Asciminib Shows Superior Tolerability Over Nilotinib in Newly Diagnosed CML in Chronic Phase

Asciminib in Newly Diagnosed CML

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Asciminib (Scemblix) demonstrated significantly better tolerability than that observed with nilotinib (Tasigna) in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CML-CP) based on treatment discontinuation due to adverse effects (TTDAE), meeting the primary end point of the phase 3b ASC4START trial (NCT05456191).1

Findings, which were shared at the 2025 ASCO Annual Meeting,2 and now at the 2025 European Hematology Association Congress,1 revealed a statistically significant difference in time to treatment discontinuation due to toxicities that favored asciminib; the cause specific hazard ratio was 0.45 (95% CI, 0.25-0.81; P = .004). Specifically, at the time of data cutoff, which was September 3, 2024, a 55% lower risk of discontinuation due to AEs was observed with asciminib vs nilotinib.

AEs that led to discontinuation were less frequent with asciminib (n = 284) vs nilotinib (n = 282). The percentage of patients who experienced at least 1 any-grade AE that resulted in discontinuation was 5.3% in the asciminib arm and 11.7% in the nilotinib arm.

In the asciminib arm, the most common AEs that led to discontinuation were thrombocytopenia (any grade, 1.4%; grade ≥3, 1.4%), increased lipase (0.7%; 0%), increased alanine aminotransferase (ALT) levels (0.4%; 0.4%), and pancreatitis (0.4%; 0.4%). In the nilotinib, the most frequently reported AEs that resulted in discontinuation were increased lipase (any grade, 2.1%; grade ≥3, 1.4%), pancreatitis (1.4%; 1.4%), increased amylase (1.1%; 0.4%), increased blood bilirubin (1.1%; 0.4%), increased ALT levels (0.7%; 0.7%), asthenia (0.7%; 0%), atrial fibrillation (0.7%; 0%), drug-induced liver injury (0.7%; 0.7%), and thrombocytopenia (0.4%; 0.4%).

Additionally, lower rates of AEs leading to dose modifications were observed with asciminib vs nilotinib, at 24.3% and 30.1%, respectively. All-grade AEs occurred in 80.3% of those in the asciminib arm vs 86.5% of those in the nilotinib arm. Grade 3 or higher AEs were reported in 25.0% of those who received asciminib vs 31.9% of those given nilotinib.

“These findings, along with data from ASC4FIRST [NCT04971226], further support the potential for asciminib to be standard of care for patients with newly diagnosed CML-CP allowing more patients to meet their treatment goals without requiring treatment switch,” Andreas Hochhaus, MD, director of the Department of Hematology and Internal Oncology of KIM II and vice dean for research at Friedrich-Schiller-Universität Jena, in Germany, said in a presentation of the data.

Analyzing What Came ASC4FIRST

Previously, asciminib (n = 201) led to a 48-week major molecular response (MMR) rate of 68% (95% CI, 61%-74%) vs 49% (95% CI, 42%-56%) with investigator’s choice of imatinib (Gleevec), nilotinib, dasatinib (Sprycel), or bosutinib (Bosulif; n = 204) in adult patients with newly diagnosed, Philadelphia chromosome–positive CML-CP, translating to a difference of 19% (95% CI, 10%-28%; P < .001).3 Additionally, within the imatinib stratum, a 69% (95% CI, 59%-78%) MMR rate was reported in the asciminib arm vs 40% (95% CI, 31%-50%) in the investigator’s choice arm, translating to a difference of 30% (95% CI, 17%-42%; P < .001).

These data from the phase 3 ASC4FIRST study supported the FDA’s decision to grant accelerated approval to asciminib for this population in October 2024.4 Hochhaus added that the agent was also cleared for this indication in China, Japan, Switzerland, and other countries worldwide.4 “Compared with second-generation TKIs, the high specificity of asciminib for BCR::ABL1 may reduce off-target effects and improve tolerability while maintaining efficacy,” he noted.1

Fast Forward to ASC4START

The phase 3b ASC4START trial enrolled patients with newly diagnosed, Ph-positive CML-CP who were at least 18 years of age and did not have prior exposure to a TKI. Participants (n = 568) were stratified by EUTOS Long-term Survival (ELTS) risk category at the time of diagnosis (high vs intermediate vs low) and were randomly assigned 1:1 to receive 80 mg of asciminib once daily (n = 284) or 300 mg of nilotinib twice daily (n = 284).

In addition to the trial’s primary end point of TTDAE, which was defined as the time from first dose of study treatment to discontinuation because of AEs, secondary safety end points included the type, frequency, and severity of AEs, as well as dose modifications due to AEs. Secondary efficacy end points included MMR, MR4 (BCR:ABL1IS ≤ 0.01%) MR4.5 (BCR:ABL1IS ≤ 0.0032%) complete hematologic response, and BCR::ABL1IS ≤1% rates at and by all scheduled time points.

The interim analysis of the primary end point occurred at 50 events to allow for early evaluation of asciminib’s tolerability. A formal interim analysis was planned when approximately 46 treatment discontinuations due to toxicities occurred. The primary analysis is planned at 65 events; this will be followed by an optional treatment-free remission phase of the study.

Hochhaus noted that the baseline characteristics were well balanced between the treatment arms. In all patients, the median age was 50.0 years (range, 18-84), and most were between the ages of 18 years and 65 years (85.2%). Fifty-nine percent of patients were male and 78.2% were White. The majority had an ECOG performance status of 0 (81.2%). Regarding ELTS, 60.4% were low risk, 26.4% were intermediate risk, and 13.2% were high risk.

By the time of the data cutoff for the interim analysis, 50 events were observed and the boundary for statistical significance was recalculated as .0062, according to Hochhaus. The median duration of follow-up was 9.7 months (range, 0-20.8) from randomization to cutoff, and more patients were continuing treatment with asciminib than with nilotinib (89.1% vs 82.0%). Moreover, 10.9% and 17.3% of patients in the respective arms discontinued treatment; 4.9% and 11.6% of them did so because of AEs. Two patients in the asciminib arm died, along with 1 patient in the nilotinib arm.

Additional Safety Insights

The most common AEs experienced in the asciminib arm (n = 284) were thrombocytopenia (all grade, 15.1%; grade ≥3, 9.2%), headache (10.2%; 0%), myalgia (10.2%; 0%), nausea (9.5%; 0%), neutropenia (9.5%; 6.0%), fatigue (8.8%; 0%), anemia (8.8%; 3.2%), rash (8.5%; 0.4%), diarrhea (8.1%; 0%), increased lipase (8.1%; 2.1%), pruritus (7.7%; 0%), hypertension (6.7%; 2.5%), asthenia (6.3%; 0%), back pain (6.3%; 0%), alopecia (3.5%; 0%), increased ALT level (3.2%; 1.4%), increased aspartate aminotransferase (AST) level (3.2%; 0.7%), increased gamma glutamyltransferase (GGT; 2.5%; 0.4%), and increased blood bilirubin (2.1%; 0%).

In the nilotinib arm (n = 282), the most common AEs were rash (all grade, 16.3%; grade ≥3, 0.7%), thrombocytopenia (13.8%; 6.4%), headache (13.1%; 0.4%), increased ALT levels (12.4%; 3.5%), fatigue (9.9%; 0.4%), increased blood bilirubin (9.9%; 2.1%), alopecia (8.5%; 0%), myalgia (8.2%; 0%), neutropenia (8.2%; 5.3%), increased AST level (7.8%; 2.1%), arthralgia (7.8%; 0%), diarrhea (7.4%; 0%), increased lipase (7.4%; 2.5%), asthenia (7.1%; 0%), anemia (7.1%; 1.4%), nausea (6.4%; 0%), increased GGT (6.0%; 1.1%), constipation (5.7%; 0%), back pain (3.5%; 0%), and hypertension (1.1%; 0.4%).

Hochhaus added that AEs of special interest were generally less common with asciminib vs nilotinib. The most common AE of special interest with asciminib was myelosuppression (all grade, 27.1%; grade ≥3, 13.7%), followed by gastrointestinal toxicity (22.9%; 0.4%), and hypersensitivity (13.4%; 0.4%). The most common AE of special interest in the nilotinib atm was hypersensitivity (all grade, 25.5%; grade ≥3, 1.1%), followed by hepatotoxicity (24.8%; 7.8%), myelosuppression (24.1%; 12.1%), and gastrointestinal toxicity (24.1%; 0.7%).

A Topline Look at Efficacy

More patients in the asciminib arm achieved early and deep molecular responses by week 12 vs those in the nilotinib arm. Specifically, BCR:ABL1IS ≤10% was achieved in 89.8% of those in the asciminib arm vs 82.0% of those in the nilotinib arm (difference, 7.8%; 95% CI, 2.1%-13.5%); BCR:ABL1IS ≤1% was achieved in 69.0% of those in the asciminib arm vs 52.5% of those in the nilotinib arm (difference, 16.6%; 95% CI, 8.8%-24.4%). The MMRs in the respective arms were 22.9% and 10.2% (difference, 12.7%; 95% CI, 6.8%-18.7%). Moreover, 4.6% and 1.1% of patients had MR4 (difference, 3.5%; 95% CI, 0.8%-6.2%); 2.5% and 0.4% had MR4.5 (difference, 2.1%; 95% CI, 0.2%-4.1%).

What’s Next?

“The study is ongoing with analyses planned for longer-term tolerability, quality of life, efficacy, and TFR,” Hochhaus concluded.

Disclosures: Hochhaus disclosed that institutional research support was received from Bristol Myers Squibb, Pfizer, TERNS, and Enliven, and honoraria and institutional research support was received from Novartis and Incyte.

References

1. Hochhaus A, Brümmendorf TH, Mahon FX, et al. Asciminib shows superior tolerability vs nilotinib in newly diagnosed chronic myeloid leukemia in chronic phase: primary end point results of the phase 3b ASC4START trial. Presented at: 2025 European Hematology Association Congress; June 12-15, 2024; Milan, Italy. Abstract S166.
2. Hochhaus A, Mahon FX, Brümmendorf TH, et al. Primary endpoint results of the phase 3b ASC4START trial of asciminib (ASC) vs nilotinib (NIL) in newly diagnosed chronic phase chronic myeloid leukemia (CML-CP): time to treatment discontinuation due to adverse events (TTDAE). J Clin Oncol. 2025;43(suppl 16):6501. doi:10.1200/JCO.2025.43.16_suppl.6501
3. Cortes JE, Hochhaus A, Hughes TP, et al. 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. Blood. 2024;144(suppl 1):475. doi:10.1182/blood-2024-203757
4. FDA grants accelerated approval to asciminib for newly diagnosed chronic myeloid leukemia. FDA. October 29, 2024. Accessed June 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-asciminib-newly-diagnosed-chronic-myeloid-leukemia