Asciminib Represents New Standard of Care for Patients With CML in Chronic Phase

Jorge E. Cortes, MD

Asciminib (Scemblix) continued to demonstrate durable, major molecular responses (MMRs) as well as a tolerable safety profile vs bosutinib (Bosulif) suggesting a long-term benefit in adult patients with chronic myelogenous leukemia in chronic phase (CML-CP) who have been previously treated with 2 tyrosine kinase inhibitors (TKIs), according to a 96-week update from the phase 3 ASCEMBL trial (NCT03106779) presented during the 2022 ASCO Annual Meeting.¹

A key secondary end point of the trial, the MMR rate at week 96 more than doubled with asciminib at 37.6% (95% CI, 29.99%-45.65%) vs 15.8% (95% CI, 8.43%-25.96%) with bosutinib. At the time of data cutoff, treatment was ongoing in 84 (53.5%) and 15 (19.7%) patients, respectively. Investigators analyzed outcomes among the intention-to-treat population, which included a total of 233 patients who were randomly assigned 2:1 to asciminib (n = 157) or bosutinib (n = 76).

At week 96, deeper molecular response rates—defined as reductions in BCR-ABL1 transcript levels—were associated with asciminib. The MR4 rate (BCR-ABL1IS ≤ 0.01%) at week 96 was 17.2% in the asciminib group compared with 10.5% in the bosutinib group. The MR4,5 rate (BCR-ABL1IS ≤ 0.0032%) was 10.8% with asciminib vs 5.3% with bosutinib.

“[In previously reported data] there is a similar benefit of asciminib compared with bosutinib at 24 weeks and at 48 weeks, and the difference has actually increased in favor of asciminib at the 96-week [landmark],” Jorge E. Cortes, MD director of the Georgia Cancer Center in Atlanta, said during a presentation of the data. “Deeper molecular responses we, of course, care about seeing. These are very heavily treated patients, and the immediate outcome is the cytogenetic and the major molecular response [MCyR]. But it is very gratifying to see that we are starting to see deep molecular responses and again in that category there is a benefit for asciminib.”

Compared with week 24 and week 48, the MR4 rate did not change for patients who received asciminib (10.8%). There was a decline in MR4 rate observed among those who received bosutinib with 5.3% of patients having a response at week 24 vs 3.9% at week 48. In terms of MR4,5 rate, patients in the asciminib arm saw a decline from 8.9% at week 24 to 7.6% at week 48. Patients who received bosutinib had an MR4,5 rate of 1.3% at both landmark time points.

Investigators also adjusted for MCyR at baseline for a treatment difference of was 21.7% (95% CI, 10.5%-33.0%; 2-sided P = .001).

ASCEMBL enrolled patients with CML-CP with failure on or intolerance to their most recent TKI. Those with TKI intolerance were required to have BCR-ABL1IS > 0.1% at baseline. Patients with T3151 or V299L mutations were not eligible for enrollment. Patients were stratified by MCyR status at baseline (yes vs no).

Individuals assigned to the investigative arm received asciminib 40 mg twice daily and those in the control arm received bosutinib 500 mg once daily. The median duration of follow-up was 2.3 years from randomization to last contact date.

The median duration of exposure was 23.7 months for asciminib vs 7 months for bosutinib.

The benefit with asciminib was maintained across all demographic and prognostic subgroup analyses including lack of efficacy with last TKI (risk difference, 23.1 [95% CI, 11.5-34.7]), intolerance to last TKI (risk difference, 14.5 [95% CI, –9.3 to 38.3]), and at least 5 lines of prior therapy (risk difference, 29.0 [95% CI, 13.1-45.0]). In terms of BCR-ABL1 mutation status the risk difference for those with no detectable mutation was 21.7 (95% CI, 9.3-34.1) and 16.2 (95% CI, –21.9 to 54.2) for those with the mutation. The risk reduction for those with BCR-ABL1IS transcript level of at least 1% at baseline was 20.6 (95% CI, 9.4-31.8) and 16.7 (95% CI, –37.8 to 71.2) for those who had transcript levels less than 1%.

The probability of maintaining MMR for at least 72 weeks was 96.7% (95% CI, 87.4%-99.2%) on asciminib vs 92.9% (95% CI, 59.1%-99.0%) with bosutinib. Of the 69 patients who achieved MMR, with asciminib 67 maintained response at the time of analysis and 17 of 18 patients with MMR in the bosutinib arm also maintained response. At the time of analysis median duration of MMR was not reached for either arm.

The probability of maintaining MR4 was 94.6% (95% CI, 86.2%-97.9%) and 95.0% (95% CI, 69.5%-99.3%), respectively.

The rate of BCR-ABL1IS of at least 1% at week 96 was 45.1% among patients who received asciminib vs 19.4% of those who received bosutinib. The probability of maintaining this status for at least 72 weeks was 94.6% (95% CI, 86.2%-97.9%) and 95.0% (95% CI, 69.5%-99.3%) with asciminib and bosutinib, respectively.

The median time to treatment failure was 24 months vs 6 months for the investigative and control arms, respectively (HR, 0.44; 95% CI 0.31-0.61; P < .0001). The proportion of patients without treatment failure at 2 years was 50.6% vs 18.9%, respectively.

In terms of safety investigators noted that the rate of discontinuation due to adverse effects (AEs) was low with asciminib, with a minimal increase observed since the primary analysis. Treatment-discontinuation rates due to AEs in the 96-week analysis were 7.0% with asciminib vs 25% with bosutinib. The top reason for treatment discontinuation was lack of efficacy (24.2% vs 35.5%, respectively).

The most common grade 3 or higher AEs with asciminib vs bosutinib were thrombocytopenia (22.4% vs 9.2%), neutropenia (19.9% vs 15.8%), diarrhea (0% vs 10.5%), and increased alanine aminotransferase (0.6% vs 14.5%). The safety profile of asciminib was more tolerable regardless of the longer duration of treatment, the investigators noted.

Arterial occlusive events were an AE of note in the trial, with investigators reporting that there was no increased risk of the event over time with asciminib. Among the 8 reported instances, prior exposure to nilotinib (Tasigna), dasatinib (Sprycel), and ponatinib (Iclusig) were noted. Most nonhematologic AEs presented in the first 6 months of treatment and rarely persisted beyond the time of presentation.

The BCR-ABL1 inhibitor, which is also known as a STAMP inhibitor (specifically targets the ABL myristoyl pocket), is approved by the FDA for the treatment of patients with Philadelphia chromosome (Ph)-positive CML-CP previously treated with at least 2 or more TKIs, and for adult patients with Ph-positive CML-CP with a T315I mutation.²

In their conclusions the study authors wrote: “These results continue to support the use of asciminib as a new CML therapy, with the potential to transform standard of care.”

References

1. Rea D, Mauro MJ, Hochhaus A, et al. Efficacy and safety results from ASCEMBL, a phase 3 study of asciminib versus bosutinib (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after ≥2 prior tyrosine kinase inhibitors (TKIs): week 96 update. J Clin Oncol. 2022;40(suppl 16):7004. doi:10.1200/JCO.2022.40.16_suppl.7004
2. FDA approves asciminib for Philadelphia chromosome-positive chronic myeloid leukemia. FDA. October 29, 2021. Accessed June 7, 2022. bit.ly/3Q6Jexu