Results from a phase I, dose-escalation study show that asciminib is active in heavily pretreated patients with chronic myeloid leukaemia (CML) who had resistance to or unacceptable side effects from tyrosine kinase inhibitors (TKIs), including patients in whom ponatinib had failed and those with a T315I mutation. The findings are published on 12 December 2019 in The New England Journal of Medicine.
Failure of TKI therapy in patients with Philadelphia chromosome (Ph)–positive CML may result from resistance to or unacceptable side effects from the drug or both. Currently approved TKIs mainly target the ATP-binding site of BCR-ABL1, and approximately half of clinical resistance is associated with the acquisition of mutations in this region of the kinase, resulting in conformational changes that render TKIs inactive.
The “gatekeeper” T315I mutation, reported in approximately 20% of patients with mutations, is associated with resistance to all clinically available TKIs except ponatinib. Unacceptable side effects from TKIs also occur in approximately 25% of patients.
Asciminib is a potent, specific, orally bioavailable BCR-ABL1 inhibitor that is distinct from approved ABL1 kinase inhibitors in that it does not bind to the ATP-binding site of the kinase. In contrast, asciminib acts as an allosteric inhibitor. It has high selectivity for only ABL1 and, hypothetically, ABL2 kinases, with low-nanomolar–range activity against unmutated BCR-ABL1 and all clinically observed ATP-site mutants, including T315I, the authors wrote in the study background.
A goal of this phase I study was to determine the safety, maximum tolerated dose or recommended dose, pharmacokinetics, and activity of asciminib in patients with Ph-positive leukaemia after failure of multiple approved TKIs.
The study team enrolled 141 patients with chronic-phase and 9 with accelerated-phase CML who had resistance to or unacceptable side effects from at least two previous ATP-competitive TKIs. Asciminib was administered once or twice daily at doses of 10 to 200 mg. The median follow-up was 14 months.
Patients were heavily pretreated, 70% had received at least three TKIs.
The maximum tolerated dose of asciminib was not reached.
Among patients with chronic-phase CML, 34 (92%) with a haematologic relapse had a complete haematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients.
Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.
The authors concluded that asciminib monotherapy showed durable clinical activity in most patients with chronic-phase CML. Low-grade, reversible toxic effects occurred in a minority of patients.
The study was designed collaboratively by the sponsor, Novartis Pharmaceuticals and study investigators.
Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med 2019; 381(24):2315-2326. DOI: 10.1056/NEJMoa1902328