Avapritinib Delivers Durability, Disease-Modification in Advanced Systemic Mastocytosis

New long-term clinical data presented at the American Society of Hematology 2025 Annual Meeting highlight the sustained efficacy and favorable safety profile of avapritinib (Ayvakit; Blueprint Medicines) for patients with advanced systemic mastocytosis (AdvSM), a rare and debilitating blood cancer.^1,2 The 4-year results from the PATHFINDER clinical study (NCT03580655) suggest that avapritinib offers durable effects and prolonged survival when used as a first-line therapy.¹

AdvSM is characterized by an excessive presence of mast cells and is mainly driven by the D816V-mutant KIT enzyme.^1,2 Patients often experience severe and systemic symptoms, including frequent, unexpected anaphylaxis, diarrhea, and vomiting, which significantly impair daily life and quality of life. Clinicians and patient experts emphasize the unmet need for effective, disease-modifying treatments that also offer fewer severe adverse effects than current standard options.²

Sustained Responses and Unreached Survival Metrics

The PATHFINDER trial evaluated avapritinib, a highly potent and selective KIT D816V inhibitor, focusing on adult patients with AdvSM confirmed centrally. The long-term analysis included data from 107 patients in the overall safety population, with a median follow-up of approximately 4 years (49 months).¹

A critical focus of the data involved 38 patients who initiated avapritinib as first-line therapy. The efficacy results in this cohort, which included subtypes like aggressive SM, SM with an associated hematological neoplasm (SM-AHN), and mast cell leukemia, were outstanding. The centrally adjudicated overall response rate (ORR) confirmed was 87% (95% confidence interval [CI]: 69-96). This high response rate consisted equally of complete remission (CR) and partial remission (PR), with 43% falling into each category. Furthermore, patients achieved rapid responses, with a median time to response (TTR) of just 3 months.¹

Crucially, the long-term survival metrics underscore the drug’s potential for transformative care. In the first-line population, the median duration of response (DOR) was not reached. Similarly, the median progression-free survival (PFS) was also not reached in the overall first-line population or specifically in the aggressive SM and mast cell leukemia subtypes. Even in the challenging SM-AHN subtype, median PFS was 48 months. The PFS rate at 48 months across the first-line population stood at 67%.¹

Perhaps the most compelling finding for clinicians treating this aggressive disease is the overall survival (OS) data. Median OS was not reached for any subtype, and the OS rate at 48 months was 79%. These durable survival and response findings highlight avapritinib’s role as a disease-modifying agent that supports long-term use.¹

Addressing the Root Causes of AdvSM and Improving Bone Health

The PATHFINDER results demonstrate that avapritinib effectively targets the underlying pathology of AdvSM, leading to significant reductions in key disease indicators. Reductions of 50% or more were observed in serum tryptase (97% of patients), KIT D816V variant allele frequency (95% of patients), and bone marrow mast cell burden (89% of patients). Additionally, 82% of patients experienced a reduction of 35% or more in spleen volume.¹

Beyond targeting the primary malignant cells, the study also revealed significant benefits for associated complications, specifically bone health. Serial dual-energy X-ray absorptiometry scans revealed that mean lumbar T-scores improved versus baseline in patients with low baseline bone density (BDlow: T-scores <-1).¹

Furthermore, normalization from baseline was observed in 2 important plasma bone turnover markers (BTMs): PINP and TRAcP-5b. These findings, including the improved effects on bone density and BTM normalization, were cited by researchers as supporting the disease-modifying effects of avapritinib.¹

Favorable Safety Profile Supports Long-Term Use

Avapritinib is FDA-approved for adults with AdvSM at a starting dose of 200 mg once daily. The safety analysis across the overall population (N=107) revealed a well-characterized safety profile.

Frequent (occurring in ≥ 20% of patients) treatment-related adverse events (TRAEs) of any grade included periorbital edema (41%), thrombocytopenia (40%), peripheral edema (38%), and anemia (32%). Although adverse effects necessitated dose reductions in 78% of patients and interruptions in 64%, only 19% discontinued treatment due to TRAEs. Importantly, the longer duration of exposure did not introduce new safety concerns compared to previous reports, with no new intracranial bleeds identified.¹

This safety profile is particularly significant when considering patient experience. Clinical and patient experts note that avapritinib offers an alternative disease-modifying option with less severe adverse effects compared to older standards such as midostaurin.² Midostaurin is often associated with gastrointestinal adverse effects, such as intolerable nausea and vomiting, which can force patients to stop treatment or significantly alter their lifestyle. Patients who have experienced both treatments generally prefer avapritinib due to its fewer adverse effects and lasting positive effects that improve quality of life dramatically.²

The 4-year data from the PATHFINDER study provide robust evidence that avapritinib, with its prolonged survival benefits, high response rates, potent disease modification, and demonstrated improvements in bone health, is a critical long-term therapeutic option for patients with AdvSM.

REFERENCES

1. Reiter A, George T, Radia D, et al. Avapritinib treatment of patients with advanced systemic mastocytosis: 4-year safety, effect on bone and first-line efficacy results of the pathfinder clinical study. Presented at: American Society of Hematology 2025 Annual Meeting. December 6-9, 2025. Orlando, FL.

2. Avapritinib for treating advanced systemic mastocytosis. National Institute for Health and Care Excellence: Technology Appraisals. November 6, 2024. Accessed December 9, 2025. https://www.ncbi.nlm.nih.gov/books/NBK610533/