FDA Grants Priority Review to Asciminib for Chronic Myeloid Leukemia


The FDA has granted priority review to a new drug application seeking the approval of asciminib for the treatment of patients with chronic myeloid leukemia.



The FDA has granted priority review to a new drug application (NDA) seeking the approval of asciminib (ABL001) for the treatment of patients with chronic myeloid leukemia (CML).1

The NDA is supported by data from the phase 3 ASCEMBL trial (NCT03106779), in which the STAMP inhibitor showcased a statistically significant and clinically meaningful improvement in the major molecular response (MMR) rate at 24 weeks vs bosutinib (Bosulif) in patients with Philadelphia chromosome (Ph)–positive CML in chronic phase (CP-CML) who received at least 2 prior TKIs.2

Asciminib elicited an MMR rate of 25.5% vs 13.2% with bosutinib and the common risk difference for MMR was 12.2%, which was determined to be statistically significant (95% CI, 2.19-22.3; 2-sided P = .029).

The phase 3 trial enrolled a total of 233 previously treated patients with CP-CML who were intolerant to their last TKI received or in whom this agent had failed. Patients who were intolerant had to have a BCR-ABL1IS that was greater than 0.1% at the time of screening. Patients who harbored T3151 or V299L mutations were excluded.

Study participants were randomized 2:1 to receive either asciminib at a twice-daily dose of 40 mg (n = 157) or bosutinib at a once-daily dose of 500 mg (n = 76) for at least 96 weeks. Participants were stratified by their major cytogenetic response (MCyR) status at baseline.

With an amendment to the trial protocol, only patients who met treatment failure criteria on bosutinib were permitted to switch over to receive the STAMP inhibitor.

The primary end point of the research was the 24-week MMR rate while on study treatment without meeting any treatment failure criteria prior to this time point. Key secondary end points comprised MMR rate at 96 weeks while on study treatment without meeting treatment failure criteria prior to this time point, safety and tolerability, and complete cytogenetic response (CCyR) and MMR rates at, and by, scheduled data collection time points.

Other end points included time to and duration of MMR, time to and duration of CCyR, time to treatment failure, progression-free survival, overall survival, and pharmacologic parameters.

At a data cutoff of May 25,2020, all patients had completed their week 24 visit or had discontinued study treatment.

The median age of participants was 52 years (range, 19-83), 51.5% were female, and 29.3% had experienced MCyRs. The most common reason that patients discontinued treatment with their last TKI was lack of efficacy (63.9%), followed by lack of tolerability (34.8%) or another reason (1.3%). Moreover, 51.9% of patients had previously received 3 or more lines of therapy and 48.1% had received 2 prior lines. At baseline, the BCR-ABLIS were not applicable, although 14.2% of patients had 1 BCR-ABLIS mutation, and 1.7% had multiple BCR-ABLIS mutations.

At the time of data cutoff, 61.8% of patients were still receiving treatment with asciminib vs 30.3% of those receiving bosutinib. Among those in the investigative and control arms, patients discontinued treatment because of lack of efficacy (21.0% vs 31.6%, respectively), toxicity (5.1% vs 21.1%), physician decision (6.4% vs 7.9%), patient decision (2.5% vs 3.9%), death (0.6% vs 0%), loss to follow-up (0.6% vs 1.3%), disease progression (0.6% vs 3.9%), or protocol deviation (0.6% vs 0%). Notably, 28.9% of patients on the control arm switched over to receive asciminib.

At a median follow-up of 14.9 months, patients on the asciminib arm were exposed to treatment for a median duration of 43.4 weeks (range, 0.1-129.9) vs 29.2 weeks (range, 1.0-117.0) of those on the bosutinib arm.

Additional data presented during the 2020 ASH Annual Meeting demonstrated that the MMR benefit derived with asciminib was observed across key patient subsets like those with MCyR (27.5%), of female sex (20.4%), or who had prior TKI failure (15.5%). Moreover, this benefit was observed irrespective of whether they did not harbor a BCR-ABLIS mutation at day 1 of week 1 (13.5%) or whether the mutation was present (15.3%).

The cumulative incidence of MMR in the investigative and control arms was 25.0% and 11.9%, respectively; the difference between the 2 treatment arms became evident around 12 weeks. At 24 weeks, the CCyR rate in the asciminib arm was 40.8% vs 24.2% in the bosutinib arm; this translated to a common risk difference of 17.3% (95% CI, 3.62%-31.0%).

Moreover, at 24 weeks, the molecular response (MR)4 rate with the STAMP inhibitor was 10.8% vs 5.3% with bosutinib; for MR4.5, these rates were 8.9% and 1.3%, respectively. Rates of BCR-ABLIS at 1% or less at week 24 in those with iIS more than 1% at baseline in the investigative and control arms were 44.5% and 22.2%, respectively.

In terms of toxicity, all-grade adverse effects (AEs) occurred in 89.7% of those who received asciminib vs 96.1% of those who were given bosutinib; grade 3 or higher effects were experienced by 50.6% and 60.5% of patients, respectively.

Two deaths were reported on the investigative arm, and they were due to arterial embolism (n = 1) and ischemic stroke (n = 1). Notably, these effects were not determined to be associated with the study drug. One death was reported on the control arm and that was because of septic shock following progressive disease. Two more patients who had been randomized to asciminib died during survival follow-up because of their disease.

The AEs that most frequently resulted in treatment discontinuation of asciminib (5.8%) included thrombocytopenia (3.2%) and neutropenia (2.6%). With bosutinib, 21.1% of patients discontinued treatment, and the toxicities that led to this decision were increased alanine aminotransferase (ALT; 5.3%) and increased aspartate aminotransferase (AST; 2.6%).

Additionally, all-grade or grade 3 or higher toxicities that resulted in either dose adjustments or interruptions were experienced by 37.8% and 34.0%, respectively, of those on the investigative arm and 60.5% and 48.7%, respectively, of those on the control arm. Of those who received asciminib, 66.0% experienced all-grade AEs that required additional treatment vs 88.2% of those who were given bosutinib; grade 3 or higher toxicities that resulted in additional therapy were experienced by 28.2% and 40.8% of patients, respectively.

The most common all-grade toxicities that were reported in 20% or more of patients on the investigative and control arms included thrombocytopenia (28.8% vs 18.4%, respectively), neutropenia (21.8% vs 21.1%), diarrhea (11.5% vs 71.1%), nausea (11.5% vs 46.1%), rash (7.1% vs 23.7%), vomiting (7.1% vs 26.3%), increased ALT (3.8% vs 27.6%), and increased AST (3.8% vs 21.1%).

Previously, in February 2021, the FDA granted breakthrough therapy designations to asciminib for the treatment of adult patients with Ph-positive CP-CML who previously received 2 or more TKIs, and for adult patients with Ph-positive CP-CML whose tumors harbor a T315I mutation.3 The decision was based on findings from ASCEMBL.


  1. FDA accelerates review of Novartis STAMP inhibitor asciminib (ABL001) for patients with chronic myeloid leukemia (CML). News release. Novartis. August 25, 2021. Accessed August 25, 2021. https://bit.ly/3gA2Z06
  2. Hochhaus A, Boquimpani B, Réa D, et al. Efficacy and safety results from ASCEMBL, a multicenter, open-label, phase 3 study of asciminib, a first-in-class STAMP inhibitor, vs bosutinib (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs). Blood. 2020;136(suppl 2):LBA-4. doi:10.1182/blood-2020-143816
  3. Novartis receives FDA breakthrough therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia. News release. Novartis. February 8, 2021. Accessed August 25, 2021. http://bit.ly/2YWE11I
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