CML-466 Asciminib Provides Durable Molecular Responses in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With the T315I Mutation: Updated Efficacy and Safety Data From a Phase I Trial

Context: In CML-CP, the BCR::ABL1 T315I mutation confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs), except ponatinib and olverembatinib. In a previous analysis of the phase I, dose-escalation trial X2101, asciminib—a BCR::ABL1 inhibitor that binds to the ABL myristoyl pocket—demonstrated efficacy and a favorable safety profile in heavily pretreated patients with T315I-mutated CML. We report updated efficacy and safety data in patients with CML-CP with the T315I mutation (data cutoff: January 6, 2021). Objective: Provide updated safety and efficacy data for patients with T315I-mutated CML-CP after added exposure. Design: Patients with T315I-mutated CML-CP and treated with ≥1 prior TKI were enrolled and received asciminib 200mg twice daily (BID). Results: 48 patients were included; 25 patients (52.1%) received ≥3 prior TKIs. At data cutoff, treatment was ongoing in 27 patients (56.3%). 45 of 48 patients were evaluable (BCR::ABL1^IS >0.1% at baseline) for major molecular response (MMR); 3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable patients, 19 (42.2%) achieved MMR by week 24 and 22 (48.9%) by week 96. Evaluable patients included 26 ponatinib-pretreated and 19 ponatinib-naive patients; 34.6% and 68.4%, respectively, achieved MMR by week 96. The probability of maintaining MMR for ≥96 weeks was 84% (95% CI, 68.1%-100.0%). 23 of 37 patients (62.2%) with BCR::ABL1^IS >1% at baseline achieved BCR::ABL1^IS ≤1% by week 96. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added exposure (median duration of exposure, 2.08 years; range, 0.04-4.13 years). The most common (≥10%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations) and thrombocytopenia (14.6%). Arterial occlusive events occurred in 4 patients (8.3%); none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation occurred in 5 patients (10.4%). Only 2 study deaths, both due to COVID-19, occurred in this patient population. Conclusions: After a median exposure of >2 years, asciminib monotherapy 200mg BID exhibited a sustained, favorable safety profile and clinical efficacy in patients with T315I-mutated CML-CP—a population with high unmet medical need. This updated analysis confirms asciminib as a treatment option for patients with T315I-mutated CML-CP, including those previously treated with ponatinib.