Scemblix (asciminib) further solidified its role in treating chronic myeloid leukemia (CML) as 96-week data showed it outperformed standard-of-care investigator-selected tyrosine kinase inhibitors (TKIs) and met key secondary goals of the phase 3 ASC4FIRST trial.
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 Scemblix (201 patients) versus all IS-TKIs (204 patients), meeting a key secondary end point of the trial; rates were 74.1% versus 52%, respectively with investigators noting the difference was 22.4%. This represented an increase in MMR as the 48-week MMR rates were 67.7% and 49%, 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, [Gleevec] and second generation TKIs, favor [Scemblix]. The ones that are powered [for it] are statistically significant [as well],” Dr. Jorge E. Cortes 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 Scemblix across the trial strata. In the Gleevec (imatinib) stratum, patients who received Scemblix (101 patients) experienced a 96-week MMR rate of 76.2% versus 47.1% among those in the IS-TKI group (102 patients), for a difference of 29.7%. In the second-generation TKI stratum, the 96-week MMR rates were 72% in the Scemblix group (100 patients) and 56.9% in the IS-TKI group (102 patients) for a difference of 15.1%.
The FDA Approval of Scemblix and ASC4FIRST Trial Enrollment
The Oct. 29, 2024 FDA accelerated approval of Scemblix for the treatment of adults with newly diagnosed Philadelphia chromosome-positive CML in chronic phase (CP) was based on the 48-week MMR data from ASC4FIRST. Findings supporting the approval showed that the 48-week MMR rate was 68% in the Scemblix group versus 49% in the IS-TKIs group, for a difference of 19%, meeting one of the trial’s primary end points. The other primary end point, 48-week MMR rate with Scemblix versus IS-TKIs in the Gleevec stratum, was also met in the primary analysis of ASC4FIRST with high statistical significance. The MMR rate was 69% versus 40%, respectively, for a difference of 30%.
ASC4FIRST enrolled adults newly diagnosed Philadelphia chromosome-positive CML-CP who had not been previously treated with a TKI. Patients received Scemblix at 80 milligrams once daily or IS-TKIs at label doses. Physicians and patients consulted to select a TKI should the patient be randomly assigned to the IS-TKI group 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 Scemblix versus all IS-TKIs and 96-week MMR with Scemblix versus IS-TKIs in the Gleevec 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 Gleevec 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.”
Scemblix’s Safety Profile Continues to Best Gleevec and Second-Generation TKIs
By the 96-week data cutoff, safety and tolerability data continued to be more favorable with Scemblix compared with Gleevec and second-generation TKIs. The risk of treatment discontinuation due to side effects was 54% lower with Scemblix versus second-generation TKIs.
“[Scemblix’s] safety and tolerability profile continued to be better than that of Gleevec 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 Scemblix (200 patients), Gleevec (99 patients), and second-generation TKIs (102 patients), grade 3 (severe) or worse side effects (44.5% versus 49.5% versus 59.8%, respectively), side effects leading to treatment discontinuation (5% versus 13.1% versus 12.7%) and side effects leading to dose adjustment/interruption (33% versus 41.4% versus 57.8%) occurred.
Additionally, arterial occlusive events (AOEs) did not occur frequently with any agents in the trial. Four patients experienced at least one AOE in the Scemblix group (200 patients), and three patients experienced at least one event in the second-generation TKI group (102 patients); one patient in each of the aforementioned groups experienced a grade 3 or worse event and no patients in the Gleevec group (99 patients) experienced an AOE.
“[Scemblix’s] favorable risk-benefit profile compared with all IS-TKIs, Gleevec, and second-generation TKIs in patients with newly diagnosed CML-CP reinforces the use of Scemblix as a SOC for this patient population,” Cortes concluded.
Additional Data From ASC4FIRST
At the Oct. 22, 2024, data cutoff, more patients were ongoing treatment with Scemblix (81.6%) than all IS-TKIs (60.3%). Patients in the Scemblix group versus all IS-TKIs group discontinued treatment (17.9% versus 38.2%, respectively) due to unsatisfactory therapeutic effect (9.5% versus 20.6%), adverse effect (AE; 6% versus 12.7%), progressive disease (1% versus 2%), physician decision (0.5% versus 0%), protocol deviation (0.5% versus 1%), patient decision (0.5% versus 1.5%), or pregnancy (0% versus 0.5%).
“The discontinuation rate was twice as high with all IS-TKIs compared with [Scemblix],” Cortes noted.
Furthermore, the cumulative incidence of MMR was higher with Scemblix (80.5%) versus all IS-TKIs (62.1%) at 96-weeks. Across strata, this was also true; in the Gleevec stratum rates were 80% in the Scemblix group and 56.5% in the IS-TKI group, and in the second-generation TKI stratum rates were 81% in the Scemblix group and 67.6% in the IS-TKI group.
At week 96, data on deep molecular responses revealed that 48.8% of patients who received Scemblix achieved an MR4 and 30.9% achieved an MR4.5; these respective rates were 27.5% and 17.7% in the all IS-TKIs group. In the Gleevec stratum 52.5% of patients treated with Scemblix experienced an MR4 and 35.6% experienced an MR4.5; respective rates were 23.5% and 11.8% in the IS-TKI group. Additionally, in the second-generation TKI stratum, 45% of patients treated with Scemblix experienced an MR4 and 26% experienced an MR4.5; respective rates were 31.4% and 23.5% in the IS-TKI group.
“There is a continued and increasing difference in favor of [Scemblix] [versus 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 [Scemblix] 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 [Scemblix] compared with the investigator selected control [group].”
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] [Scemblix] have been myristoyl pocket mutations,” Cortes noted.
References:
“Scemblix (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” by Dr. Jorge E. Cortes et al., Blood.
For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.
