First-in-class STAMP inhibitor versus bosutinib in resistant or intolerant CML

ASCEMBL is the first controlled study comparing different tyrosine kinase inhibitors (TKIs) for resistant or intolerant patients with chronic myeloid leukaemia (CML). Asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superior efficacy compared with bosutinib and a favourable safety profile [1]. These results support the use of asciminib as a new treatment option in CML, particularly in patients with resistance or intolerance to ≥2 prior TKIs.

Current therapies for patients with resistance or intolerance to ≥2 TKIs are limited by either modest efficacy, safety concerns, or both [2]. All currently approved TKIs bind to the ATP site of the BCR-ABL1 oncoprotein. Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action [3]. In a previous phase 1 study, asciminib monotherapy showed clinical activity in heavily pretreated patients with CML. Based on this finding, the question was if asciminib could provide superior efficacy to bosutinib, a second-generation ATP-competitive TKI, beyond second line of treatment.

Dr Andreas Hochhaus (Universitätsklinikum Jena, Germany) presented results from ASCEMBL, a randomised, open-label, phase 3 study in 233 adult patients with CML-CP previously treated with ≥2 TKIs [1]. Fewer patients on asciminib discontinued their last TKI due to lack of efficacy and fewer received ≥3 prior lines of TKI therapy compared with bosutinib-treated patients.

Major molecular response (MMR) rate at 24 weeks was 25.5% with asciminib and 13.2% with bosutinib, meeting the primary objective. The between-arm common treatment difference for MMR at 24 weeks, after adjustment for major cytogenetic response status at baseline, was 12.2% (2-sided P=0.029; see Figure). Among those patients who achieved MMR, median time to MMR was 12.7 weeks with asciminib and 14.3 weeks with bosutinib.

Figure: MMR rate at 24 weeks [1]



MMR, major molecular response

At 24 weeks, a total of 61.8% of patients receiving asciminib and 30.3% of patients on bosutinib were still on treatment. The most common reason for treatment discontinuation was lack of efficacy (asciminib 21.0%; bosutinib 31.6%). Grade ≥3 adverse events (AEs) occurred in 50.6% and 60.5% of patients, respectively. Most frequent grade ≥3 AEs with asciminib were thrombocytopenia (17.3%) and neutropenia (14.7%). The proportion of patients who discontinued treatment due to AEs was lower with asciminib (5.8%) than bosutinib (21.1%).

1. Hochhaus A, 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). 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract LBA-4.
2. Hochhaus A, et al. Leukemia. 2020;34:966-84.
3. Wylie AA, et al. 2017;543:733-7.

Posted on 18 February, 20217 September, 2023