Front-Line Asciminib for Chronic Myeloid Leukemia

First- and second-generation tyrosine kinase inhibitors (TKIs) targeting the BCR::ABL1 chimeric protein offer durable remission for many patients with chronic myeloid leukemia (CML), but resistance develops in the setting of ATP active-site mutations. Asciminib, a TKI that binds to the ABL myristoyl pocket, is approved for patients with CML that has failed to respond to two prior TKIs due to resistance or treatment intolerance. Investigators now report an industry-sponsored, randomized, phase 3 trial comparing asciminib (80 mg once daily) with investigator's choice of imatinib or a second-generation TKI (nilotinib, dasatinib, or bosutinib) in 405 adults with newly diagnosed chronic-phase CML.

The rate of major molecular response (BCR::ABL1 transcript levels ≤0.1%) at week 48 of treatment (the primary endpoint) was significantly improved with asciminib compared with imatinib (69.3% vs. 40.2%) and with asciminib compared with other TKIs (67.7% vs. 49.0%). Rates of treatment discontinuation due to inadequate therapeutic effect were lower for asciminib versus imatinib and second-generation TKIs (6.0% vs. 20.6% and 9.8%, respectively). The toxicity profile also was improved with asciminib. Fewer treatment-related adverse events led to treatment discontinuation with asciminib compared with imatinib and other TKIs (4.5% vs. 11.1% and 9.8%); dose reductions and interruptions occurred in 39.5%, 49.5%, and 63.7%, respectively.