In newly diagnosed CML in the chronic phase, aximinib/asinib shows better tolerability than nilotinib

Asciminib/asciminib was significantly better tolerated than nilotinib in patients with newly diagnosed chronic myeloid leukemia (CML) chronic phase (CML-CP) who discontinued treatment due to adverse effects (TTDAE), meeting the primary endpoint of the phase 3b ASC4START trial (NCT05456191). Results shared at multiple conferences in 2025 showed a statistically significant difference in time to discontinuation of treatment due to toxicity in favor of asinib; the cause-specific hazard ratio was 0.45 (95% CI, 0.25-0.81; P=0.004). Specifically, at the data cutoff of September 3, 2024, a 55% reduction in the risk of discontinuation due to adverse events was observed with asnib versus nilotinib.

The incidence of adverse events leading to discontinuation was lower with asinib (n=284) compared with nilotinib (n=282). The percentage of patients who experienced at least 1 adverse event of any grade leading to discontinuation was 5.3% in the asinib group and 11.7% in the nilotinib group. In the asinib group, the most common adverse events leading to discontinuation were thrombocytopenia, increased lipase, increased alanine aminotransferase (ALT) levels, and pancreatitis. In nilotinib, the most common adverse events leading to discontinuation were increased lipase, pancreatitis, increased amylase, increased blood bilirubin, increased ALT levels, fatigue, atrial fibrillation, drug-induced liver injury, and thrombocytopenia.

In addition, compared with nilotinib, the incidence of adverse events leading to dose adjustment was lower with asinib, which was 24.3% and 30.1%, respectively. Adverse events of all grades occurred in 80.3% of patients in the asinib group and 86.5% in the nilotinib group. Grade 3 or higher adverse events were reported in 25.0% of patients treated with asinib and 31.9% of patients treated with nilotinib. These findings, along with data from ASC4FIRST [NCT04971226], further support the potential of asinib to become the standard of care for patients with newly diagnosed CML-CP, enabling more patients to achieve treatment goals without the need to switch therapies.

Previously, in adults with newly diagnosed Philadelphia chromosome-positive CML-CP, asinib (n=201) resulted in a major 48-week major outcome when researchers chose imatinib, nilotinib, dasatinib, or bosutinib. The molecular response (MMR) rate was 68% (95% CI, 61%-74%), compared with 49% (95% CI, 10%-28%; P<0.001) for the investigators' choice of imatinib, dasatinib, dasatinib (Spryscel) or bosutinib. -78%) The MMR rate in the asinib group was 40% (95% CI, 31%-50%), and compared with the investigator's choice group, the difference was 30% (95% CI, 17%-42%; P<0.001).

These data from the ASC4FIRST Phase 3 study support the U.S. Food and Drug Administration's decision in October 2024 to accelerate approval of asinib for this population. The drug is also approved for this indication in China, Japan, Switzerland and other countries around the world. Compared with second-generation TKIs, asinib's high specificity for BCR:ABL1 may reduce off-target effects and improve tolerability while maintaining efficacy.

The phase 3b ASC4START trial enrolled patients with newly diagnosed Ph-positive CML-CP who were at least 18 years old and had no prior exposure to TKIs. Participants (n=568) were stratified by EUTOS long-term survival (ELTS) risk category (high, intermediate, low) at diagnosis and randomly assigned 1:1 to receive 80 mg of nilotinib once daily (n=284) or 300 mg of nilotinib twice daily (n=284).

In addition to the trial's TTDAE primary endpoint, defined as the time from the first dose of study treatment to discontinuation due to an adverse event, secondary safety endpoints include the type, frequency and severity of adverse events, and dose adjustments due to adverse events. Secondary efficacy endpoints include MMR, MR4 (BCR:ABL1IS≤0.01%), MR4.5 (BCR:ABL1IS≤0.0032%) complete hematologic response, and the incidence of BCR:ABL1WIS≤1% at all predetermined time points.

The interim analysis of the primary endpoint occurred at50 events to allow early assessment of tolerability of asinib. A formal interim analysis is planned when treatment is discontinued due to toxicity in approximately 46 patients. Preliminary analysis is planned over 65 events; subsequently, the study will enter an optional treatment-free remission phase.

Baseline characteristics were well balanced between treatment groups. Among all patients, the median age was 50.0 years (range, 18-84 years), with the majority of patients aged between 18 and 65 years (85.2%). 59% of patients were male and 78.2% were white. The majority of patients had an ECOG performance status of 0 (81.2%). Regarding ELTS, 60.4% were low risk, 26.4% were medium risk, and 13.2% were high risk.

By the data cutoff for the interim analysis,50 events were observed and the margin of statistical significance was recalculated to 0.0062. The median follow-up time from randomization to the cutoff date was 9.7 months (range, 0-20.8), with more patients continuing on asinib than on nilotinib (89.1% vs. 82.0%). Additionally, 10.9% and 17.3% of patients in each group discontinued treatment; 4.9% and 11.6% did so because of adverse events. Two patients in the asinibgroup died and one patient died in the nilotinib group.

The most common adverse events in the aspartate group (n=284) were thrombocytopenia, headache, myalgia, nausea, neutropenia, fatigue, back pain, alopecia, increased ALT levels, increased aspartate aminotransferase (AST) levels, increased gamma-glutamyl transferase (GGT), and increased blood bilirubin. In the nilotinib group (n=282), the most common adverse events were rash, thrombocytopenia, headache, increased ALT levels, fatigue, increased lipase, asthenia, anemia, nausea, increased GGT, constipation, back pain, and hypertension.

Specific adverse events were generally less common with asinib compared with nilotinib. The most common specific adverse events with asinib were myelosuppression, followed by gastrointestinal toxicity and hypersensitivity reactions. The most common specific adverse events of nilotinib are hypersensitivity reactions, followed by hepatotoxicity, myelosuppression, and gastrointestinal toxicity.

Reference materials:https://www.onclive.com/view/asciminib-shows-superior-tolerability-over-nilotinib-in-newly-diagnosed-cml-in-chronic-phase