First-in-class STAMP inhibitor shows promise in heavily pretreated CML

Asciminib, a first-in-class investigational treatment specifically targeting the ABL myristoyl pocket (STAMP), offers superior efficacy and a favourable safety profile vs the BCR-ABL tyrosine kinase inhibitor (TKI) bosutinib in patients with heavily pretreated chronic myeloid leukaemia (CML), according to results of the open-label phase III ASCEMBL trial presented at the 62^nd American Society of Hematology Annual Meeting and Exposition (ASH 2020).

The trial included 233 adult patients (median age, 52 years; female, 51.5 percent) with CML in chronic phase previously treated with ≥2 TKIs who experienced treatment failure with or were intolerant of the most recent TKI. Patients intolerant of the most recent TKI were eligible if they had BCR-ABL1^IS >0.1 percent at screening. Those with known bosutinib-resistant T315I or V299L mutations were excluded. [Hochhaus A, et al, ASH 2020, abstract LBA-4] 

Improved responses vs bosutinib

Patients in the study were followed up for a median of 14.9 months. Results showed a significant improvement in the primary endpoint of major molecular response (MMR) rate at 24 weeks among patients randomized to receive asciminib 40 mg BID (n=157) vs those who received bosutinib 500 mg QD (n=76).

“MMR rate at 24 weeks was 25.5 percent in the asciminib group vs 13.2 percent in the bosutinib group,” reported investigator Dr Andreas Hochhaus of the University Hospital, Jena, Germany. “The common treatment difference after adjustment for major cytogenetic response [MCyR] status at baseline was 12.2 percent [95 percent confidence interval (CI), 2.19 to 22.3; 2-sided p=0.029].”

“The between-group difference in MMR started to become evident at week 12,” he added.

Among patients who achieved MMR, median time to MMR was 12.7 weeks with asciminib vs 14.3 weeks with bosutinib.

“A consistent treatment effect of asciminib on MMR at 24 weeks was observed across subgroups evaluated,” said Hochhaus.  

Subgroup analysis of MMR at 24 weeks showed a risk difference of 27.5 (95 percent CI, 5.9 to 49.1) and 6.0 (95 percent CI, -4.9 to 16.9) in patients with and without MCyR at baseline, respectively. The risk difference for patients who discontinued the last TKI due to failure or intolerance was 15.5 (95 percent CI, 5.3 to 25.7) and 2.1 (95 percent CI, -20.8 to 25.0), respectively. In female and male patients, and patients with unmutated or mutated BCR-ABL1 at baseline, the risk difference was 20.4 (95 percent CI, 7.2 to 33.7), 2.6 (95 percent CI, -13.9 to 19.1), 13.5 (95 percent CI, 2.6 to 24.4), and 15.3 (95 percent CI, -18.3 to 48.9), respectively.

“Notably, MMR at 24 weeks was consistently higher with asciminib in patients who had received two, three, or ≥4 prior lines of therapy,” highlighted Hochhaus. The risk difference for patients who received randomized treatment as third-, fourth-, or ≥5th-line therapy was 9.3 (95 percent CI, -8.1 to 26.6), 11.2 (95 percent CI, -6.7 to 29.1) and 16.1 (95 percent CI, 3.2 to 29.1), respectively.

The treatment effect of asciminib vs bosutinib was similar after adjustment for baseline MCyR (odds ratio [OR], 2.35; 95 percent CI, 1.08 to 5.12), as well as for MCyR and other important covariates at baseline (OR, 2.38; 95 percent CI, 1.06 to 5.35). According to Hochhaus, this indicated that the treatment effect of asciminib remained significant after accounting for imbalances between treatment groups at baseline, including the proportion of patients who had received ≥3 prior lines of therapy (47.8 percent in the asciminib group vs 60.5 percent in the bosutinib group), and those who discontinued the last TKI due to lack of efficacy (60.5 percent vs 71.1 percent) or intolerability (37.6 percent vs 28.9 percent).

Complete cytogenetic response (CCyR), a key secondary endpoint, was achieved by 40.8 percent of patients in the asciminib group vs 24.2 percent of those in the bosutinib group at 24 weeks, with a common treatment difference of 17.3 percent (95 percent CI, 3.62 to 31.0) after adjustment for MCyR status at baseline.

“At 24 weeks, more patients treated with asciminib vs bosutinib achieved MR⁴ [10.8 percent vs 5.3 percent] and MR^4.5 [8.9 percent vs 1.3 percent]. Most patients who achieved MR⁴ with asciminib also achieved MR^4.5,” noted Hochhaus. “Among patients with BCR-ABL1IS >1 percent at baseline, 44.5 percent vs 22.2 percent of those in the asciminib vs bosutinib group achieved BCR-ABL1^IS ≤1 percent at 24 weeks.”

Safety and tolerability

The median duration of exposure was 43.4 weeks for asciminib and 29.2 weeks for bosutinib. At data cut-off, treatment was ongoing in 61.8 percent vs 30.3 percent of patients in the asciminib vs bosutinib group. The most common reasons for treatment discontinuation were lack of efficacy (21 percent vs 31.6 percent) and adverse events (AEs; 5.1 percent vs 21.1 percent). Among patients who discontinued bosutinib due to lack of efficacy, 28.9 percent switched to receive asciminib.

“Asciminib demonstrated a favourable safety profile compared with bosutinib. Grade ≥3 AEs occurred in 50.6 percent vs 60.5 percent of the patients,” said Hochhaus.

The most frequent all-grade AEs in the asciminib group were thrombocytopenia (28.8 percent vs 18.4 percent with bosutinib) and neutropenia (21.8 percent vs 21.1 percent). AEs associated with bosutinib were most frequently gastrointestinal events, including diarrhoea (71.1 percent vs 11.5 percent with asciminib), nausea (46.1 percent vs 11.5 percent), and vomiting (26.3 percent vs 7.1 percent).

“AEs in the asciminib group were generally manageable and rarely led to treatment discontinuation,” noted Hochhaus. “AEs led to treatment discontinuation in 5.8 percent vs 21.1 percent, and to dose adjustment or interruption in 37.8 percent vs 60.5 percent of patients in the asciminib vs bosutinib group, respectively.”

Fatal AEs during or within 30 days after end of treatment included arterial embolism in one patient and ischaemic stroke in one patient in the asciminib group, and septic shock in one patient in the bosutinib group. “These events were not considered to be related to study treatment,” said Hochhaus.

A potential treatment option

“ASCEMBL is the first controlled study comparing treatments for resistant/intolerant patients with CML. Results showed statistically significant and clinically meaningful superior efficacy as well as a favourable safety profile of asciminib, a first-in-class STAMP inhibitor, vs bosutinib. These results support the use of asciminib as a new treatment option in CML, particularly in patients with resistance or intolerance to ≥2 TKIs,” he concluded. “BCR-ABL1 mutations remain the key driver of CML even in patients treated in the third line or beyond.”