The FDA has approved avapritinib for the treatment of patients with indolent systemic mastocytosis.
The FDA has approved avapritinib (Ayvakit) for adult patients with indolent systemic mastocytosis (ISM).1 Avapritinib selectively inhibits KIT D816V, the primary underlying driver of the rare hematologic disorder.
The approval is supported by findings from the phase 2 double-blind, placebo-controlled PIONEER trial (NCT03731260), which demonstrated that the drug in combination with best supportive care (BSC) led to favorable improvements in overall symptoms and mast cell burden measures, compared with placebo plus BSC. Data presented at the 2023 American Academy of Allergy, Asthma, and Immunology showed that patients who received avapritinib achieved statistically significant and clinically meaningful improvements in total symptom scores (TSS) at 24 weeks, and improvements across all symptoms, as measured by the Indolent Systemic Mastocytosis Symptom Assessment Form.2
Among patients enrolled in the study, 93% had KIT D816V–mutant disease. Patients in the intervention arm (n = 141) had a median of 3 concomitant BSC therapies at baseline and patients in the placebo arm (n = 71) had received a median of 4 therapies. The most common therapies were H1 antihistamines (97%), H2 antihistamines (66%), leukotriene inhibitors (35%), and cromolyn sodium (30%) in the avapritinib arm.3
Overall, patients in the intervention arm achieved a –15.6-point (95% CI, –18.36 to –12.31) reduction from baseline in TSS by week 24 compared with a –9.2-point (95% CI, –13.61 to –5.68) reduction among those who received placebo (P = .003).2,3 Moreover, TTS in the intervention arm continued to decrease hitting –20.2 points by week 48. In the avapritinib arm, 24.8% of patients achieved at least a 50% reduction in TSS at 24 weeks vs 9.9% of patients in the placebo arm at 24 weeks (P = .005); 39.3% of patients receiving avapritinib achieved a 50% reduction in TSS by 48 weeks.2
In addition, the percentage of patients who achieved at least a 50% reduction in serum tryptase with treatment was 53.9% with avapritinib vs 0% with placebo (P < .0001). The proportion of patients with at least a 50% reduction in KIT D816V variant allele fraction was 67.8% vs 6.3%, respectively (P < .0001), and the proportion of patients with at least a 50% reduction in bone marrow mast cell aggregates was 52.8% vs 22.8%, respectively (P < .0001).2
Lastly, the mean percent change in the Mastocytosis Quality of Life Questionnaire total score was –34.3% with avapritinib and –17.9% with placebo (P = .001).
The agent was also associated with a manageable safety profile; 96% of patients in the avapritinib arm and 93% of patients in the placebo arm completed treatment. The rate of adverse events (AEs) was 90.8% vs 93%, respectively, and the rate of serious AEs were 5% vs 11.3%.
The most common treatment-related AEs included headache, nausea, peripheral edema, periorbital edema, and dizziness. In the experimental arm, the rates of these AEs were 7.8%, 6.4%, 6.4%, 6.4%, and 2.8%; in the control arm, these rates were 9.9%, 8.5%, 1.4%, 2.8%, and 7.0%.
“Despite the use of multiple supportive care treatments, a considerable number of patients with indolent systemic mastocytosis continue to experience a substantial disease burden. [Avapritinib] advances the treatment of indolent systemic mastocytosis by targeting KIT D816V, the primary underlying cause of the disease, and establishes a new standard of care for a broad population of patients with this disorder,” investigator Cem Akin, MD, PhD, a clinical professor of medicine at the University of Michigan, said in the news release.1
“[Avapritinib] delivered statistically significant and consistent clinical improvements in the PIONEER trial, and based on these practice-changing data, I feel a tremendous sense of hope for the future for all those [with indolent systemic mastocytosis,” he added.1
Avapritinib Prescribing Information Highlights
Of note, avapritinib is not recommended for patients with ISM with platelet counts of less than 50 × 109/L.3 The recommended dose is 25 mg, orally, once daily. For patients who experience a severe hepatic impairment, a dose reduction of 25 mg every other day is recommended.3
Although the prescribing information has a warning for intercranial hemorrhage, no events occurred among patients at any dose of avapritinib in the PIONEER study. Cognitive AEs were reported in 7.8% of patients and had a median time to onset of 2.3 months (range, 0-5.4) with a median time to improvement to grade 1 or resolution of 2.1 months (range, 0.4-2.1).3