CML-121: Efficacy and Safety of Asciminib in Heavily Pretreated Patients with Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP) with Sensitivity to Tyrosine Kinase Inhibitors (TKIs)

Abstract

Context There is a need for new therapies that will improve molecular responses in patients with Ph+ CML lacking deep response to TKIs. Asciminib is a novel, specific BCR-ABL1 inhibitor that binds the myristoyl-binding pocket and is expected to result in improved safety/tolerability vs. available ATP-binding TKIs. Objective To evaluate the safety and efficacy of asciminib monotherapy in heavily pretreated patients with baseline BCR-ABL1IS ≤ 1%. Design A phase I, dose-escalation and -expansion study for asciminib monotherapy or combination therapies ( NCT02081378 ). Patients Eligible adults with Ph+ CML in CP or accelerated phase who were relapsed/refractory to or intolerant of ≥2 TKIs were enrolled. In the current analysis, patients in the monotherapy cohorts (any dose) with BCR-ABL1IS ≤ 1%, regardless of the reason for TKI discontinuation, without a T315I mutation at baseline were included. Results Of 48 patients with CML-CP in 9 dose cohorts; 42 (87.5%) are still on treatment and 36 (75.0%) achieved major molecular response (MMR) or better at the data cutoff (30 Aug 2019). The most common grade 3/4 AEs (>10%), regardless of study drug relationship, were lipase increase (27.1%) and hypertension (12.5%). Serious AEs, regardless of study drug relationship, occurred in 16/48 pts (33.3%), with myocardial infarction being the most common (n=2; 4.2%). Among patients without MMR, MR4, or MR4.5 at baseline, 18/24 (75.0%), 16/38 (42.1%), and 18/42 (42.9%) achieved MMR, MR4, and MR4.5, respectively. All 18 patients who achieved MMR maintained MMR or better for ≥2 y, except 3 whose BCR-ABL1IS fluctuated around 0.1% but who were still in MMR at ≈ 60 mo. Among the 6 patients who did not achieve MMR by the cutoff date, 1 had BCR-ABL1IS > 1%, and 5 remained between BCR-ABL1IS 0.1% and 1%. Among patients who achieved MR4 or MR4.5, 9/16 (56.3%) and 10/18 (55.6%), respectively, maintained the response for ≥2 y. Conclusion Asciminib monotherapy was well tolerated and efficacious in patients with baseline BCR-ABL1IS ≤ 1%. Asciminib should be further investigated in patients lacking optimal outcomes and in those that have discontinued TKIs. Study sponsored by Novartis Pharmaceuticals Corporation. This abstract was accepted and previously published at the 25th EHA Annual Congress.