Asciminib (ASC) in chronic myeloid leukemia in chronic Phase (CML-CP): Efficacy and safety results of the Phase 2 ASC2ESCALATE trial in the cohort of patients (pts) with 1 prior tyrosine kinase inhibitor (TKI)

Abstract Introduction ASC previously demonstrated efficacy, safety, and tolerability in newly diagnosed (1L) CML-CP and CML-CP after ≥2 prior TKIs. ASC indications were updated in the US to include accelerated approval for 1L CML-CP and full approval for previously treated CML-CP. ASC2ESCALATE (NCT05384587) is a US trial evaluating ASC in CML-CP after 1 prior TKI (2L). A previous interim analysis (IA) of the 2L cohort reported ASC's safety (n=101) and wk 24 efficacy (n=63). Here, we report updated IA safety (n=101) and wk 48 efficacy (n=72) results in the 2L CML-CP cohort in ASC2ESCALATE. Methods ASC2ESCALATE is a single-arm, open-label study of ASC in adults with 1L or 2L CML-CP without the T315I mutation that uses a dose-escalation strategy for pts not meeting response milestones. The 2L cohort–eligible pts discontinued prior treatment (Tx) due to warning or failure per ELN 2020 or intolerance with BCR::ABL1IS >0.1% at screening. All pts started Tx with ASC 80 mg once daily (QD). Pts with BCR::ABL1IS >1% at wk 24 had a dose increase to 200 mg QD. Pts with BCR::ABL1IS >0.1% at wk 48 had a dose increase from 80 to 200 mg QD or from 200 mg QD to 200 mg twice daily (BID) or could be taken off study. In pts with grade 3/4 or persistent grade 2 toxicity refractory to optimal management, dose escalation was not considered and the same ASC dose was continued. Results This IA included all 101 pts with 2L CML-CP. Prior TKIs included dasatinib (44.6%), imatinib (42.6%), nilotinib (9.9%), or bosutinib (5.0%). Pts received prior Tx for ≥12 mo (66.3%), ≥6 to <12 mo (16.8%), or <6 mo (16.8%) and discontinued due to lack of efficacy (56.4%; Tx failure [24.8%], warning response [31.7%]), or intolerance (43.6%). Baseline BCR::ABL1IS levels included >0.1% to 1% (39.6%), >1% to 10% (30.7%), and >10% (29.7%). By the cutoff (May 16, 2025), 85 pts (84.2%) remained on ASC; 16 pts (15.8%) discontinued Tx due to adverse events (AEs; n=8), pt decision (n=4), loss to follow-up (n=2), physician decision (n=1), and unsatisfactory therapeutic effect (n=1). Median duration of ASC exposure was 51.3 (range, 6-126) wk. Median dose was 80 (range, 40-197) mg/day; most pts (78.2%) received a relative dose of >90% to 100%. Dose escalation from 80 to 200 mg QD occurred in 16/101 pts (15.8%) per response level at wk 24 (n=4) and 48 (n=12); 2 of 4 pts with dose escalation to 200 mg QD at wk 24 escalated to 200 mg BID at wk 48. Pts evaluable for all efficacy analyses at wk 24 (n=98) and 48 (n=72) completed assessments for the respective time point or discontinued earlier. At wk 24 and 48, 84/98 (85.7%) and 56/72 (77.8%) pts, respectively, had BCR::ABL1IS ≤1%. Major molecular response (MMR) was achieved by 55/98 (56.1%) and 40/72 (55.6%) pts at wk 24 and 48, respectively; the MMR rate was numerically higher in those who discontinued prior Tx due to intolerance vs lack of efficacy at wk 24 (29/42 [69.0%] vs 26/56 [46.4%]) and 48 (18/31 [58.1%] vs 22/41 [53.7%]). Pts also achieved deep molecular responses at wk 24 and 48, including MR4(27/98 [27.6%] and 18/72 [25.0%]) and MR4.5 (11/98 [11.2%] and 8/72 [11.1%]). Most AEs were grade 1/2. Most common all-grade AEs (≥20%) were headache (26.7%) and nausea (25.7%). Grade ≥3 AEs (≥5%) were hypertension (9.9%), thrombocytopenia (6.9%), and neutropenia (6.9%). AEs led to dose adjustment/interruption in 36 pts (35.6%). Discontinuation due to AEs occurred in 8 pts (7.9%) including 7 on-Tx (thrombocytopenia [n=2], and dyspepsia, neutrophil count decreased, tremor, vomiting and nausea, and weight decreased [n=1 each]) and 1 >30 days after last ASC dose (platelet count decreased [n=1]). Arterial-occlusive events occurred in 2 pts (2.0%: grade 2 cerebral infarction [n=1], grade 1 troponin T increased [n=1]); none led to dose reduction or discontinuation and all resolved by cutoff. No on-Tx deaths occurred. New AEs occurring in pts after dose escalation were mostly grade 1/2. Conclusions InASC2ESCALATE, the first prospective trial of ASC in 2L, ASCcontinued to demonstrate high molecular response rates and a safety profile consistent with previously established ASC data with no new or worsening safety signals. ASC was well tolerated with few AEs leading to discontinuation. These IA results support ASC as a Tx option in 2L CML-CP. The impact of dose escalation in pts not meeting response milestones continues to be explored. All 101 pts will be evaluated for safety and efficacy in the primary wk 48 analysis, which will be presented at ASH2025.