Long-Term PIONEER Data Reinforce Avapritinib’s Benefit–Risk Profile in ISM, with Cem Akin, MD

Avapritinib continues to deliver durable symptom control and quality-of-life improvements nearly 4 years into treatment for patients with indolent systemic mastocytosis (ISM), reinforcing its role as a long-term targeted therapy for this chronic disease.1

Avapritinib was approved for treating ISM by the United States (US) Food and Drug Administration (FDA) in May 2023.2 Updated data from the Phase 2/3 PIONEER trial (NCT03731260) were presented at the American Academy of Allergy, Asthma & Immunology (AAAAI) 2026 Annual Meeting held in Philadelphia, Pennsylvania, by Cem Akin, MD, Professor of Medicine at the University of Michigan Division of Allergy and Immunology.

In the updated PIONEER analysis, 226 patients with indolent systemic mastocytosis initiated avapritinib 25 mg once daily across Parts 1, 2, and 3. The median duration of treatment was 46.5 months (range, 0.7–67.2 months).

Long-term efficacy was sustained through approximately 4 years. Among all patients treated with avapritinib, the mean change from baseline in ISM-SAF TSS was −17.66 (SD, 19.32) at Week 48 (n=141) and −17.66 (SD, 19.07) at Week 204 (approximately 4 years; n=85). For the most severe symptom domain (Figure 3), improvement was maintained at 1 year (n=193) and 4 years (n=85).

In an interview with HCPLive at AAAAI, AKin emphasized the importance of the long-term consistency of benefit for ISM, where more than 80% of patients fall into the non-advanced category and historically have relied only on symptomatic therapies such as antihistamines. Prior to avapritinib, available treatments did not meaningfully reduce mast cell burden or target the underlying KIT D816V mutation, which drives over 90% of ISM cases.

Quality-of-life gains were similarly durable: the mean percentage change from baseline in MC-QoL was −30.96% (SD, 37.48) at 1 year and −35.41% (SD, 35.71) at 4 years. In patients who dose-escalated to 50 mg once daily in Part 3 (n=74), median time on 50 mg was 16.5 months (range, 0.2–33.6). These patients had higher baseline KIT D816V VAF and symptom burden; after 24 weeks on 50 mg, 42 of 48 evaluable patients (88%) achieved stable-to-improved ISM-SAF TSS, including 38 with improved TSS, and 42 of 46 (91%) had stable-to-improved MC-QoL, including 38 with improvement.

Safety remained consistent with prior reports. In Part 2, any adverse events occurred in 128 patients (91%) receiving avapritinib 25 mg plus best supportive care versus 66 (93%) with placebo plus best supportive care; grade ≥3 adverse events occurred in 30 (21%) and 15 (21%), respectively. Serious adverse events were reported in 7 (5%) and 8 (11%), and treatment-related adverse events (TRAEs) in 77 (55%) and 32 (45%). In the combined 25 mg cohort across Parts 1–3 (N=226), any adverse events occurred in 224 patients (99%), grade ≥3 events in 108 (48%), serious adverse events in 53 (23%), and serious TRAEs in 3 (1%). TRAEs leading to discontinuation occurred in 6 patients (3%). Among those escalating to 50 mg (n=74), any adverse events occurred in 64 (86%), grade ≥3 events in 13 (18%), serious adverse events in 10 (14%), and grade ≥3 TRAEs in 1 (1%), with no serious TRAEs reported and no treatment discontinuations due to adverse events at the 50 mg dose.

“In the 4 year trial now we are extending those observations, there are some patients who are on the drug for more than 5 years, but on average, 4 year follow up, and the efficacy was sustained at the same level, maybe slightly even improved at 4 years than at 6-month and 1-year time frames,” Akin said.

Akin’s disclosures include Blueprint Medicines, Cogent, Telios, GSK, and Novartis.

References

1. Akin C, Tashi T, Elberink HO, et al. Avapritinib continues to demonstrate durable symptom control with a well-tolerated safety profile: Long-term outcomes from PIONEER. Presented at: AAAAI 2026 Annual Meeting, February 27-March 2, Philadelphia, Pennsylvania. Abstract #509

2. FDA Approves Avapritinib for the Treatment of Adult Patients with Indolent Systemic Mastocytosis. News release. ACCC. May 24, 2023. https://www.accc-cancer.org/view/fda-approves-ayvakit-(avapritinib)-for-the-treatment-of-adult-patients-with-indolent-systemic-mastocytosis-(ism)