In a phase I trial, the combination of the BCR-ABL1 inhibitor asciminib and the small-molecule kinase inhibitor imatinib showed preliminary efficacy, safety, and tolerability in patients with chronic myeloid leukemia (CML) resistant to or intolerant of treatment with two or more prior tyrosine kinase inhibitors. These data were presented by Talpaz et al at the 2019 Society of Hematologic Oncology (SOHO) Annual Meeting and published in Clinical Lymphoma, Myeloma & Leukemia.
A total of 25 patients with chronic phase CML were enrolled in the trial; 15 of the 25 had been treated with more than two prior tyrosine kinase inhibitors and 17 of the 25 had previously been treated with imatinib. Asciminib was administered in continuous 28-day cycles at 40 mg (n = 9), 60 mg (n = 6), or 80 mg (n = 4) once a day or 40 mg twice a day (n = 6) plus imatinib at 400 mg once a day (n = 6).
At data cutoff, treatment was ongoing in 17 patients. Four patients had discontinued treatment due to patient/physician decision, three had discontinued treatment due to adverse events, and one had discontinued treatment due to disease progression. The median treatment exposure was 54.6 weeks.
Among patients with BCR-ABL1 > 1% at baseline, 9 of 15 patients achieved < 1% by 48 weeks. Of evaluable patients without baseline major molecular remission (BCR-ABL1 ≤ 0.1%), 8 of 19 patients achieved major molecular remission and 3 of 20 achieved molecular remission (BCR-ABL1 ≤ 0.0032%) by 48 weeks. No loss of major molecular remission occurred among patients with major molecular remission at baseline.
Asciminib given at doses of 40 mg and 60 mg once daily plus imatinib provided exposure comparable to asciminib alone given at 40 mg twice daily.
“Asciminib/imatinib demonstrated promising preliminary efficacy with good safety/tolerability in [patients with] CML resistant [to or] intolerant of ≥ 2 prior tyrosine kinase inhibitors.”— Talpaz et al
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A total of 22 patients (88%) reported any-grade drug-related adverse events, with the most commonly reported events being nausea (32%), increased lipase (20%), abdominal pain (16%), peripheral edema (16%), and vomiting (16%).
Dose-limiting toxicities by asciminib dose included decreased neutrophil count in one patient given a 40-mg dose once daily; abdominal pain in one patient given a 60-mg dose once daily; nausea in one patient given a 60-mg dose once daily; pancreatitis in one patient given an 80-mg dose once daily; increased lipase in one patient given an 80-mg dose once daily; and pancreatitis in one patient given a 40-mg dose twice daily.
There were no drug-related cardiovascular events or on-treatment deaths reported.
The authors concluded, “Asciminib/imatinib demonstrated promising preliminary efficacy with good safety/tolerability in [patients with] CML resistant [to or] intolerant of ≥ two prior tyrosine kinase inhibitors. Asciminib/imatinib is being investigated in a phase II trial in patients without deep molecular response on imatinib.”
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