In a phase I trial reported in The New England Journal of Medicine, Hughes et al found that asciminib, an oral BCR-ABL1 inhibitor with a mechanism of action different from available ABL1 tyrosine kinase inhibitors, was active in patients with chronic myeloid leukemia (CML) after failure of ABL kinase inhibitor treatment.
“Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from tyrosine kinase inhibitors, including patients in whom ponatinib had failed and those with a T315I mutation.”— Hughes et al
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As written by the investigators, asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, "locking" BCR-ABL1 into an inactive conformation via a mechanism other than binding to the kinase ATP-binding site (the mechanism for other available tyrosine kinase inhibitors). Through allosteric binding of the myristoyl site, asciminib restores inhibition of kinase activity. The agent targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant.
Study Details
In the phase I dose-escalation and expansion phase study, 141 patients with chronic-phase CML and 9 with accelerated-phase CML with resistance to or unacceptable side effects during treatment with least two prior ATP-competitive kinase inhibitors were enrolled between May 2014 and September 2017. Patients received asciminib once or twice daily at doses of 10 to 200 mg. Overall, 70% of 150 patients had received at least three tyrosine kinase inhibitors and 31% had at least one BCR-ABL1 kinase domain mutation, with the most frequent being T315I (22%).
Key Findings
Median follow-up was 14 months. The maximum tolerated dose of asciminib was not reached. In patients treated on a twice-daily schedule, dose-limiting toxicities consisted of:
- Grade 3 elevated lipase in two patients at a dose of 40 mg
- Grade 2 myalgia/arthralgia in one patient at 80 mg
- Grade 3 acute coronary syndrome in one patient at 150 mg
- Grade 3 bronchospasm in one patient at 200 mg.
Among patients treated on a once-daily schedule of 200 mg, dose-limiting toxicities consisted of:
- Grade 3 elevation in lipase with clinical pancreatitis
- Grade 3 asymptomatic elevation in lipase
- Grade 3 abdominal pain of undetermined cause.
Among patients with chronic-phase CML, 34 of 37 (92%) with hematologic relapse had a complete hematologic response and 31 of 57 (54%) without complete cytogenetic response at baseline had a complete cytogenetic response.
Major molecular response was achieved or maintained by 12 months in 44 of 91 (48%) evaluable patients, including 8 of 14 (57%) with resistance to or unacceptable side effects from ponatinib. Major molecular response was achieved or maintained by 12 months in 28% of patients with a T315I mutation at baseline.
Among 44 patients with who achieved or maintained major molecular response, all except 4 continued to receive treatment at time of analysis. Median time to major molecular response was 20 weeks and median duration of response was longer than 61 weeks. Among the four patients who lost major molecular response, response was lost between week 28 and 100 of treatment.
Common adverse events of any grade included fatigue (29%), headache (28%), increased lipase (27%), arthralgia (24%), nausea (24%), rash (23%), thrombocytopenia (22%), and hypertension (19%). The most common grade 3 or 4 adverse events included increased lipase (10%), thrombocytopenia (9%), and hypertension (9%).
The investigators concluded: “Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from tyrosine kinase inhibitors, including patients in whom ponatinib had failed and those with a T315I mutation.”
Disclosure: The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit nejm.org.
