Targeted therapy with an allosteric inhibitor of BCR::ABL1 at the ABL1 myristoyl pocket

A prospective study (NCT04971226) included 405 patients with newly diagnosed CML. Patients were randomly assigned to receive asciminib (n = 201) (an allosteric inhibitor of BCR::ABL1 at the ABL1 myristoyl pocket, a site unique from those used by other TKIs) or either imatinib mesylate (n = 102) or nilotinib, dasatinib, or bosutinib (n = 102).[14]

A prospective study (NCT04971226) included 405 patients with newly diagnosed CML. Patients were randomly assigned to receive asciminib (n = 201) (an allosteric inhibitor of BCR::ABL1 at the ABL1 myristoyl pocket, a site unique from those used by other TKIs) or either imatinib mesylate (n = 102) or nilotinib, dasatinib, or bosutinib (n = 102).[14]

With a median follow-up of 16.3 months, the 48-week MMR rate was 67.7% for patients who received asciminib and 49% for patients who received imatinib, nilotinib, dasatinib, or bosutinib (P < .002).[14][Level of evidence B3]

A prospective study (NCT04971226) included 405 patients with newly diagnosed CML. Patients were randomly assigned to receive asciminib (n = 201) (an allosteric inhibitor of BCR::ABL1 at the ABL1 myristoyl pocket, a site unique from those used by other TKIs) or either imatinib mesylate (n = 102) or nilotinib, dasatinib, or bosutinib (n = 102).[14]

Patients who received asciminib had fewer grade 3 or greater adverse events (38%) compared with imatinib (44%) and the other TKIs (55%). The rate of discontinuation due to adverse events was lower for patients who received asciminib (5%) compared with patients who received imatinib (11%) or the other TKIs (10%).

A prospective study (NCT04971226) included 405 patients with newly diagnosed CML. Patients were randomly assigned to receive asciminib (n = 201) (an allosteric inhibitor of BCR::ABL1 at the ABL1 myristoyl pocket, a site unique from those used by other TKIs) or either imatinib mesylate (n = 102) or nilotinib, dasatinib, or bosutinib (n = 102).[14]

Asciminib showed improved efficacy in this early reporting of the trial, and it also showed better tolerability based on adverse events and discontinuations. On this basis, the U.S. Food and Drug Administration approved the use of asciminib as first-line therapy. Use of asciminib will pose significant financial toxicity ($260,000 per year in 2024) versus imatinib ($500 per year in 2024). The price of the other TKIs may decrease because dasatinib is available as a generic, and nilotinib, bosutinib, and ponatinib are expected to be released as generics in 2027.

A prospective study (NCT04971226) included 405 patients with newly diagnosed CML. Patients were randomly assigned to receive asciminib (n = 201) (an allosteric inhibitor of BCR::ABL1 at the ABL1 myristoyl pocket, a site unique from those used by other TKIs) or either imatinib mesylate (n = 102) or nilotinib, dasatinib, or bosutinib (n = 102).[14]

A prespecified subgroup analysis compared asciminib with the second-generation TKIs (not including imatinib). At week 48, 66.0% of patients who received asciminib had an MMR, and 57.8% of patients who received second-generation TKIs had an MMR. The 8.2% difference was not statistically significant (95% confidence interval [CI], -5.1 to 21.5). In the first year, it appears that the efficacy of asciminib is equivalent to those of second-generation TKIs. Longer follow-up is required to fully assess efficacy and toxicity outcomes.[14]