Abstract
Background: Advanced systemic mastocytosis (AdvSM) is a rare, life-threatening myeloid neoplasm predominantly driven by KIT D816V mutations. Avapritinib is a selective and potent KIT D816V inhibitor approved for the treatment of AdvSM.
Methods: PATHFINDER (NCT03580655) is a clinical study evaluating avapritinib in adults with AdvSM. This analysis reports long-term outcomes in patients who initiated avapritinib as first-line therapy. The primary endpoint was centrally adjudicated overall response rate (ORR) per modified International Working Group–Myeloproliferative Neoplasms Research and Treatment–European Competence Network on Mastocytosis criteria. Secondary endpoints included changes in disease burden markers, progression-free survival (PFS), overall survival (OS), bone density, bone turnover markers, and safety.
Results: As of March 13, 2025, 38 first-line patients were treated with avapritinib, with a median follow-up of 49 months. The confirmed ORR was 87%, including 43% complete remission or complete remission with partial hematologic recovery. Median time to response was 3 months, while median duration of response, PFS, and OS were not reached. Sustained reductions in bone marrow mast cell burden, serum tryptase, KIT D816V variant allele frequency, and spleen volume were observed. Patients with low baseline bone density demonstrated significant improvement in lumbar T-scores, accompanied by normalization of bone turnover markers. The safety profile remained consistent with prior reports, with no new safety signals identified.
Conclusions: With approximately four years of follow-up, first-line avapritinib demonstrated durable disease control, prolonged survival, and meaningful improvements in bone health across AdvSM subtypes. These findings support avapritinib as a disease-modifying first-line therapy for AdvSM.
Introduction
Advanced systemic mastocytosis (AdvSM) is a rare clonal mast cell disorder characterized by aggressive clinical behavior, multiorgan involvement, and reduced survival. AdvSM encompasses aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). The disease is driven in over 90% of cases by the activating KIT D816V mutation, which confers resistance to most multikinase inhibitors.
Avapritinib is a highly selective and potent inhibitor of KIT D816V and has demonstrated robust clinical activity in patients with AdvSM. Based on these findings, avapritinib is approved in the United States for first-line treatment of AdvSM and in Europe for patients who have received at least one prior systemic therapy. However, long-term data describing durability of response, survival outcomes, and effects on bone disease remain limited. Here, we report four-year efficacy, survival, bone health, and safety outcomes in first-line avapritinib-treated patients enrolled in the PATHFINDER study.
Methods
Study Design
PATHFINDER (NCT03580655) is an ongoing clinical study enrolling adults with centrally confirmed AdvSM. The present analysis includes patients who initiated avapritinib as first-line therapy.
Treatment
Patients received oral avapritinib once daily. Dose modifications were permitted to manage adverse events according to protocol-specified guidelines.
Efficacy Assessments
The primary endpoint was overall response rate (ORR), centrally adjudicated using modified International Working Group–Myeloproliferative Neoplasms Research and Treatment–European Competence Network on Mastocytosis response criteria. Responses included complete remission (CR), CR with partial hematologic recovery (CRh), partial remission (PR), and clinical improvement.
Secondary endpoints included:
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Changes from baseline in bone marrow mast cell burden
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Serum tryptase levels
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Blood KIT D816V variant allele frequency (VAF)
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Spleen volume
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Duration of response (DOR)
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Time to response (TTR)
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Progression-free survival (PFS)
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Overall survival (OS)
Bone Health Analyses
Patients with serial dual-energy X-ray absorptiometry (DXA) scans were categorized by baseline lumbar T-score into low (<–1), normal (≥–1 to ≤1), or high (>1) bone density groups. Changes from baseline were evaluated. Bone turnover markers, procollagen I N-propeptide (PINP) and tartrate-resistant acid phosphatase 5b (TRAcP-5b), were measured in a subset of patients.
Safety
Safety was assessed in all patients receiving at least one dose of avapritinib. Adverse events were graded according to standard criteria.
Results
Patient Characteristics
A total of 107 patients received avapritinib, including 38 treated as first-line therapy. Median age was 68 years, 53% were male, and 95% harbored KIT D816V mutations. Median follow-up was 49 months.
Efficacy Outcomes
Among 30 response-evaluable first-line patients, the confirmed ORR was 87%. Median TTR was 3 months. Median DOR, PFS, and OS were not reached, with a 48-month PFS rate of 67% and OS rate of 79%.
Substantial and durable reductions in disease burden were observed across AdvSM subtypes, including marked decreases in bone marrow mast cell infiltration, serum tryptase, KIT D816V VAF, and spleen volume.
Bone Health
Improvement in lumbar bone density was observed in patients with low baseline bone density, while bone density remained stable in patients with normal or high baseline values. Bone turnover markers demonstrated normalization over time, consistent with improved bone remodeling.
Safety
The most common treatment-related adverse events were edema, thrombocytopenia, and anemia. Dose modifications were frequent but manageable. No new safety signals, including intracranial bleeding, were identified with extended follow-up.
Discussion
This four-year analysis of first-line avapritinib in AdvSM demonstrates durable clinical benefit, prolonged survival, and significant improvements in bone health. The depth and durability of responses observed across disease subtypes underscore the disease-modifying potential of selective KIT D816V inhibition. Importantly, avapritinib favorably impacted mastocytosis-associated bone disease, a major contributor to morbidity in this population.
The safety profile remained consistent with prior reports, supporting long-term administration with appropriate dose management. Limitations include the non-randomized study design and limited sample size; however, the rarity of AdvSM and the consistency of observed benefit strengthen the clinical relevance of these findings.
Conclusions
First-line avapritinib provides durable disease control, prolonged survival, and meaningful improvement in bone health in patients with AdvSM. These long-term data support avapritinib as a standard-of-care first-line therapy and highlight its disease-modifying effects across AdvSM subtypes.
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