Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results

Abstract

Asciminib targets the BCR::ABL1 myristoyl pocket, maintaining activity against BCR::ABL1^T315I, which is resistant to most approved adenosine triphosphate-competitive tyrosine kinase inhibitors. We report updated phase I results (NCT02081378) assessing safety/tolerability and antileukemic activity of asciminib monotherapy 200 mg twice daily in 48 heavily pretreated patients with T315I-mutated chronic-phase chronic myeloid leukemia (CML-CP; data cutoff: January 6, 2021). With 2 years' median exposure, 56.3% of patients continued receiving asciminib. Overall, 62.2% of evaluable patients achieved BCR::ABL1 ≤1% on the International Scale (IS); 47.6% and 81.3% of ponatinib-pretreated and -naive patients, respectively, achieved BCR::ABL1^IS ≤1%. Of 45 evaluable patients, 48.9% achieved a major molecular response (MMR, BCR::ABL1^IS ≤0.1%), including 34.6% and 68.4% of ponatinib-pretreated and -naive patients, respectively. MMR was maintained until data cutoff in 19 of 22 patients who achieved it. The most common grade ≥3 adverse events (AEs) included increased lipase level (18.8%) and thrombocytopenia (14.6%). Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib's effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.

Fig. 1. Cumulative molecular response in ponatinib-pretreated and -naive patients without the indicated response at baseline.

Cumulative (A) BCR::ABL1^IS ≤1%, (B) MMR, (C) MR⁴, and (D) MR^4.5 in evaluable patients. IS International Scale, MMR major molecular response, MR⁴ BCR::ABL1^IS ≤0.01%, MR^4.5 BCR::ABL1^IS ≤0.0032%. ^a CIs are based on the Clopper–Pearson method. 95% CIs were used for all patients, and 90% CIs were used for ponatinib-pretreated and -naive patients. ^b The rate of MMR by week 24 was 42.2% (95% CI, 27.7–57.8%) in all patients, 57.9% (90% CI, 36.8–77.0%) in ponatinib-naive patients, and 30.8% (90% CI, 16.3–48.7%) in ponatinib-pretreated patients. ^c The rate of MMR by week 48 was 44.4% (95% CI, 29.6–60.0%) in all patients, 57.9% (90% CI, 36.8–77.0%) in ponatinib-naive patients, and 34.6% (90% CI, 19.4–52.6%) in ponatinib-pretreated patients. ^d The rate of MMR by week 96 was 48.9% (95% CI, 33.7–64.2%) in all patients, 68.4% (90% CI, 47.0–85.3%) ponatinib-naive patients, and 34.6% (90% CI, 19.4–52.6%) in ponatinib-pretreated patients.

Fig. 2. Cumulative BCR::ABL1^IS ≤1% by time point in patients with baseline BCR::ABL1^IS > 1%^a.

Cumulative BCR::ABL1^IS ≤1% in all evaluable patients (A) overall, (B) by BCR::ABL1^IS at baseline, and (C) by prior treatment with ponatinib. IS International Scale. ^a Treatment discontinuations for any reason were treated as competing events.

Fig. 3. Cumulative MMR by time point in patients not in MMR at baseline.

^a Cumulative MMR in all evaluable patients (A) overall, (B) by BCR::ABL1^IS at baseline, and (C) by prior treatment with ponatinib. IS International Scale, MMR major molecular response. ^a Treatment discontinuations for any reason were treated as competing events.

Fig. 4. Adverse reactions (≥10% at first occurrence) over time.

^a,bADR adverse drug reaction, AE adverse event, LRTI lower respiratory tract infection, URTI upper respiratory tract infection. ^a Includes reported AEs and adverse drug reactions. ^b Proportions are calculated based on the number of patients at risk of an event (ie, patients ongoing treatment and event-free at the start of the interval). A patient with multiple occurrences of an event in the same time interval is counted only once in that time interval. The safety topics correspond to either single preferred terms or groups of preferred terms according to the adverse drug reaction definitions.