Efficacy and Safety of Asciminib in Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Interim Results from the Phase 2 ASC2ESCALATE Trial in the Cohort of Patients (Pts) after 1 Prior Tyrosine Kinase Inhibitor (TKI)

Introduction:

Resistance/intolerance is common in pts with CML-CP who have received 1 prior TKI. Pts requiring treatment switch may have limited subsequent treatment options and experience worse survival outcomes with each successive TKI. Asciminib is a BCR::ABL1 inhibitor that, unlike ATP-competitive TKIs, inhibits kinase activity by binding to the ABL myristoyl pocket. Asciminib has previously demonstrated efficacy, safety, and tolerability in CML-CP after ≥2 prior TKIs and in the recently published positive phase 3 ASC4FIRST study in newly diagnosed CML-CP. ASC2ESCALATE (NCT05384587) is the first prospective clinical trial to assess asciminib in pts with CML-CP who have received 1 prior TKI with a dose-escalation strategy for pts not meeting certain treatment milestones. ASC2ESCALATE is also further studying asciminib in a separate cohort of newly diagnosed pts as frontline therapy. These preliminary results focus on the efficacy and safety of asciminib in the cohort of pts with CML-CP after 1 prior TKI in the ASC2ESCALATE trial.

Methods:

ASC2ESCALATE is a phase 2, single-arm, open-label study of asciminib with dose escalation in adults with CML-CP who are newly diagnosed (1L cohort) or have received 1 prior ATP-competitive TKI (2L cohort) in the US. Pts with T315I are excluded. In the 2L cohort, pts must have discontinued their prior TKI due to warning response (BCR::ABL1^IS >1%-10% after 6 mo or >0.1%-1% after 12 mo of 1L treatment), resistance (BCR::ABL1^IS >10% during 6-12 mo, or >1% or loss of major molecular response [MMR] after >12 mo of 1L treatment), or intolerance with BCR::ABL1^IS >0.1% at screening.

All pts started treatment with asciminib 80 mg once daily (QD). In pts with BCR::ABL1^IS >1% at wk 24, dose was increased to 200 mg QD. Pts with BCR::ABL1^IS >0.1% at wk 48 had their dose increased from 80 to 200 mg QD or from 200 mg QD to 200 mg twice daily, 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 asciminib was continued.

This trial aims to enroll 92 pts with CML-CP in the 2L setting and is currently recruiting.

Results:

This interim analysis included 43 pts with CML-CP in 2L who enrolled and received ≥1 dose of asciminib on or before the data cutoff (March 22, 2024). Pts had received prior treatment with imatinib (32.6%), dasatinib (48.8%), nilotinib (16.3%), or bosutinib (2.3%); 76.7% had received their prior TKI for ≥12 mo. Pts discontinued their prior TKI due to lack of efficacy (27 [62.8%]) or intolerance (16 [37.2%]). With a median duration of asciminib exposure of 11.4 (range, 0-66) wk at data cutoff, most pts (95.3%) remained on treatment; 2 (4.7%) pts had discontinued asciminib treatment, 1 due to adverse events (AEs) and 1 due to loss to follow-up.

At wk 4, 12, and 24, respectively, 36, 22, and 14 pts were evaluable for efficacy analyses, defined as having completed assessments for the respective timepoint or having discontinued earlier. BCR::ABL1^IS ≤1% was achieved in 17 (47.2%), 15 (68.2%), and 12 (85.7%) pts at wk 4, 12, and 24, respectively. Deeper responses were also achieved at wk 12 (MMR, 6 [27.3%]; MR⁴, 2 [9.1%]; MR^4.5, 1 [4.5%]) and wk 24 (MMR, 8 [57.1%]; MR⁴, 4 [28.6%]; MR^4.5, 1 [7.1%]). Two pts had dose escalation from 80 to 200 mg QD per protocol (1 at wk 24 and 1 at wk 48).

The safety profile of asciminib is consistent with the current established safety profile, with no new or worsening safety concerns. The most common (>15%) all-grade AEs were fatigue and hypertension (16.3% each). Grade ≥3 AEs occurred in 16.3% of pts; the only grade ≥3 AE occurring in >1 pt was hypertension (11.6%). Dose interruptions due to AEs occurred in 3 pts and included platelet count decreased (grade 3), tooth abscess (grade 2), and cough (grade 1) (n=1 each). AEs leading to discontinuation occurred in 1 (2.3%; grade 3 nausea) pt. No arterial-occlusive events or on-study deaths were reported.

Conclusions:

In this interim analysis of the first prospective trial of asciminib in 2L CML-CP, asciminib demonstrated high molecular response rates at wk 24, including BCR::ABL1^IS ≤1%, MMR, and early deep molecular responses (MR⁴ and MR^4.5), with consistent safety and tolerability. These promising results support asciminib as a potential treatment option in these pts. Updated data (data cutoff June 28, 2024) will be presented at the ASH 2024 Annual Meeting.