First-in-class STAMP inhibitor asciminib outperforms bosutinib in patients with chronic myeloid leukaemia, previously treated with at least two tyrosine kinase inhibitors
The ASCEMBL study is the first controlled study to report on the comparison of different tyrosine kinase inhibitors (TKIs) for resistant or intolerant patients with chronic myeloid leukaemia, previously treated with at least two TKIs. In this trial, the first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor asciminib demonstrated statistically significant and clinically meaningful superiority in efficacy compared with bosutinib, with deeper molecular response rates and a favourable safety profile.
Background
Current therapies for patients with chronic myeloid leukaemia (CML) with resistance or intolerance to at least two tyrosine kinase inhibitors (TKIs) are limited by modest efficacy, safety concerns, or both. Thus far, bosutinib is the only second-generation TKI that demonstrated clinical efficacy in patients with CML who received at least two TKIs. Asciminib, unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action. The multicentre, open-label, phase III ASCEMBL study evaluated whether asciminib could provide superior efficacy over bosutinib in patients with CML in chronic phase (CML-CP) who were previously treated with at least two TKIs. In total, 223 patients were randomly assigned (2:1) to receive either asciminib (40 mg, twice daily) or bosutinib (500 mg, once daily). Patients with a treatment failure on bosutinib were permitted to switch to asciminib per investigator judgement, while patients with known bosutinib-resistance T315I or V299L mutations were excluded from the study.
Results
Compared to bosutinib, fewer patients on asciminib discontinued their last TKI due to a lack of efficacy (60.5% versus 71.1%) and fewer patients received ≥3 prior lines of TKI therapy (47.8% versus 60.5%). At the time of data cut-off (May 25, 2020), treatment was ongoing in a higher proportion of patients in the asciminib arm (61.8%) compared to the bosutinib arm (30.3%). Lack of efficacy and adverse events (AEs) were the main reasons for treatment discontinuation and were both less frequently observed with asciminib.
After a median follow-up of 14.9 months, the study met its primary objective of a superior major molecular response (MMR) rate at 24 weeks among asciminib treated patients. In fact, the MMR rate at 24 weeks was reported at 25.5% with asciminib as compared to 13.2% with bosutinib. This represents a statistically significant common treatment difference after adjusting for major cytogenic response (MCyR) status at baseline of 12.2% (p=0.029). The median duration of exposure was 43.4 weeks for asciminib versus 29.2 weeks for bosutinib. A consistent treatment benefit for asciminib was observed across all investigated subgroups, including patients who received ≥3 prior TKIs, patients who discontinued their prior TKI due to treatment failure, and regardless of baseline cytogenetic response. Furthermore, the probability of achieving a MMR by 24 weeks was 25.0% for patients treated with asciminib as compared to 11.9% in the bosutinib arm. The median time to a MMR was 12.7 weeks and 14.3 weeks with asciminib and bosutinib, respectively. The rate of complete cytogenetic response (CCyR) at 24 weeks was 40.8% with asciminib versus 24.2% with bosutinib. The common risk difference for CCyR after adjusting for MCyR status at baseline was 17.3%. At 24 weeks, more patients on asciminib (10.8% and 8.9%) than on bosutinib (5.3% and 1.3%) achieved deep molecular response with MR4 and MR4.5, respectively.
Adverse events (AEs) of at least grade 3 were observed in 50.6% of patients on asciminib and in 60.5% of patients on bosutinib. Two deaths occurred in the asciminib arm, one due to an arterial embolism and one as a result of an ischemic stroke. One bosutinib-treated patient died from sepsis after disease progression. Treatment was discontinued due to AEs in 5.8% of patients in the asciminib arm, while this was the case for 21.1% of patients on bosutinib. In 37.8% of patients on asciminib and 60.5% of patients on bosutinib, doses had to be adjusted or interrupted due to AEs. All-grade AEs regardless of study drug relationship occurred in 89.7% and 96.1% of patients on asciminib and bosutinib, respectively. Most frequent grade ≥3 AEs with asciminib versus bosutinib were thrombocytopenia (17.3% versus 6.6%), neutropenia (14.7% versus 11.8%), diarrhoea (0% versus 10.5%), and increased alanine aminotransferase (0.6% versus 14.5%). The frequency of arterial occlusive events was 3.2% with asciminib and 1.3% with bosutinib.
Conclusions
The ASCEMBL study is the first controlled study to compare different TKIs for resistant or intolerant patients with CML. In this trial, asciminib demonstrated statistically significant and clinically meaningful superior efficacy and a favourable safety profile as compared to bosutinib. Therefore, the ASCEMBL results support the use of asciminib as a new treatment option in CML, particularly in patients with resistance or intolerance to at least two TKIs.
Reference
Hochhaus A, Boquimpani C, Rea 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). Presented at ASH 2020; Abstract LBA-4.
