Asciminib Continues to Best SOC TKIs as Secondary End Points of ASC4FIRST Trial are Met

Asciminib (Scemblix) has further cemented its role in the chronic myeloid leukemia (CML) treatment landscape as 96-week updated data showed the agent bested standard-of-care (SOC) investigator-selected tyrosine kinase inhibitors (IS-TKIs) and met key secondary end points of the phase 3 ASC4FIRST trial (NCT04971226).1

Data presented at the 2024 ASH Annual Meeting showed that the major molecular response (MMR) rate at week 96 continued to be superior among patients who received asciminib (n = 201) vs all IS-TKIs (n = 204), meeting a key secondary end point of the trial; rates were 74.1% vs 52.0%, respectively with investigators noting the difference was 22.4% (95% CI, 13.6%-31.3%; P < .001). This represented an increase in MMR as the 48-week MMR rates were 67.7% and 49.0%, respectively, which originally met the primary end point of the trial.

“The 96-week data that I am showing you today for the first time [reveal that] all of these comparisons against all TKIs, imatinib [Gleevec], and second generation TKIs, favor asciminib.The ones that are powered [for it] are statistically significant [as well],” Jorge E. Cortes, MD, said in a presentation of the data. Cortes is director for the Georgia Cancer Center and the Cecil F. Whitaker Jr, GRA Eminent Scholar Chair in Cancer in Augusta.

The 96-week MMR rates were also consistently higher with asciminib across the trial strata. In the imatinib stratum, patients who received asciminib (n = 101) experienced a 96-week MMR rate of 76.2% vs 47.1% among those in the IS-TKI arm (n = 102), for a difference of 29.7% (95% CI, 17.6%-41.8%; P < .001). In the second-generation TKI stratum, the 96-week MMR rates were 72.0% in the asciminib arm (n = 100) and 56.9% in the IS-TKI arm (n = 102) for a difference of 15.1% (95% CI, 2.3%-28.0%).

The FDA Approval of Asciminib and ASC4FIRST Trial Enrollment

The October 29, 2024 FDA accelerated approval of asciminib for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase (CP) was based on the 48-week MMR data from ASC4FIRST.2 Findings supporting the approval showed that the 48-week MMR rate was 68% (95% CI, 61%-74%) in the asciminib arm vs 49% (95% CI, 42%-56%) in the IS-TKIs arm, for a difference of 19% (95% CI, 10%-28%, P < .001), meeting one of the trial’s primary end points.1,2 The other primary end point, 48-week MMR rate with asciminib vs IS-TKIs in the imatinib stratum, was also met in the primary analysis of ASC4FIRST with high statistical significance.2 The MMR rate was 69% (95% CI, 59%-78%) vs 40% (95% CI, 31%-50%), respectively, for a difference of 30% (95% CI, 17%-42%; P < .001).

ASC4FIRST enrolled adult patients newly diagnosed Philadelphia chromosome-positive CML-CP who had not been previously treated with a TKI. Patients received asciminib at 80 mg once daily or IS-TKIs at label doses.1 Physicians and patients consulted to select a TKI should the patient be randomly assigned to the IS-TKI arm of the trial and stratification occurred by prerandomization TKI selection and EUTOS long-term survival score (ELTS) risk category. Secondary end points of the trial included 96-week MMR with asciminib vs all IS-TKIs and 96-week MMR with asciminib vs IS-TKIs in the imatinib stratum.

“The patient characteristics were very well balanced,” Cortes said. “When you look at the individual strata, however, it becomes obvious that the patients in the imatinib strata were somewhat older and had a higher Framingham [risk] score, whereas the patients in the second-generation TKI strata tended to have more patients in the high-risk ELTS risk classification.”

Additional Data From ASC4FIRST

At the October 22, 2024, data cutoff, more patients were ongoing treatment with asciminib (81.6%) than all IS-TKIs (60.3%). Patients in the asciminib arm vs all IS-TKIs arm discontinued treatment (17.9% vs 38.2%, respectively) due to unsatisfactory therapeutic effect (9.5% vs 20.6%), adverse effect (AE; 6.0% vs 12.7%), progressive disease (1.0% vs 2.0%), physician decision (0.5% vs 0.0%), protocol deviation (0.5% vs 1.0%), patient decision (0.5% vs 1.5%), or pregnancy (0.0% vs 0.5%).

“The discontinuation rate was twice as high with all IS-TKIs compared with asciminib,” Cortes noted.

Furthermore, the cumulative incidence of MMR was higher with asciminib (80.5%) vs all IS-TKIs (62.1%) at 96-weeks.1 Across strata, this was also true; in the imatinib stratum rates were 80.0% in the asciminib arm and 56.5% in the IS-TKI arm, and in the second-generation TKI stratum rates were 81.0% in the asciminib arm and 67.6% in the IS-TKI arm.

At week 96, data on deep molecular responses revealed that 48.8% of patients who received asciminib achieved an MR4 and 30.9% achieved an MR4.5; these respective rates were 27.5% and 17.7% in the all IS-TKIs arm. In the imatinib stratum 52.5% of patients treated with asciminib experienced an MR4 and 35.6% experienced an MR4.5; respective rates were 23.5% and 11.8% in the IS-TKI arm. Additionally, in the second-generation TKI stratum, 45.0% of patients treated with asciminib experienced an MR4 and 26.0% experienced an MR4.5; respective rates were 31.4% and 23.5% in the IS-TKI arm.

“There is a continued and increasing difference in favor of asciminib [vs IS-TKI] for both MR4 and MR4.5,” Cortes explained. “One important analysis is to look at the difference in subsets of patients. These are small subsets [and the study was] not powered for any one of them, but it is very good to see that in any individual subgroup—whether it’s by ELTS, sex, race and ethnicity, age category, [or] Framingham score—all of them favor the treatment of asciminib in terms of the rate of MMR at [week] 96. There’s really no subset of patients where we don’t see at least a trend in benefit for asciminib compared with the investigator selected control [arm].”

Investigators also examined postbaseline treatment-emergent BCR::ABL1 gene mutations by next-generation sequencing. “In summary, all the mutations that emerged in this study with the treatment [of] asciminib have been myristoyl pocket mutations,” Cortes noted.

Asciminib’s Safety Profile Continues to Best Imatinib and Second-Generation TKIs

By the 96-week data cutoff, safety and tolerability data continued to be more favorable with asciminib compared with imatinib and second-generation TKIs. The risk of treatment discontinuation due to AEs was 54% lower with asciminib vs second-generation TKIs (HR, 0.46; 95% CI, 0.215-0.997).

“Asciminib’s safety and tolerability profile continued to be better than that of imatinib and second-generation TKIs after longer follow-up and [data were] consistent with its known safety profile,” Cortes said.

In the safety populations of patients who received asciminib (n = 200), imatinib (n = 99), and second-generation TKIs (n = 102), grade 3 or higher AEs (44.5% vs 49.5% vs 59.8%, respectively), AEs leading to treatment discontinuation (5.0% vs 13.1% vs 12.7%), and AEs leading to dose adjustment/interruption (33.0% vs 41.4% vs 57.8%) occurred.

Additionally, arterial occlusive events (AOEs) did not occur frequently with any agents in the trial. Four patients experienced at least 1 AOE in the asciminib arm (n = 200), and 3 patients experienced at least 1 event in the second-generation TKI group (n = 102); 1 patient in each of the aforementioned arms experienced a grade 3 or greater event and no patients in the imatinib group (n = 99) experienced an AOE.

“Asciminib’s favorable risk-benefit profile compared with all IS-TKIs, imatinib, and second-generation TKIs in patients with newly diagnosed CML-CP reinforces the use of asciminib as a SOC for this patient population,” Cortes concluded.

Disclosures: Dr Cortes cited having a consultancy role with Biopath Holdings, Nerviano, Syndax, Rigel, Sun Pharma, Pfizer, Novartis, and Lilly. He has received research funding from Ascentage, AbbVie, Sun Pharma, and Novartis. Cortes cited having membership on an entity’s Board of Directors or advisory committee with Biopath Holdings and he is a current holder of stock options as well.

References

1. Cortes JE, Hochhaus A, Hughes TP, et al. Asciminib (ASC) demonstrates favorable safety and tolerability compared with each investigator-selected tyrosine kinase inhibitor (IS TKI) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) in the pivotal phase 3 ASC4FIRST study. Blood. 2024;144(suppl 1):475. doi:10.1182/blood-2024-203757
2. FDA grants accelerated approval to asciminib for newly diagnosed chronic myeloid leukemia. FDA. October 29, 2024. Accessed December 8, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-asciminib-newly-diagnosed-chronic-myeloid-leukemia