CML-413: Asciminib Provides Durable Responses and a Favorable Safety Profile in Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) with the T315I Mutation in a Phase 1 Study

Abstract

Context: While tyrosine kinase inhibitors (TKIs) are an effective therapy for patients with CML, the T315I ABL1 mutation confers resistance to all approved TKIs except ponatinib. Asciminib, a novel STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, may be an option for these patients. Objective: Evaluate efficacy and safety of asciminib in patients with T315I-mutated CML-CP/accelerated phase (AP). Patients: This study enrolled adult patients with CML-CP/AP previously treated with ≥2 TKIs without T315I and ≥1 TKI with T315I. This analysis focuses on patients with T315I who received asciminib 200 mg twice daily (BID) (data cutoff: April 2, 2020). Results: Of 52 patients with T315I who received asciminib 200 mg BID, 35 (67.3%) continued treatment at cutoff, while 17 (32.7%) discontinued. Thirty-one of 35 (88.6%) patients still on treatment received asciminib for >48 weeks; median duration of exposure was 68.4 weeks (range, 2–175) and median dose intensity was 399.0 mg/day (range, 188–400). Twenty-three of 49 (46.9%) evaluable patients not in major molecular response (MMR) at baseline achieved MMR, 21 of whom were still in MMR at cutoff; 13/49 (26.5%) and 10/49 (20.4%) achieved MR4 and MR4.5, respectively. Among patients achieving MMR, median time to MMR was 12.1 weeks (range, 4–84). The Kaplan-Meier–estimated rate of durable first MMR was 87% at 96 weeks and remained stable until week 144. MMR was achieved in 57.1% and 28.6% of ponatinib-naive and ponatinib-pretreated patients by week 24, respectively. Three of 26 patients who did not achieve MMR had additional mutations at baseline (E255K, E355G, F359I), and 6 patients acquired new mutations postbaseline (F359I [n=2], A337T/F359V, M351T, M244V, E453Q). Forty-five of 52 (86.5%) patients experienced treatment-related AEs, with grade ≥3 AEs reported in 17/52 (32.7%) patients and serious all-grade AEs in 12 (23.1%) patients. No on-treatment deaths were reported. AEs leading to discontinuation included disease progression, grade 2 thrombocytosis, grade 3 lipase elevation, and grade 4 pancytopenia (n=1 each). Twenty-nine patients experienced dose reductions and/or interruptions. Conclusions: Asciminib is a promising therapy for patients with T315I-mutated CML-CP/AP, demonstrating clinical efficacy and a favorable safety profile in these patients, including those with treatment failure on ponatinib.