Asciminib (ASC) in chronic myeloid leukemia in chronic Phase (CML-CP): Interim analysis (IA) efficacy and safety results of the Phase 2 ASC2ESCALATE trial in the cohort of newly diagnosed (1L) patients (pts)

Abstract

Abstract Introduction ASC, a BCR::ABL1 inhibitor that inhibits kinase activity by specifically targeting the ABL myristoyl pocket, has previously demonstrated efficacy, safety, and tolerability in 1L CML-CP and CML-CP after ≥1 tyrosine kinase inhibitor (TKI). ASC showed consistent safety across a wide dose range of 10-200 mg twice daily (BID) in CML-CP after ≥1 TKI. The ASC2ESCALATE (NCT05384587) trial evaluates ASC in 1L CML-CP and CML-CP after 1 prior TKI (2L). A dose-escalation strategy is being assessed for pts not meeting ELN2020 optimal response milestones at 6 and 12 mo. We report the first IA of ASC efficacy and safety in the cohort of pts with 1L CML-CP in the ASC2ESCALATE trial. Methods ASC2ESCALATE is a phase 2, single-arm, open-label trial of ASC with dose escalation in adults with 1L or 2L CML-CP without the T315I mutation in the US. All pts started treatment (Tx) with ASC 80 mg once daily (QD). Pts with BCR::ABL1IS >1% at wk 24 had their dose increased to 200 mg QD. Pts with BCR::ABL1IS >0.1% at wk 48 had their dose increased from 80 to 200 mg QD or from 200 mg QD to 200 mg 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 dose of ASC was continued. The primary endpoint is major molecular response (MMR) at wk 48 in the 2L cohort; this endpoint will be repeated in the 1L cohort as a secondary endpoint. Results This IA included all 95 pts with 1L CML-CP (cutoff: May 16, 2025; median follow-up: 11.0 [range 1.2-19.4] mo). Most pts were White (78.9%), male (64.2%), and <65 years old (76.8%). Baseline ECOG scores included 0 (63.2%), 1 (34.7%), and 2 (2.1%). Median age was 51 (range 21-90) years. The median time since initial diagnosis was 5.4 (2-38) wk. By the cutoff, 70 pts (73.7%) remained on ASC. Twenty-five pts (26.3%) discontinued ASC (16 before wk 48 and 9 between wk 48 and 96; 10 due to adverse events [AEs], 9 due to unsatisfactory therapeutic effect, 3 due to pt decision, 2 due to physician decision, and 1 due to death). The median duration of ASC exposure was 50.4 (range, 1-94) wk. Pts received a median ASC dose of 80 (range, 44-232) mg QD; most pts (78.9%) received a relative dose of >90% to 100%. Dose escalation from 80 to 200 mg QD occurred in a total of 16/95 pts (16.8%) due to suboptimal response at wk 24 (n=8) or 48 (n=8); 3 of 8 pts with dose escalation from 80 to 200 mg QD at wk 24 escalated to 200 mg BID at wk 48. Pts evaluable for all efficacy analyses at wk 12 (n=91), 24 (n=93), and 48 (n=75) completed assessments for the respective time point or discontinued earlier; 1 pt with undetectable BCR::ABL1 at baseline was excluded. At wk 12, 83 of 91 pts (91.2%) had BCR::ABL1IS ≤10%. At wk 24 and 48, 73 of 93 (78.5%) and 54 of 75 (72.0%), respectively, had BCR::ABL1IS ≤1%; 51 of 93 (54.8%) and 40 of 75 (53.3%), respectively, had MMR. Pts also had deep molecular responses at wk 48, including MR4 (18/75 [24.0%]) and MR4.5 (9/75 [12.0%]). The most common all-grade AEs (≥20%) were fatigue (35.8%), nausea (30.5%), diarrhea (25.3%), headache (24.2%), thrombocytopenia (22.1%), and hypertension (21.1%). Grade ≥3 AEs (≥5%) were hypertension (13.7%), thrombocytopenia (7.4%), and neutropenia (6.3%). AEs led to dose adjustment/interruption in 38 pts (40.0%). AEs led to discontinuation in 11 pts (11.6%); 1 of these 11 pts died due to multiple organ dysfunction syndrome; this was the only on-Tx death reported and was unrelated to ASC per the investigator. Arterial-occlusive events (AOEs) occurred in 4 pts (4.2%); ASC was discontinued due to grade 3 cerebrovascular accident in 2 pts; ASC was continued for 1 pt with grade 3 angina pectoris and 1 pt with grade 2 transient blindness. All AOEs resolved by the cutoff. ASC was discontinued in 1 pt with grade 3 acute pancreatitis which resolved by the cutoff. New AEs occurring in pts after dose escalation were mostly grade 1/2. Conclusions 1L ASC demonstrated early and deep molecular responses with safety profile consistent with previous ASC data; no new or worsening safety signals were observed. After ≈1 year of median exposure, ASC was well tolerated with few AEs leading to discontinuation. These IA results support ASC as a standard-of-care Tx option in 1L CML-CP. The impact of dose escalation in pts not meeting response milestones continues to be explored. The trial is ongoing with results including additional pts and extended follow-up to be reported in the future.