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
Authors: Cortes Jorge E. , Hochhaus Andreas , Hughes Timothy P , Wang Jianxiang , Kim Dong-Wook , Kim Dennis Dong Hwan , Mayer Jiri , Goh Yeow Tee , le Coutre Philipp , Etienne Gabriel , Takahashi Naoto , Kim Inho , Andorsky David , Issa Ghayas C. , Bombaci Felice , Kapoor Shruti , Jinwal Rajendra , Yau Lillian , Larson Richard 
Published: December 2024

Introduction: About 1/3rd of patients (pts) with newly diagnosed CML discontinue/switch treatments (Tx) regardless of TKI (imatinib [IMA], nilotinib [NIL], dasatinib [DAS], or bosutinib [BOS]). Many pts have poor quality of life on existing therapies. Tx-free remission is a key Tx goal, but only 30%-40% pts on IMA and 40%-50% on 2nd-generation (2G) TKIs meet discontinuation criteria. A frontline agent with a superior benefit-risk profile is needed. ASC is the first BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket. ASC4FIRST is a randomized phase 3 study of ASC vs all standard-of-care TKIs in newly diagnosed CML-CP. We present primary efficacy results and additional safety/tolerability data for ASC vs each IS TKI from the primary analysis (wk 48) data cutoff. Key secondary results from the wk 96 cutoff (Oct 21, 2024) will be presented at the 2024 ASH Meeting.

Methods: Adults with newly diagnosed CML-CP were stratified by ELTS risk category and TKI (IMA/2G TKIs [NIL, DAS, or BOS]) selected by investigators before randomization, accounting for pt preference. Pts were randomized 1:1 to receive either ASC 80 mg once daily or an IS TKI at label doses. The 2 primary and 2 key secondary efficacy endpoints are major molecular response (MMR) rate at wk 48 and 96, respectively, with ASC vs IS TKI and with ASC vs IS TKI in the IMA stratum; time to Tx discontinuation due to adverse events (AEs) is a secondary safety endpoint.

Results: In ASC4FIRST, 201 pts randomized to ASC and 204 to IS TKIs (IMA/2G TKIs) were included in efficacy analyses. Safety analyses were done in pts who received ASC (n=200), IMA (n=99), and 2G TKIs (NIL, n=49; DAS, n=42; BOS, n=11). At the wk 48 cutoff, after a median duration of follow-up of ≈16 months across study arms, Tx was ongoing in 86%, 62%, and 75% of pts on ASC, IMA, and 2G TKIs, respectively. Both primary objectives were met: MMR rate at wk 48 was superior with ASC (67.7%) vs IS TKIs (49.0%) (difference, 18.9%; 95% CI, 9.6%-28.2%; adjusted 2-sided P&lt;.001) and with ASC (69.3%) vs IMA (40.2%) in the IMA stratum (difference, 29.6%; 95% CI, 16.9%-42.2%; adjusted 2-sided P&lt;.001).

The rates of optimal responses at wk 12 (BCR::ABL1IS ≤10%) and wk 24 (BCR::ABL1IS ≤1%), respectively, were higher with ASC vs IS TKIs (89.6% vs 70.1%; 88.6% vs 63.7%), ASC vs IS TKI in the IMA stratum (88.1% vs 59.8%; 88.1% vs 52.9%), and ASC vs IS TKI in the 2G TKI stratum (91.0% vs 80.4%; 89.0% vs 74.5%).

Safety/tolerability of ASC was more favorable vs IMA and individual 2G TKIs. Grade ≥3 AEs were lower with ASC (38.0%) vs IMA (44.4%), NIL (51.0%), DAS (54.8%), and BOS (72.7%). Any-grade AEs leading to Tx discontinuation were lower with ASC (4.5%) vs IMA (11.1%), NIL (8.2%), DAS (11.9%), and BOS (9.1%), the most frequent (≥2% in any arm) being generalized edema (BOS, 9.1%), pleural effusion (DAS, 4.8%), cardiac failure, colitis, hypersensitivity, and muscular weakness (DAS, 2.4% each), lymphopenia and diarrhea (IMA, 2.0% each), QT prolongation, rash, and maculopapular rash (NIL, 2.0% each), and thrombocytopenia (ASC, 1.0%; NIL, 2.0%). Any-grade AEs leading to dose adjustment and/or interruption were lower with ASC (30.0%) vs IMA (39.4%), NIL (49.0%), DAS (54.8%), and BOS (63.6%). Arterial occlusive events occurred in 2 (1.0%) pts with ASC (arteriosclerosis coronary artery, n=1; cerebrovascular accident, n=1), 1 (1.0%) with NIL (vertebral artery arteriosclerosis), and 1 (1.0%) with DAS (myocardial infarction and ischemia). Two pts had cardiac failure with DAS.

Any-grade AEs of special interest (≥5% in any arm), defined as serious or nonserious safety events of medical concern, were lower with ASC vs IMA and/or 2G TKIs and included gastrointestinal toxicity (34.5%, 42.4%, 48.0%), myelosuppression (43.0%, 51.5%, 62.7%), hypersensitivity (24.0%, 41.4%, 41.2%), hepatotoxicity (16.5%, 19.2%, 34.3%), acute pancreatitis (isolated enzyme elevations) (13.0%, 16.2%, 14.7%), hemorrhage (6.0%, 7.1%, 9.8%), edema and fluid retention (3.5%, 13.1%, 11.8%), and ischemic heart and CNS conditions (6.0%, 5.1%, 7.8%).

Conclusions: In ASC4FIRST, ASC had a better benefit-risk profile compared with IS TKIs. ASC's superior efficacy vs all IS TKIs and more favorable safety/tolerability compared with each IS TKI (IMA, NIL, DAS, and BOS) suggests that ASC may transform the CML Tx paradigm. Key secondary endpoints, including MMR rate at wk 96, and other long-term secondary efficacy and safety/tolerability results, will be presented at ASH 2024.