Efficacy and safety of asciminib (ASC) in patients (pts) with chronic-phase chronic myeloid leukemia (CML-CP) after 1 tyrosine kinase inhibitor (TKI): Interim analysis (IA) of the phase 2 ASC2ESCALATE trial.

6516 Background: ASC2ESCALATE (NCT05384587) is the first prospective trial of ASC in CML-CP after 1 TKI (2L) with dose escalation for pts with suboptimal response; ASC is also being assessed in a separate newly diagnosed (1L) cohort. A previous IA of the 2L cohort reported ASC’s safety (n=71) and wk 24 efficacy (n=28; BCR::ABL1 IS ≤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 ASC in adults with 1L or 2L CML-CP without the T315I mutation. In the 2L cohort, eligible pts had discontinued their prior TKI due to warning or failure per ELN2020 or intolerance with BCR::ABL1 IS >0.1% at screening. Pts received ASC 80 mg once daily (QD). If BCR::ABL1 IS >1% at wk 24, dose was increased to 200 mg QD. If BCR::ABL1 IS >0.1% at wk 48, 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. If pts had any grade 3/4 or persistent grade 2 toxicity refractory to optimal management, they were ineligible for dose escalation at wk 24 and/or 48 and continued the same dose. Results: This IA included all 101 pts enrolled with 2L CML-CP; all pts had received ≥1 ASC dose by the cutoff (Nov 15, 2024). Prior treatment (Tx) included dasatinib (44.6%), imatinib (42.6%), nilotinib (9.9%), or bosutinib (5.0%); 66.3% of pts had received prior Tx for ≥12 mo. Pts discontinued prior Tx due to lack of efficacy (56.4%) or intolerance (43.6%). By the cutoff, 92 pts (91.1%) remained on ASC; 9 pts (8.9%) discontinued ASC, mostly due to adverse events (AEs; n=4) and pt decision (n=3). Median duration of ASC exposure was 26.1 (range, 6-100) wk. Pts evaluable for all efficacy analyses completed assessments for the respective timepoint or discontinued earlier (wk 4, n=94; wk 12, n=86; wk 24, n= 63). At wk 4, 12, and 24, 46.8%, 84.9%, and 82.5% pts, respectively, had BCR::ABL1 IS ≤1%. Deeper responses were also achieved at wk 12 (MMR, 39.5%; MR 4 , 11.6%; MR 4.5 , 2.3%) and 24 (MMR, 44.4%; MR 4 , 25.4%; MR 4.5 , 9.5%). Seven pts had dose escalation from 80 to 200 mg QD per their response level at wk 24 (n=3) and 48 (n=4). All-grade AEs ≥20% 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 in 4 pts; 1 of these AEs occurred >30 d after last ASC dose. No arterial-occlusive events or on-Tx deaths occurred. Conclusions: 2L ASC demonstrated high molecular response rates at wk 24 and safety consistent with previously established ASC data across Tx lines; no new or worsening safety signals arose. ASC was tolerable with few AEs leading to discontinuation. These IA results support ASC as a Tx option in 2L CML-CP. The impact of dose escalation continues to be explored. Clinical trial information: NCT05384587 .