A Review of KIT Inhibition in Severe Asthma: Treatment with Imatinib

Severe asthma is a heterogenous disease that has a high risk of future exacerbations and loss of lung function. Mast cells are present in the airways of patients who have severe asthma, and these cells are associated with poor quality of life and inadequate asthma control. Mast cells depend on stem cell factor signaling through KIT. The tyrosine kinase inhibitor imatinib, which is approved to treat certain types of cancer, is a KIT inhibitor that may improve airway hyperresponsiveness and reduce airway mast cell counts and activity.

During a session at the 2018 AAAAI Annual Meeting, Katherine N. Cahill, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, discussed KIT inhibition in severe asthma and presented findings from a trial that was previously published in the New England Journal of Medicine.

In the randomized, double-blind, placebo-controlled, 24-week study, Dr. Cahill and colleagues assessed the use of imatinib in 62 patients with poorly controlled severe asthma and airway hyperresponsiveness despite receiving maximal medical therapy. Patients (18-65 years) were randomized 1:1 to receive imatinib (n=32) or placebo (n=30) once daily. Imatinib was initiated at 200 mg per day for two weeks, and then increased to 400 mg, “which is the dose that has been shown to inhibit the KIT receptor,” the authors noted.

The primary endpoint was change in airway hyperresponsiveness (defined as provocative concentration of methacholine causing a decrease in forced expiratory volume in 1 second of 20% [PC₂₀]) from baseline to three and six months, and the researchers found that imatinib better reduced airway reactivity than placebo. Imatinib increased the methacholine PC₂₀ by a mean of 1.20±0.52 doubling doses from baseline to three months (P=.03) and by 1.73±0.60 doubling doses from baseline to six months (P=.008) compared with increases of 0.03±0.42 (P=.94) and 1.07±0.60 (P=.08) doubling doses, respectively, in the placebo group (P=0.048 for the difference between imatinib and placebo).

Imatinib also better reduced levels of serum tryptase than placebo: decrease of 2.02±2.32 versus 0.56±1.39 ng per milliliter, respectively (P=.02). Airway mast cell numbers declined in both groups from baseline to six months.

In an exploratory analysis, Dr. Cahill and co-authors observed that patients who responded to imatinib had lower blood eosinophil counts and higher bronchoalveolar lavage neutrophil percentages at baseline.

Adverse events (AEs) were reported by 123 patients in the imatinib cohort (94%) and 118 in the placebo cohort (80%; P=.86). Severe AEs were reported by three (9.4%) and five (16.7%) patients, respectively. Two patients in the imatinib group discontinued treatment due to neutropenia and legs cramps (n=1 for each).

“Targeting mast cells offers therapeutic potential in severe asthma,” Dr. Cahill concluded.

Presentation 2811: Targeting Mast Cells in Asthma and Other Allergic Diseases