Over the past 2 decades, the development of tyrosine kinase inhibitors (TKIs) targeting the ATP-binding site of the constitutively activated tyrosine kinase in the fusion BCR::ABL1 protein has resulted in markedly improved treatment outcomes among patients with chronic myeloid leukemia (CML). Despite this progress, however, many patients discontinue TKI treatment because of drug resistance or intolerance.

Now, results are available from the phase III ASC4FIRST study (ClinicalTrials.gov identifier NCT04971226), which compared the efficacy of oral asciminib, a first-in-class allosteric inhibitor of BCR::ABL1, vs all current standard-of-care TKIs in patients with newly diagnosed CML. Findings from the trial showed that asciminib was significantly superior in efficacy and was found to have markedly favorable safety and tolerability than the traditionally used agents. Asciminib, according to the study authors, has the potential to be the therapy of choice for patients with CML. The study was presented by Hughes et al at the 2024 ASCO Annual Meeting (Abstract LBA6500).

Study Methodology

In the phase III, multicenter, open-label, randomized study, patients with newly diagnosed Philadelphia chromosome–positive CML in chronic phase either received oral asciminib at 80 mg once daily or an investigator-selected TKI (either imatinib, nilotinib, dasatinib, or bosutinib) at standard label doses. Researchers randomly assigned a total of 405 patients 1:1 to receive asciminib or an investigator-selected TKI, stratified by EUTOS long-term survival score and a pre–random assignment selected TKI (imatinib or second-generation TKIs), accounting for patient preference.

Patients diagnosed with CML within 3 months before trial enrollment with no prior treatment except imatinib or second-generation TKIs for ≤ 2 weeks prior to random assignment were eligible. 

The primary objectives of the study were to demonstrate superior major molecular response (MMR) rate at week 48 with asciminib vs an investigator-selected TKI, and asciminib vs an investigator-selected TKI within the stratum of patients receiving imatinib as the pre–random assignment selected TKI. The study was deemed positive if either objective was met. Comparing the MMR rate of ascminib vs investigator-selected TKIs at week 48 within the stratum of patients receiving second-generation TKIs as their prerandomization-selected TKI was an unpowered secondary objective. 

Results

Two hundred and one patients received asciminib (asciminib with imatinib as their pre–random assignment TKI, n = 101; asciminib with a second-generation TKI as their pre–random assignment TKI, n = 100) and 204 received an investigator-selected TKI (imatinib as their pre–random assignment TKI, n = 102; second-generation TKIs as their pre–random assignment TKI, n = 102 [nilotinib, 48%; dasatinib, 41%; bosutinib, 11%]). Median follow-up was 16.3 and 15.7 months for asciminib and an investigator-selected TKI, respectively (cutoff was November 28, 2023). At cutoff, treatment was ongoing in 86%, 62%, and 75% of patients receiving asciminib, imatinib, and second-generation TKIs, respectively, with patients most commonly discontinuing treatment due to unsatisfactory therapeutic effect (6%, 21%, 10%; treatment failure per European LeukemiaNet 2020 recommendations [5%, 16%, 8%], MMR loss [0.5%, 0%, 0%], physician decision [0.5%, 5%, 2%]) and adverse events (5%, 11%, 10%).

The MMR rate at week 48 (per intent-to-treat) was superior with asciminib (67.7%) vs investigator-selected TKI (49.0%) and with asciminib with imatinib as the pre–random assignment TKI  (69.3%) vs investigator-selected TKI with imatinib as the pre–random assignment TKI  (40.2%), meeting both primary objectives with high statistical significance; the rate difference was 18.9% (95% confidence interval [CI] = 9.6%–28.2%) and 29.6% (95% CI = 16.9%–42.2%), respectively, both with adjusted 1-sided P < .001. 

The MMR rate at week 48 was higher with asciminib with a second-generation TKI as the pre–random assignment TKI vs investigator-selected with a second-generation TKIs as the pre–random assignment TKI (66.0% vs 57.8%). BCR::ABL1^IS ≤ 1% rate at week 48 was 87% with asciminib vs 73% with an investigator-selected TKI and 84% with asciminib with imatinib as the pre–random assignment TKI  vs 62% with investigator-selected TKI with imatinib as the pre–random assignment TKI. 

At week 48, 4-log and 4.5-log reductions in BCR::ABL1 levels (MR⁴ and MR^4.5) were higher in patients receiving asciminib vs investigator-selected TKI (39% vs 21%; 17% vs 9%), asciminib with imatinib as the pre–random assignment TKI vs investigator-selected TKI with imatinib as the pre–random assignment TKI (43% vs 15%; 18% vs 5%), and asciminib with second-generation TKI as the pre–random assignment TKI vs investigator-selected TKI with second-generation TKI as the pre–random assignment TKI (35% vs 26%; 16% vs 13%). 

The study found that asciminib had markedly favorable safety and tolerability vs imatinib and second-generation TKIs, with patients receiving the agent experiencing fewer grade ≥ 3 adverse reports (38%, 44%, 55%), half the rate of adverse events leading to treatment discontinuation (5%, 11%, 10%), and less dose adjustments/interruptions to manage adverse events (30%, 39%, 53%). The rate of arterial occlusive events was 1%, 0%, and 2%, respectively. 

Conclusions

“Asciminib is the only agent to show a statistically significant superior efficacy and excellent safety and tolerability vs all current standard-of-care frontline treatments, with the potential to be the therapy of choice for CML,” concluded the study authors. 

Disclosure: Funding for this study was provided by Novartis. For full disclosures of the study authors, visit coi.asco.org.