Asciminib Bests Standard-of-Care TKIs in Ph+ CML

Jorge E. Cortes, MD

Asciminib (Scemblix) was the first and only agent to display a significant efficacy improvement compared with standard-of-care TKIs in the frontline setting for the treatment of patients with newly diagnosed chronic myeloid leukemia (CML), according to findings from the phase 3 ASC4FIRST study (NCT04971226) presented during the 2024 ASCO Annual Meeting.¹

Primary results shared during a press briefing showed that, at a data cutoff of November 28, 2023, patients with Philadelphia chromosome (Ph)–positive chronic phase CML who received asciminib (n = 201) achieved a 48-week major molecular response (MMR) rate of 67.7% (95% CI, 60.7%-74.1%) compared with 49.0% (95% CI, 42.0%-56.1%) among patients who were treated with an investigator-selected TKI (n = 204); this represented an 18.9% (95% CI, 9.6%-28.2%; P < .001) improvement. Furthermore, in the imatinib (Gleevec) stratum of both arms, the 48-week MMR rates were 69.3% (95% CI, 59.34%-78.10%) in the investigational arm (n = 101) vs 40.2% (95% CI, 30.61%-50.37%) in the comparator arm (n = 102), for an improvement of 29.55% (95% CI, 16.91%-42.18%; P < .001).

“A significant number of patients [with CML]—more than half—do not get the deep molecular responses and the type of outcomes that we aim for now that treatment-free remission is becoming increasingly important,” Jorge E. Cortes, MD, the director of the Georgia Cancer Center at Augusta University, said during the press event. “Asciminib is a TKI with a novel mechanism of action that binds to the myristoyl pocket, raising the possibility of greater selectivity and less toxicity. The drug has been approved for patients who have received multiple prior therapies, and in a randomized trial in that setting [it] showed improved efficacy and safety. [Therefore], we decided to bring it to the frontline setting to see if something similar could be observed.”

ASC4FIRST was a multicenter, open-label study that enrolled adult patients with newly diagnosed Ph-positive chronic phase CML who had not received prior treatment with a TKI. Prior to randomization, investigators selected a TKI in consultation with the patient in the event that the patient was assigned to the comparator TKI arm. Patients were stratified by prerandomization TKI selection (imatinib vs second-generation TKI) and European Treatment and Outcome Study (EUTOS) long-term survival risk category (low vs intermediate vs high).

Eligible patients were randomly assigned 1:1 to receive either asciminib at a dose of 80 mg daily or a TKI of the investigator’s choice. Within the investigator-selected TKI arm, patients were further divided to receive a second-generation TKI or imatinib; the investigational arm included imatinib and second-generation TKI stratums.

The primary end point was 48-week MMR rate. Secondary end points included 96-week MRR rate, time to discontinuation due to adverse effects (AEs), MMR at scheduled data collection time points, complete hematological response rate, duration of MMR, event-free survival, progression-free survival, and overall survival, among others.²

The baseline patient characteristics were well balanced between the asciminib and TKI comparator arms; the median age was 52.0 years (range, 18.0-79.0) and 50.5 years (range, 19.0-86.0), respectively. Most patients in both arms were between 18 and less than 65 years old (77.1% vs 76.0%), males (65.2% vs 61.3%), had low-risk disease by Framingham estimated 10-year cardiovascular disease risk categories (54.2% vs 54.9%), and had a low EUTOS long-term survival score (60.7% vs 61.3%).¹

Additional findings from ASC4FIRST showed that more patients who received asciminib experienced deep molecular responses compared with those treated with investigator-selected TKIs. The MR4 rates at week 48 were 38.8% vs 20.6%, respectively, and the 48-week MR4.5 rates were 16.9% vs 8.8%, respectively.

In the imatinib stratums, the MR4 rates were 42.6% in the asciminib arm (n = 101) and 17.8% in the TKI arm (n = 102); the MR4.5 rates were 17.8% and 4.9%, respectively. In the second-generation TKI stratum, the MR4 rates were 35.0% and 26.5% in the investigational (n = 100) and control (n = 102) arms, respectively; the MR4.5 rates were 16.0% and 12.8%, respectively.

In terms of safety, the most common non-hematologic any-grade AEs observed among all patients treated with asciminib (n = 200) were diarrhea (15.5%), fatigue (14.0%), and headache (13.5%). Patients who received imatinib (n = 99) experienced diarrhea (26.3%), nausea (21.2%), and periorbital/face edema (20.2%) most frequently. Any-grade AEs in the second-generation TKI group (n = 102) included diarrhea (25.5%), headache (21.6%), and rash (21.6%).

Any-grade hematologic toxicities in all patients who received asciminib vs imatinib vs second-generation TKIs consisted of thrombocytopenia (28.0% vs 28.3% vs 34.3%), neutropenia (25.0% vs 31.3% vs 34.3%), leukopenia (19.0% vs 29.3% vs 19.6%), anemia (11.5% vs 26.3% vs 22.5%), and lymphopenia (6.0% vs 16.2% vs 6.9%).

Most patients in the asciminib imatinib stratum (84.2%) and second-generation TKI stratum (88.0%) were still receiving study treatment at the data cutoff. Comparatively, these rates were 61.8% and 75.5%, respectively, in the investigator-selected TKI imatinib stratum and investigator-selected second-generation TKI stratum.

“This is the first study to compare a new drug, in this case asciminib, with any of the TKIs that are approved in the frontline setting of chronic phase CML,” Cortes said in conclusion. “We demonstrated a statistically superior response in terms of MMR at 48 weeks, both against imatinib and against all TKIs, and a safety and tolerability profile that favors asciminib against all of the TKIs, suggesting that this strong benefit-risk profile may change the treatment paradigm in CML.”

References

1. Hughes TP, Hochhaus A, Takahashi N, et al. ASC4FIRST, a pivotal phase 3 study of asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS TKIs) in newly diagnosed patients (pts) with chronic myeloid leukemia (CML): primary results. J Clin Oncol. 2024;42(suppl 17):LBA6500. doi:10.1200/JCO.2024.42.17_suppl.LBA6500
2. A study of oral asciminib versus other TKIs in adult patients with newly diagnosed Ph+ CML-CP. ClinicalTrials.gov. Updated May 3, 2024. Accessed May 29, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04971226