Updated ASCEMBL results boost asciminib potential for CML

In the week-96 analysis of the phase III ASCEMBL trial, the first BCR::ABL1 STAMP* inhibitor asciminib sustained superiority over bosutinib for individuals with CML-CP** who have failed ≥2 lines of prior tyrosine kinase inhibitors (TKIs).

“After ≥2 years of follow-up … asciminib continued to demonstrate clinically and statistically significant superior efficacy over bosutinib, with more patients achieving molecular responses (MRs) over time, as well as deep MRs,” said Dr Delphine Réa from the Hôpital Saint-Louis, Paris, France, at EHA 2022.

After adjusting for major cytogenetic response (MCyR) at baseline, 38 percent of asciminib recipients achieved major MR (MMR***). “[This] was more than double than with bosutinib – which was only 16 percent – [thus] meeting the key secondary objective and supporting the long-term benefit of continuing asciminib treatment,” explained Réa. The treatment difference was 22 percent (p=0.001). [EHA 2022, abstract S155]

These findings come on the heels of the week-24 and -48 analyses that also showed higher MMR rates with asciminib vs bosutinib (26 percent vs 13 percent and 29 percent vs 13 percent, respectively). [Blood 2021;138:2031-3041; ASH 2021, abstract 310]

Sixty-seven out of the 69 asciminib recipients who achieved MMR maintained response at the time of their last evaluation, while only one out of the 18 bosutinib recipients was not able to maintain response. These translated to a very high probability of maintaining MMR for ≥72 weeks in both asciminib and bosutinib arms (97 percent and 93 percent).

MMR rates were consistently higher with asciminib vs bosutinib across all^# demographic and prognostic subgroups.

 

Other MRs

Asciminib also trumped bosutinib in terms of the percentage of participants achieving MR²*** (45 percent vs 19 percent; p=0.000) and deep MRs (17 percent vs 10 percent [MR⁴***] and 11 percent vs 5 percent [MR^4.5***]).

“In the later-line setting, some patients may not be able to achieve an MMR,” Réa explained. “MR² is an important response for [these] patients because it provides a certain degree of protection against progression to CML … [Our MR² result is] a milestone response associated with improved long-term outcomes.” [Leukemia 2020;34:966-984]

“Although patients in the later-line setting may rarely obtain deep MRs, this is still a possibility. Achievement of a deep MR is a condition for stopping TKIs. [However,] patients with a history of resistance may not be good candidate for treatment discontinuation,” she continued.

 

Favourable safety profile sustained

“The safety and tolerability of asciminib continued to be better than bosutinib,” noted Réa. There were no new or worse safety findings nor on-treatment deaths in either arm since primary analysis cutoff.

Most all-grade haematologic toxicities associated with asciminib occurred during the first 6 months of treatment (29, 22, and 10 percent for thrombocytopenia, neutropenia, and anaemia, respectively). By ≥18 months, most have resolved, occurring at a rate of 1 to 2 percent only.

A majority of non-haematologic^## AEs also occurred during the first 6 months. “Overall, these AEs rarely persisted beyond the initial time period of presentation. The most frequent non-haematologic AEs were manageable and did not lead to any treatment discontinuations,” noted Réa.

Median duration of exposure was longer with asciminib than bosutinib (24 vs 7 months). “[This is] important to consider [as it leads] to a longer duration for the possibility of AE reporting. [It] is also an indicator of drug tolerability,” she added.

 

New SoC for CML?

A total of 233 participants (median age 52 years, 54 percent female) were randomized 2:1 to receive asciminib 40 mg BID or bosutinib 500 mg QD. At week 96, 54 percent of asciminib recipients were still on the drug vs only 20 percent of bosutinib recipients. “[This implies that more asciminib recipients] continued to benefit from therapy over time,” said Réa.

“Based on our results, asciminib may become a new CML therapy … with the potential to transform standard-of-care treatment in the third-line setting or beyond,” she concluded.

Asciminib is FDA-approved for the treatment of adults with Ph+^### CML-CP previously treated with ≥2 TKIs and in those with the T315I mutation and was added to the recent NCCN⁺ guidelines. [www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-scemblix-asciminib-patients-philadelphia-chromosome-positive#; NCCN: Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia v3.2022]