Paper Details

ABSTRACT

Introduction: Tolerability is an important factor influencing treatment persistence in CML-CP. Improved tolerability may help patients stay on treatment longer to achieve durable molecular responses (MRs), while maintaining quality of life and reducing the proportion of patients (pts) bothered by treatment. ASC4START (NCT05456191) is a phase 3b study of pt-relevant outcomes comparing asciminib, the first BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket, with nilotinib in newly diagnosed CML-CP. The study met its primary endpoint at first interim analysis (cutoff: September 3, 2024), demonstrating significantly superior tolerability of asciminib vs nilotinib based on time to treatment discontinuation due to adverse events (TTDAE). We report tolerability, safety, pt-reported outcomes (PROs), and MR efficacy results from ASC4START through wk 96 (cutoff: April 17, 2026).

Methods: Adults with newly diagnosed CML-CP were randomized 1:1 to receive asciminib 80 mg once daily or nilotinib 300 mg twice daily, stratified by ELTS risk category. Tolerability was assessed by TTDAE, defined as time from first dose to treatment discontinuation due to AEs, including death due to AEs. Safety, EORTC QLQ-C30/CML24 PROs, and efficacy outcomes were secondary endpoints; FACT-GP5 PROs was exploratory. Both arms followed the same protocol-defined approach for dose modifications and discontinuations due to AEs.

Results: Overall, 568 pts were randomized (asciminib, n=284; nilotinib, n=284); 566 received treatment (safety analysis set); 2 pts randomized to nilotinib were not treated.

At wk 96, more pts remained on asciminib than nilotinib (75.7% vs 60.9%); median treatment exposure was 117.4 vs 112.0 wk and relative dose intensity >90% to 110% was 83.1% vs 73.8%, respectively.

Asciminib maintained superior tolerability vs nilotinib based on TTDAE, with a cause-specific hazard ratio of 0.40 (95% CI, 0.26-0.62; nominal P<.0001); fewer pts discontinued due to AEs with asciminib (28/284 [9.9%]) vs nilotinib (64/282 [22.7%]), and AE-related dose adjustments or interruptions were also less frequent (92/284 [32.4%] vs 121/282 [42.9%]).

Most common any-grade AEs (>5% in any arm) with ≥5% difference between asciminib and nilotinib were increased blood bilirubin (2.5% vs 16.3%), ALT (6.7% vs 16.0%), and AST (5.3% vs 10.3%), rash (12.3% vs 17.7%), alopecia (3.9% vs 12.4%), and hypertension (13.4% vs 3.9%).  

Selected any-grade AEs of special interest with asciminib vs nilotinib included acute pancreatitis (0.4% vs 2.5%), myelosuppression (28.2% vs 25.5%), gastrointestinal toxicity (33.1% vs 30.1%), and arterial occlusive events (AOEs; 3.9% vs 4.3%). Exposure-adjusted AOE rates were 1.8 and 2.3 cases per 100 pt-treatment years with asciminib and nilotinib, respectively; most were associated with ≥1 cardiovascular risk factor, and none were fatal.

Through the wk 96 cutoff, 6 on-treatment deaths were reported, 3 in each arm (asciminib: suicide, cardiac arrest, congestive heart failure; nilotinib: cardiac arrest, pulmonary embolism, multiple organ dysfunction syndrome); none were considered treatment related.

At all postbaseline time points through wk 96, more pts receiving asciminib vs nilotinib reported being “not at all” bothered by side effects as assessed by FACT-GP5 (65.3% vs 40.2% at wk 96, with completion by 124/162 [76.5%] and 107/133 [80.5%] eligible pts, respectively). 

The proportion of pts with improved EORTC QLQ-C30/CML24 scores at wk 96 was higher (8/21) or similar (11/21) with asciminib vs nilotinib across functioning, quality of life, and symptom domains.

At wk 96, MR rates with asciminib vs nilotinib included MMR (67.3% vs 59.2%), MR⁴ (38.4% vs 32.0%), and MR^4.5 (25.4% vs 22.5%). MR rates in responders were durable, with Kaplan-Meier estimated probabilities of maintaining response >95% at all subsequent time points through wk 96.

Conclusion: ASC4START continued to show sustained superior tolerability of asciminib vs nilotinib through wk 96, with fewer discontinuations due to AEs and dose modifications. PROs reinforced this tolerability benefit, with scores generally maintained or improved across domains and fewer pts reporting being bothered by side effects. 

These findings support asciminib as a frontline treatment option with superior tolerability that may allow more pts to stay on treatment longer to achieve durable, deep responses. The study is ongoing to explore treatment-free remission eligibility and success.