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An investigational tyrosine kinase inhibitor (TKI), asciminib, doubled the major molecular response (MMR) rate in previously treated chronic myeloid leukemia (CML) as compared with the second-generation TKI bosutinib (Bosulif), a randomized trial showed.

MMR at 24 weeks was 25.5% with asciminib versus 13.2% with bosutinib. The superiority of asciminib extended across all prespecified subgroups, including sex, number of prior lines of therapy, and BCR-ABL1 mutation status.

After adjustment for baseline differences in prior major cytogenetic response (MCyR), treatment with asciminib remained more than twice as likely to achieve MMR, Andreas Hochhaus, MD, at University Medical Center Jena in Germany, reported during the .

"Asciminib demonstrated statistically significant superior efficacy compared with bosutinib and favorable safety profile," Hochhaus said during a media presentation. "The assembled data support the use of asciminib as a new treatment option in CML, particularly in patients with resistance or intolerance to at least two TKIs. BCR-ABL remains the key driver of CML, even in patients beyond second line."

The favorable findings involved a difficult-to-treat patient population, commented Robert Brodsky, MD, of Johns Hopkins Medical Institutions in Baltimore.

"These were patients that were either refractory or intolerant of previous tyrosine kinase inhibitors, and this is a drug that has a slightly different mechanism of action and has a different target," said Brodsky, who moderated a press briefing that included Hochhaus's presentation. "The results signal that asciminib may provide a good opportunity for third-line treatment in CML patients."

Current CML therapies for patients with resistance or intolerance to two or more TKIs have limited efficacy, toxicity concerns, or both. Ponatinib (Iclusig), for example, has efficacy after prior therapies but also has an increased risk of cardiovascular issues, said Hochhaus.

Currently, bosutinib is the only second-generation TKI that has demonstrated clinical efficacy in CML beyond second line, he continued. Like other TKIs, it targets the ATP binding site of the kinase domain. In contrast, asciminib is the first so-called STAMP (specifically targeting the ABL myristoyl pocket) inhibitor.

Hochhaus reported initial findings from the , which compared asciminib and bosutinib in patients who had received at least two prior lines of therapy for CML. Patients were randomized 2:1 to asciminib or bosutinib; crossover to asciminib was permitted for patients who met criteria for treatment failure with bosutinib. Primary endpoint was MMR at 24 weeks without treatment failure at any time during randomized treatment.

Data analysis included 233 patients, whose median age was 52. Women accounted for a higher proportion of the bosutinib arm (59.2% vs 47.8% in the asciminib group), more patients in the control arm discontinued their last TKI because of lack of efficacy (71.1% vs 60.5%), and more patients randomized to bosutinib had received three or more prior lines of therapy (60.5% vs 47.8%). Overall, 14.2% of patients had a BCR-ABL1 mutation, and 1.7% had multiple BCR-ABL1 mutations.

Median follow-up was 14.9 months. At that point the results showed a 12.2% absolute difference in the primary endpoint in favor of asciminib. After adjustment for baseline MCyR status, the difference translated into an odds ratio of 2.35 in favor of asciminib (95% CI 1.08-5.12). Further adjustment for sex, lines of prior therapy, and reason for discontinuation of prior TKI (intolerance vs failure), treatment with asciminib remained a significant predictor of MMR (OR 2.38, 95% CI 1.06-5.35). Patients assigned to asciminib had a median treatment exposure of 43.4 weeks versus 29.2 weeks with bosutinib.

"Notably, MMR rates at 24 weeks were consistently higher for asciminib versus bosutinib across all lines of prior therapy," said Hochhaus.

The difference in MMR became apparent at 12 weeks and persisted during follow-up to 96 weeks. Additionally, the rate of complete CyR at 24 weeks was 40.8% with asciminib and 24.2% with bosutinib, a difference that remained significant after adjustment for major cytogenetic response status at baseline.

Grade ≥3 adverse events occurred in 50.6% of asciminib-treated patients and 60.5% of patients in the bosutinib arm. Almost four times as many patients in the bosutinib arm discontinued treatment because of adverse events (21.1% vs 5.8%).

The most frequent adverse events (all grades) associated with asciminib were thrombocytopenia (28.8% vs 18.4%) and neutropenia (21.8% vs 21.1%). Gastrointestinal adverse events were predominant in the bosutinib arm, including diarrhea (71.1% vs 11.5%), nausea (46.1% vs 11.5%), and vomiting (26.3% vs 7.1%). Rash and elevated liver enzymes (ALT and AST) also occurred substantially more often with bosutinib).

New BCR-ABL1 mutations occurred in two patients who had mutations at baseline in the asciminib group and in three patients without mutations at baseline. No new mutations occurred in patients treated with bosutinib. Hochhaus said the small number of new mutations and their heterogeneity precluded conclusions about the impact of treatment on mutations.

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