FDA Approves Avapritinib in Indolent Systemic Mastocytosis

Data from the phase 2 PIONEER trial supported the FDA's approval of avapritinib in indolent systemic mastocytosis.

The FDA has granted approval to avapritinib (Ayvakit) as the first and only treatment for adult patients with indolent systemic mastocytosis, according to a press release from Blueprint Medicines.¹

The approval of avapritinib was supported by data from the phase 2 PIONEER trial (NCT03731260).

According to data read out at the 2023 American Academy of Allergy Asthma, and Immunology, avapritinib yielded a statistically significant and clinically meaningful improvement in total symptom scores at 24 weeks, with improvements across all symptoms measured by the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF). The mean change in total symptom scores at 24 weeks was –15.6 points vs –9.2 points with avapritinib vs placebo, respectively (P = .003).²

Avapritinib also elicited a statistically significant improvement in mean change in most severe symptom score compared with placebo after 24 weeks (P = .015).

"[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," investigator Cem Akin, MD, PhD, a professor of medicine at the University of Michigan, said in the press release.

In the randomized, double-blind, placebo-controlled phase 2 PIONEER study, patients were randomly assigned to receive either 25 mg of avapritinib once a day (n = 141) or matched placebo (n = 71) plus best supportive care at 49 treatment sites across 13 countries.

The primary end points of the trial were the recommended phase 2 dose and the mean change in ISM-SAF scores on a scale of 0 to 100 points, with a higher score reflecting worse symptom outcomes. Secondary end points included the proportion of patients with at least 50% reduction in serum tryptase, changes in KIT D816V allele burden in blood, and changes in bone marrow mast cells.

Patients 18 years and older with systemic mastocytosis confirmed by Central Pathology Review of a bone marrow biopsy and central review of B- and C-findings by World Health Organization diagnostic criteria were able to enroll on the trial. Additional inclusion criteria included having moderate-to-severe symptoms of indolent systemic mastocytosis and an ECOG performance status of 2 or less.

The proportion of patients with at least a 50% reduction in serum tryptase was 53.9% with avapritinib vs 0.0% among those receiving placebo (P <.0001). The proportion of patients with at least a 50% reduction in KIT D816V variant allele was 67.8% vs 6.3% in each respective population (P <.0001). Additionally, the proportion of those with at least 50% reductions in bone marrow mast cell aggregates was 52.8% vs 22.8% (P <.0001) in each respective arm.

Avapritinib produced a significant and clinically meaningful improvement in the mean percent change in Mastocytosis Quality of Life Questionnaire total score compared with placebo at 24 weeks. Avapritinib yielded a mean percent change of –34.3% vs –17.9% with placebo (P = .001).

Most observed adverse effects (AEs) were mild to moderate in severity, and 1.4% of patients in each arm discontinued therapy due to treatment-related AEs (TRAEs). Serious AEs occurred in 5.0% of patients receiving avapritinib vs 11.3% of those receiving placebo.

Among patients receiving avapritinib and those receiving placebo, respectively, common TRAEs included headache (7.8% vs 9.9%), nausea (6.4% vs 8.5%), peripheral edema (6.4% vs 1.4%), periorbital edema (6.4% vs 2.8%), and dizziness (2.8% vs 7.0%). Most events of edema were low-grade and did not result in discontinuation.

The FDA originally accepted a supplemental new drug application for avapritinib in indolent systemic mastocytosis in January 2023.³ The application was supported by data from the PIONEER study.

References

1. FDA Approves AYVAKIT® (avapritinib) as the first and only treatment for indolent systemic mastocytosis. News release. Blueprint Medicines. May 22, 2023. Accessed May 22, 2023. bit.ly/3IANHqa
2. Blueprint Medicines presents registrational data from PIONEER Trial of AYVAKIT® (avapritinib) in patients with indolent systemic mastocytosis at 2023 AAAAI Annual Meeting. News release. Blueprint Medicines. February 26, 2023. Accessed February 28, 2023. bit.ly/3Y8kOXd
3. Blueprint Medicines announces FDA acceptance of supplemental new drug application for AYVAKIT® (avapritinib) for the treatment of indolent systemic mastocytosis. News release. Blueprint Medicines. January 23, 2023. Accessed February 28, 2023. bit.ly/3kGmfy3