Head-to-head trial STAMPs asciminib mark in CML treatment landscape

In the exploratory analyses of the phase III ASCEMBL trial, individuals with chronic myeloid leukaemia in chronic phase (CML-CP) who have failed ≥2 prior tyrosine kinase inhibitors (TKIs) continued to achieve deep responses with asciminib, the first BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP).

“At week 96, patients receiving asciminib achieved BCR::ABL1^IS* ≤1 percent and major molecular response (MMR**) after resistance to all prior second-generation (2G) TKI therapies, and response rates were higher with asciminib than with bosutinib,” said the researchers.

The study comprised 233 CML-CP patients who failed or had intolerance to their most recent TKI. Those with intolerance must have BCR::ABL 1^IS >0.1 percent at screening. They were randomized 2:1 to receive asciminib 40 mg BID or bosutinib 500 mg QD. [EHA 2023, abstract P665]

In the subgroup of patients who have received 2G TKI ± imatinib prior to study treatment and developed resistance to all lines of 2G TKIs, half of asciminib recipients (10/20) achieved BCR::ABL1^IS ≤1 percent as opposed to only 17 percent (2/12) of bosutinib-treated patients. A similar effect was seen in terms of the percentage of participants achieving MMR at week 96 (n=7/20 vs 2/12).

Furthermore, asciminib consistently outdid bosutinib in terms of BCR::ABL1^IS ≤1 percent and MMR rates across most*** TKI subgroups.

“A significant proportion of participants who continued treatment beyond week 24 [were still able to] achieve MMR at later timepoints if they had not achieved these responses by week 24,” said the researchers. Among those who continued asciminib and have achieved BCR::ABL1^IS >0.1 percent by week 24, the probability of MMR was 18 percent at week 48, which doubled (38 percent) by week 96.

Although the cumulative incidence of MMR increased in both arms regardless of baseline BCR::ABL1^IS levels (≥10 or <10 percent), the numbers consistently favoured asciminib over bosutinib at week 96 (28 percent vs 13 percent [≥10 percent] and 62 percent vs 41 percent [<10 percent]). Asciminib also outdid bosutinib in terms of deep molecular response (DMR^#; 8 percent vs 4 percent and 31 percent vs 26 percent, respectively).

The cumulative incidences of MMR and DMR were also higher in asciminib than bosutinib recipients who discontinued their last prior TKI due to lack of efficacy (33 percent vs 9 percent [MMR] and 15 percent vs 6 percent [DMR]). Among those who discontinued due to intolerance, the cumulative incidences were similar (56 percent vs 54 percent [MMR] and 21 percent vs 27 percent [DMR]).

When stratifying by line of randomized therapy, asciminib still trumped bosutinib in terms of cumulative incidence of MMR (46 percent vs 33 percent [third line] and 41 percent vs 25 percent [fourth line]).

Superior to comparator beyond 6 months

The week-24 (primary analysis) findings of ASCEMBL helped support the initial approval of asciminib in the US for this patient subgroup. [Blood 2021;138:2031-2041] However, the number of TKIs previously received, sequence of treatment, and reason for discontinuation of last TKI are known to influence responses. “All patients in ASCEMBL had received ≥2 prior TKIs, but treatment sequencing and reason for discontinuation of the last TKI varied,” the researchers noted.

“The response rates (MMR and DMR) were consistently higher with asciminib than bosutinib in most demographic and prognostic subgroups,” they said. The current findings also reinforce the previously reported week-96 efficacy and safety results. [EHA 2022, abstract S155]

“[Hence,] the efficacy of asciminib after failure of 2G TKI treatment supports a new standard of care for patients with CML-CP for whom ≥2 prior TKIs have failed,” the researchers concluded.