Asciminib Provides Long-Term, Durable Molecular Responses in Patients with T315I-Mutated CML-CP: Final Analysis from a Phase 1 Trial

Background: T315I-mutated CML-CP is resistant to ATP-competitive tyrosine kinase inhibitors (TKIs), except ponatinib, which may be associated with safety concerns. A follow-up analysis of a phase 1 trial (NCT02081378) previously demonstrated durable efficacy and favorable safety of asciminib, the first BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP), in patients with T315I-mutated CML-CP after ≥1 prior TKI. We provide final safety and efficacy data for patients with T315I-mutated CML-CP treated with asciminib monotherapy. Methods: This analysis includespatients with T315I-mutated CML-CP after ≥1 prior TKI who received asciminib 200 mg twice daily (BID). Patients were enrolled between 2014 and 2020 (data cutoff: March 14, 2023). Results: Forty-eight patients with T315I were included; 2 patients (4.2%) had additional baseline BCR::ABL1 mutations; 37 patients were male (median age 56.5 (range, 26-86) years. Forty patients (83.3%) had received ≥2 prior TKIs. At end of study, 25 patients (52.1%) continued asciminib therapy. Twenty-three patients discontinued treatment early, primarily due to lack of efficacy (11 [22.9%]) and adverse events (AEs; 4 [8.3%]). Forty-five of 48 patients were evaluable for molecular response analysis; 3 were excluded for BCR::ABL1 atypical/e1a2/e1a3/unknown transcripts. No patients had major molecular response (MMR) at baseline. Nineteen of 45 evaluable patients (42.2%) achieved MMR of 53.3% by week 24, with rates increasing until week 264; 20 of 24 maintained or improved this response by the cutoff. Evaluable patients included 26 ponatinib-pretreated and 19 ponatinib-naive patients; 38.5% and 73.7%, respectively, achieved MMR by the data cutoff. The probability of maintaining MMR for ≥144 weeks was 86.0% (95% CI, 71.9-100.0). Of 45 evaluable patients, 31 (68.9%) achieved/maintained BCR::ABL1IS ≤1% and 14 (31.1%) and 12 (26.7%) achieved MR4 and MR4.5, respectively, by the data cutoff. Median duration of exposure was 3.5 (range, 0.04-6.0) years; most patients (27 [56.3%]) received treatment for ≥2.8 years. The safety/tolerability profile of asciminib remained favorable after 1.4 years' added exposure. Rates of any-grade (100.0%) and grade ≥3 (60.4%) AEs were consistent with rates at the January 6, 2021, cutoff. Most frequent (≥10%) grade ≥3 AEs included increased lipase (20.8%) and thrombocytopenia (14.6%). Two new patients had AEs leading to dose adjustment/interruption. No new AEs leading to discontinuation occurred. Two additional patients, both with baseline cardiovascular risk factors, experienced arterial occlusive events (AOEs; 6 [12.5%]). One experienced acute coronary syndrome and received continued access to asciminib; the other experienced cerebrovascular accident and myocardial infarction after discontinuation, while receiving continued access to asciminib, and died. This was the only study death reported in this patient population since the January 2021 cutoff. Conclusions: Asciminib 200 mg BID exhibited clinical efficacy and sustained tolerability in patients with T315I-mutated CML-CP, a population with limited treatment options. After up to ≈6 years' exposure, no new safety signals emerged, and efficacy was sustained with durable MMR achieved in 53% of patients. Asciminib remains an excellent treatment option for patients with T315I-mutated CML-CP, including those with prior ponatinib treatment.