) duration of ASC exposure was 88.2 (33-107) wk. Any-grade AEs occurred in 18 pts (90.0%); 8 (40.0%) had grade ≥3 AEs. Any-grade AEs leading to tx discontinuation, dose adjustment/interruption, and additional therapy occurred in 1 (5.0%), 5 (25.0%), and 16 (80.0%) pts, respectively. Two pts (10.0%) had SAEs (urinary tract infection and edematous pancreatitis [n=1, each]). The most frequent (≥20%) any-grade AEs were arthralgia (30.0%), upper abdominal pain (25.0%), increased lipase (25.0%), and rash (20.0%). Grade ≥3 AEs (≥10%) were increased lipase (15.0%) and hypertension (10.0%). No arterial occlusive events were reported. Per EORTC QLQ-C30 at wk 48 vs BL, the following pt proportions (of an evaluable n=16) had improved or unchanged scores, respectively: functional scales (physical [18.8%, 50.0%], role [18.8%, 62.5%], cognitive [18.8%, 50.0%], social [18.8%, 62.5%], and emotional [18.8%, 43.8%]), symptom/item scores (fatigue [43.8%, 25.0%], nausea/vomiting [18.8%, 68.8%], diarrhea [12.5%, 75.0%], pain [6.3%, 75.0%], dyspnea [6.3%, 62.5%], insomnia [12.5%, 68.8%], appetite loss [6.3%, 68.8%], constipation [0%, 87.5%], and financial difficulties [0%, 87.5%]), and global health status/QOL (43.8%, 31.3%). Conclusions In ASC4MORE, 19/20 pts remained on ASC 80 mg QD at cutoff, highlighting the benefit of early tx switching. Rates of MR4.5 at wk 48 were numerically higher in the nonrandomized ASC monotherapy arm (35.0%) vs with ASC add-on to IMA (19.0% and 28.6%), continued IMA (0.0%), or switch to NIL (4.8%), suggesting ASC 80 mg QD alone may be sufficient to provide DMR. No new or worsening safety signals were observed compared with prior ASC studies and overall QOL improved or remained stable in most pts. Results support early switching to ASC as an effective strategy to achieve DMR while maintaining favorable safety/tolerability and QOL.