FDA Grants Breakthrough Therapy Designations to Asciminib for CML

Feb 9, 2021

February 9, 2021 - The FDA has granted breakthrough therapy designations to asciminib for the treatment of adult patients with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase who received prior treatment with 2 or more TKIs, and for adult patients with Ph-positive CML in chronic phase whose tumors harbor the T315I mutation.

The FDA has granted breakthrough therapy designations to asciminib (ABL001) for the treatment of adult patients with Philadelphia chromosome (Ph)–positive chronic myeloid leukemia (CML) in chronic phase who received prior treatment with 2 or more TKIs, and for adult patients with Ph-positive CML in chronic phase whose tumors harbor the T315I mutation.1

The designations were based on data from the phase 3 ASCEMBL trial (NCT03106779), which compared asciminib with bosutinib (Bosulif) in patients with Ph-positive CML who received prior treatment with 2 TKIs, and findings from a phase 1 trial examining the agent in patients with Ph-positive CML, some of them harboring the T315I mutation.

The investigational, first-in-class treatment was designed to specifically target the ABL myristoyl pocket (STAMP). Previously, in August 2020, Novartis, the manufacturer of the agent, announced that the FDA had granted the agent a fast track designation.2

Data from the phase 3 ASCEMBL trial were presented during the 2020 ASH Annual Meeting and showed that the STAMP inhibitor induced a statistically significant and clinically meaningful improvement in the major molecular response (MMR) rate at 24 weeks compared with bosutinib in patients with CML in chronic phase who have previously received 2 TKIs.3

The MMR rate achieved with asciminib was 25.5% versus 13.2% with bosutinib. Moreover, the common risk difference for MMR was 12.2%, which was determined to be of statistical significance (95% CI, 2.19-22.3; P = .029).

The goal of the phase 3 trial was to evaluate the safety and efficacy of asciminib versus bosutinib in a total of 233 patients. In the trial, participants were randomized 2:1 to asciminib at a twice-daily dose of 40 mg (n = 157) or bosutinib at a once-daily dose of 500 mg (n = 76). Patients were stratified by major cytogenetic response (MCyR) status at baseline and they received treatment for at least 96 weeks. Notably, only patients who met treatment failure criteria on bosutinib were able to switch over to receive asciminib.

To be eligible for participation, patients had to have CML in chronic phase and have received 2 or more prior TKIs. They had to have relapsed on or have been intolerant to the most recent TKI that they received and those with intolerance must have had BCR-ABL1IS that was greater than 0.1% at the time of screening. Patients could not harbor T3151 or V299L mutations.

The primary objective of the trial was MMR rate at 24 weeks while on study treatment without meeting any treatment failure criteria prior to 24 weeks. Key secondary objectives comprised MMR rate at 96 weeks while on study treatment without meeting treatment failure criteria prior to 96 weeks, safety and tolerability, and complete cytogenetic response (CCyR). Other end points included MMR rates at and by scheduled data collection time points, time to and duration of MMR, time to and duration of CCyR, time to treatment failure, progression-free survival, and pharmacologic parameters.

The median age of participants was 52 years and 51.5% were female. About 29% of patients experienced MCyR. Moreover, 63.9% of patients discontinued their last TKI because of lack of efficacy, while 34.8% did so due to lack of tolerability and 1.3% discontinued for another reason. Approximately 48% of patients had received 2 prior lines of treatment, while 51.9% had received 3 prior lines. Although the BCR-ABLIS at baselines were not applicable, 14.2% of patients had a BCR-ABL1 mutation; 1.7% of patients had several BCR-ABL1 mutations.

At the May 25, 2020 data cutoff, all participants had completed their week 24 visit or had discontinued treatment. Treatment was ongoing in more than half of patients on the asciminib arm (61.8%) versus 30.3% of those on the bosutinib arm.

Additional results revealed that the MMR benefit achieved with asciminib was reported across subgroups analyzed, including MCyR (27.5%), female sex (20.4%), failure on previous TKI (15.5%); also, patients benefitted from the agent irrespective of whether they received it in the third (9.3%), fourth (11.2%), or fifth (16.1%) line.

The cumulative incidence of MMR was 25.0% in the asciminib arm versus 11.9% in the bosutinib arm; the difference between the 2 arms became noticeable around 12 weeks. At 24 weeks, the rate of CCyR was 40.8% with asciminib versus 24.2% with bosutinib; the common risk difference waws 17.3% (95% CI, 3.62%-31.0%).

All-grade toxicities proved to be comparable between the investigational and control arms, at 89.7% versus 96.1%, respectively; the same was true for grade 3 or higher toxicities, at 50.6% and 60.5%, respectively. Two deaths were reported on the asciminib arm because of arterial embolism and ischemic stroke, although they were not determined to be associated with the study treatment. One death was observed on the bosutinib arm because of septic shock following progressive disease. Two more patients on the asciminib arm died during survival follow-up because of CML.

Just under 6% of patients on the asciminib arm discontinued treatment; the most common adverse effects to lead to discontinuation included thrombocytopenia (3.2%) and neutropenia (2.6%). The most frequent toxicities that led to discontinuation on the bosutinib arm (21.1%) included increased alanine aminotransferase (5.3%) and increased alanine aminotransferase (2.6%).

A real-world analysis presented during the meeting also showed that asciminib was a safe and effective option for patients with CML without any alternatives to clinical practice, specifically those who proved to be intolerant to previous TKIs and who have previously achieved CCyR.3

The rate of complete hematologic response, CCyR, and MMR pre- and post-asciminib, respectively, were 100%, 47%, and 66%, and 17% and 41%. The probability of maintaining or improving CCyR responses among global patients was 48%, among resistant patients was 11%, and among intolerant patients was 47%.

References

1. Novartis receives FDA breakthrough therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia. News release. Novartis. February 8, 2021. Accessed February 8, 2021. http://bit.ly/2YWE11I.

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. Luna A, Estrada N, Boqué C, et al. Safety and efficacy of asciminib as treatment in chronic myeloid leukemia patients after several tyrosine-kinase inhibitors failure. Blood. 2020;136(suppl 1):49-50. doi:10.1182/blood-2020-138690

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