Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results

Abstract

Asciminib is approved for patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10-200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.

Fig. 1. Patient disposition as of the data cutoff (January 6, 2021) and history of prior TKIs.

A Disposition of patients with CML-CP without BCR::ABL1 T315I mutations who received asciminib monotherapy. B History of prior TKIs. AE adverse event, CML chronic myeloid leukemia, CP chronic phase, IS International Scale, MMR major molecular response (BCR::ABL1 ≤ 0.1% on the IS), MR⁴ BCR::ABL1^IS ≤ 0.01%, MR^4.5 BCR::ABL1^IS ≤ 0.0032%, TKI tyrosine kinase inhibitor.

Fig. 2. First-ever all-grade AEs (incidence) and first-ever, recurring, and ongoing all-grade AEs (prevalence by year) within individual time periods of asciminib treatment (≥10% of patients within year 1).

Percentages are calculated based on the number of patients at risk of an event (left column: patients with ongoing treatment who were event free at the start of the interval; right column: patients with ongoing treatment at the start of the interval). In the left column (incidence), the number of patients at risk of an event differs from year to year, and percentages in each year should thus not be summed. A patient with multiple occurrences of an event within the same time interval was counted only once in that time interval. AE adverse event, URTI upper respiratory tract infection.

Fig. 3. Cumulative rate of molecular response.

Cumulative rate of A MMR by number of lines of prior TKI therapy, B MMR by BCR::ABL1^IS level at screening, and C BCR::ABL1^IS ≤ 1% by BCR::ABL1^IS level at screening. Treatment discontinuations for any reason were treated as competing events. BCR::ABL1^IS BCR::ABL1 on the International Scale, L line of asciminib treatment (e.g., 3L indicates patients who were treated with asciminib in the third line), MMR major molecular response (BCR::ABL1^IS ≤ 0.1%), TKI tyrosine kinase inhibitor.

Fig. 4. Event-free survival.

A EFS for patients overall. B EFS by BCR::ABL1^IS at screening. EFS was estimated using the Kaplan–Meier method, with treatment discontinuation due to AEs, on-treatment progression to AP/BC, and on-treatment death for any reason considered as events. Survival data were not collected after patients discontinued the study. AE adverse event, AP accelerated phase, BC blast crisis, EFS event-free survival.