Asciminib, a Specific Allosteric BCR-ABL1 Inhibitor, in Patients with Chronic Myeloid Leukemia Carrying the T315I Mutation in a Phase 1 Trial

All tyrosine kinase inhibitors (TKIs) approved to treat chronic myeloid leukemia (CML) inhibit BCR-ABL1 by targeting the ATP-binding site. Some patients (pts) develop mutations (muts) conferring resistance to these TKIs. The T315I mut confers resistance to all TKIs except ponatinib (PON), which is known to be efficacious. However, pts with cardiovascular (CV) risk factors might not be eligible for PON, and pts failing PON have no other targeted therapies available; thus, new treatments are needed for pts with the T315I mut. Asciminib is a new, potent, and specific TKI targeting the BCR-ABL1 myristoyl-binding site, an allosteric regulatory domain, and has potential to treat pts carrying muts conferring resistance to ATP-binding-site TKIs, including T315I. Preclinical in vitro data showed asciminib activity in BaF3 cells expressing the BCR-ABL1 construct and various muts, including T315I; an approximately 4- to 5-fold increase in exposure was required to inhibit the T315I mut relative to other muts (Wylie et al. Nature. 2017;543:733-737; Wylie et al. Blood. 2014;124 [abstract 398]).

This phase 1 study (NCT02081378) enrolled pts ≥ 18 y old with CML in chronic phase (CP) or accelerated phase resistant to or intolerant of (R/I) ≥ 2 prior TKIs; pts carrying the T315I mut were eligible after ≥ 1 prior TKI. Pts with uncontrolled CV conditions were excluded. Previous results showed single-agent asciminib was well tolerated and demonstrated activity in pts with CML (Hughes et al. Blood. 2016;128 [abstract 625]). A dose of 40 mg twice daily (BID) was recommended for pts with CML-CP without the T315I mut. Enrolled pts carrying the T315I mut were assigned to asciminib 20 mg BID (1 pt), 40 mg BID (1 pt), 80 mg BID (4 pts), 150 mg BID (7 pts), 160 mg BID (7 pts), 200 mg BID (24 pts), 80 mg once daily (QD; 1 pt), 120 mg QD (4 pts), or 200 mg QD (1 pt) cohorts. We report results from the largest cohort: pts with confirmed T315I mut at screening (tested locally by Sanger sequencing) and treated with asciminib 200 mg BID, which showed the most robust efficacy (data cutoff: April 30, 2018).

At the data cutoff, treatment was ongoing in 23/24 pts (95.8%) (Table); 1 pt (4.2%) had ended treatment. Median duration of follow-up and asciminib exposure were both 28.5 wk (range, 0.1-74.7 wk). Most pts had received multiple prior TKIs, and PON was the most recent TKI for 12/24 (50.0%). Pts who were PON naive had underlying conditions, such as CV risk factors. Eight of 24 pts achieved MMR by 24 wk; 1 achieved MMR after 24 wk. Ten of 24 pts had BCR-ABL1 < 10% on the International Scale (IS) at screening and ≥ 1 postbaseline evaluation; 6/10 (60%) achieved a ≥ 1-log reduction in BCR-ABL1^IS by 24 wk. Among PON-naive and PON-R/I pts, 5/11 and 3/13, respectively, achieved MMR by 24 wk (Figure). One PON-R/I pt with isolated T315I at screening lost MMR 3 mo after achieving it (prior TKIs: imatinib, dasatinib, and PON). Analysis of 200 mg BID pharmacokinetic data is planned.

A total of 20/24 pts (83.3%) experienced any-grade AEs (grade 3/4, 8/24 [33.3%]); the most frequent any-grade AEs were arthralgia, fatigue, lipase increased, and nausea (4/24 [16.7%] each). Any-grade AEs suspected to be study drug related were reported in 15/24 pts (62.5%; grade 3/4, 3/24 [12.5%]) and most frequently included arthralgia and nausea (3/24 [12.5%] each). One pt experienced a serious AE of grade 3 peripheral arterial occlusive disease requiring angioplasty, not considered study drug related, after 17 mo of treatment. This pt was previously treated with imatinib (33 mo), dasatinib (10 mo), bosutinib (5 mo), and PON (17 mo), started asciminib 3 d after stopping PON, had history of hypertension and stroke (on PON), and was on clopidogrel; the pt had asciminib dose reductions to 160 mg BID at 1.5 mo and 120 mg BID at 4 mo due to AEs but remained on asciminib. No deaths were reported.

Overall, asciminib 200 mg BID monotherapy showed a favorable safety profile and clinical efficacy in PON-naive and PON-R/I pts carrying the T315I mut. This cohort will be expanded to enroll additional pts carrying the T315I mut. Asciminib may represent a new option for pts with CML and the T315I mut who are not eligible for PON or have failed PON treatment.

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