Asciminib Active in Patients With Heavily Pretreated CML

Results from a phase 1 dose-escalation study confirm the activity of asciminib in patients with heavily pretreated chronic myeloid leukemia (CML) resistant to, or who experienced unacceptable toxicity with, tyrosine kinase inhibitors (TKIs; N Engl J Med. 2019;381[24]:2315-2326).

“Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant,” explained Timothy P. Hughes, MD, South Australian Health and Medical Research Institute and the University of Adelaide, et al, who aimed to assess the safety and antileukemic activity of asciminib in patients with Philadelphia chromosome (Ph)-positive CML.

The phase 1, dose-escalation study included 150 heavily pretreated patients with CML (chronic-phase, n = 141; accelerated-phase, n = 9) who were resistant to, or experienced unacceptable toxicity with, ≥2 prior TKIs. Patients received asciminib once or twice daily at doses of 10 mg to 200 mg.

The primary objective of the trial was to determine the maximum tolerated and/or recommended dose of asciminib.

Of the 150 patients enrolled in the trial, 105 (70%) had received ≥3 prior TKIs.

Among patients with chronic-phase CML, 34 (92%) with hematologic relapsed achieved a complete hematologic response and 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response.

Additionally, a major molecular response (MMR) was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 (57%) of 14 deemed to have resistance to or unacceptable side effects from ponatinib. MMR was achieved or maintained by 12 months in 5 (28%) patients with a T315I mutation at baseline.

Dr Hughes and colleagues noted that clinical responses were durable, and that MMR was maintained in 40 of 44 patients.

Dose-limiting toxicities included asymptomatic elevations in the lipase level and clinical pancreatitis. The most common adverse events were fatigue, headache, arthralgia, hypertension, and thrombocytopenia.

The maximum tolerated dose of asciminib was not reached.

“Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation,” Dr Hughes and colleagues concluded.—Janelle Bradley