INTERIM ANALYSIS (IA) RESULTS FROM ASC2ESCALATE SUPPORT ASCIMINIB (ASC) AS A TREATMENT (TX) OPTION IN CHRONIC-PHASE CHRONIC MYELOID LEUKEMIA (CML-CP) AFTER 1 TYROSINE KINASE INHIBITOR (TKI)

Ehab Atallah et al.
Medical College of Wisconsin, Division of Hematology & Oncology, Milwaukee, United States of America

Background
  • Within 1 year of tx, ≤30% of patients with CML-CP on a second TKI (2L) require tx switch, leading to worse outcomes and limited subsequent tx options. Initially approved for CML-CP after ≥2 TKIs (3L+), ASC was recently approved in the US for newly diagnosed (1L) and previously treated (2L+) CML-CP. ASC2ESCALATE (NCT05384587) is a trial of 1L and 2L ASC in CML-CP with dose escalation for pts with suboptimal response.
  • A previous IA of the 2L cohort reported ASC's safety (n=71) and wk 24 efficacy (n=28; BCR::ABL1IS ≤1%, 85.7%; major molecular response [MMR], 42.9%). We report updated safety (n=101) and wk 24 efficacy (n=63) results.
Methods
  • ASC2ESCALATE is a phase 2, single-arm, open-label US study of 1L and 2L ASC in adults with CML-CP without the T315I mutation. 2L cohort-eligible pts had discontinued prior tx due to warning or failure per ELN 2020 or intolerance with BCR::ABL1IS >0.1% at screening.
  • Pts received ASC 80 mg once daily (QD). At wk 24, dose was increased to 200 mg QD if BCR::ABL1IS >1%. At wk 48, if BCR::ABL1IS >0.1%, dose was increased from 80 to 200 mg QD or from 200 mg QD to 200 mg twice daily, or pts could be taken off study.
  • At wk 24 and/or 48, pts were ineligible for dose escalation and continued the same dose if they had any grade 3/4 or persistent grade 2 toxicity refractory to optimal management.
Results
  • This IA included all 101 pts with CML-CP in 2L (cutoff: Nov 15, 2024). Pts had received prior dasatinib (44.6%), imatinib (42.6%), nilotinib (9.9%), or bosutinib (5.0%) for ≥12 mo (66.3%), ≥6 to <12 mo (15.8%), or <6 mo (17.8%). Pts discontinued prior tx due to lack of efficacy (56.4%) or intolerance (43.6%). Baseline BCR::ABL1IS levels included >0.1% to 1% (39.6%), >1% to 10% (30.7%), and >10% (29.7%; Figure).
  • By the cutoff, 92 pts (91.1%) remained on ASC; 9 pts (8.9%) discontinued ASC due to adverse events (AEs; n=4), pt decision (n=3), or physician decision (n=1) or were lost to follow-up (n=1). Median duration of ASC exposure was 26.1 (range, 6-100) wk.
  • Pts evaluable for all efficacy analyses completed assessments for the respective time point or discontinued earlier (wk 24, n= 63). At wk 24, 82.5% of pts had BCR::ABL1IS ≤1% (Figure). MMR was achieved at wk 24 in 44.4% of pts and was higher in those who discontinued prior tx due to intolerance (57.7%) vs lack of efficacy (35.1%). Deeper responses were also achieved at wk 24, including MR4 (25.4%) and MR4.5 (9.5%). Dose escalation from 80 to 200 mg QD occurred in 7 pts per response level at wk 24 (n=3) and 48 (n=4).
  • Most AEs were grade 1/2 (Figure). Most common all-grade AEs were headache (22.8%) and nausea (20.8%). Grade ≥3 AEs (≥5%) were hypertension (8.9 %), thrombocytopenia (6.9%), and neutropenia (5.9%). AEs led to dose adjustment/interruption in 27 pts (26.7%). AEs led to discontinuation (all before wk 24) in 4 pts; 1 of these AEs occurred >30 d after last ASC dose, and of 3 pts with on-tx events, AEs included grade 3 nausea and vomiting, grade 2 dyspepsia, and grade 2 tremors (n=1 each). No arterial-occlusive events or on-tx deaths occurred.
Conclusion
  • In the first prospective trial of 2L ASC in CML-CP, ASC provided high wk 24 molecular response rates and safety and tolerability consistent with previously established 1L and 3L+ ASC data.
  • No new or worsening safety signals arose, and AEs led to discontinuation in <5% of pts. These IA results support ASC as a 2L tx option in CML-CP. The impact of dose escalation continues to be explored.