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Abstract Introduction: Advanced systemic mastocytosis (AdvSM) is a rare clonal hematologic neoplasm mainly driven by D816V-mutant KIT. Avapritinib is a highly potent and selective KIT D816V inhibitor approved at a starting dose of 200 mg once daily in the USA for treatment of adults with AdvSM and in Europe for treatment of adults with AdvSM after ≥1 prior systemic therapy. Here, we present 4-year results from avapritinib-treated patients in the PATHFINDER (NCT03580655) clinical study. Methods: Efficacy analyses included adult patients with centrally confirmed AdvSM enrolled in PATHFINDER who initiated avapritinib as first-line (1L) therapy. Primary endpoint was centrally adjudicated overall response rate (ORR), per modified International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis response criteria, including complete remission (CR), CR with partial hematologic recovery (CRh), partial remission (PR), and clinical improvement. Secondary endpoints included: change from baseline in bone marrow (BM) mast cell (MC) burden, serum tryptase, blood KIT D816V variant allele frequency (VAF), and spleen volume; duration of response (DOR); time to response (TTR); progression-free survival (PFS); overall survival (OS); and safety. Patients with serial dual-energy X-ray absorptiometry (DXA) scans were grouped by baseline bone density (BD) in lumbar T-scores (BDlow: <–1; BDhigh: >1; BDnorm: ≥–1 and ≤1), with change from baseline evaluated. Plasma concentrations of bone turnover markers (BTMs) procollagen I N-propeptide (PINP) and tartrate-resistant acid phosphatase type 5b (TRAcP-5b) were measured in a subset of these patients. Safety was reported in the overall population. Results: As of March 13, 2025, 107 patients with AdvSM received avapritinib, including 38 as 1L therapy (7 aggressive SM [ASM], 28 SM with an associated hematological neoplasm [SM-AHN], and 3 mast cell leukemia [MCL]) with median follow-up (95% confidence interval [CI]) of 49 months (44–55), median average daily dose (range) of 101 mg (37–200), and median relative dose intensity (range) of 45% (10–100). Median age (range) was 68 years (39–88), 53% were male, and 18% had Eastern Cooperative Oncology Group performance status of 2–3. Median baseline serum tryptase (range) was 178 ng/mL (37–1336) and 95% were positive for KIT D816V. Thirty of 38 patients were response evaluable. Best confirmed ORR (95% CI) was 87% (69–96), including 43% CR/CRh and 43% PR. Median TTR was 3 months. Median DOR (95% CI) was not reached (37–not evaluable [NE]) regardless of subtype. Median PFS (95% CI) was not reached in the 1L population (39–NE), ASM, or MCL subtypes, and was 48 months (25–NE) in SM-AHN; PFS rate at 48 months was 67% (49–85). Median OS (95% CI) was not reached (NE–NE) regardless of subtype and OS rate at 48 months was 79% (64–93). Reductions of ≥50% were observed in BM MC burden (89%, n=34/38), serum tryptase (97%, n=37/38), and KIT D816V VAF (95%, n=36/38). A ≥35% reduction in spleen volume was observed in 31/38 (82%) patients. Serial DXA scans were available for 56 patients. Mean (standard deviation) lumbar T-scores at last visit improved versus baseline in BDlow (–2.4 [0.46] vs –1.65 [1.25]; P<0.05; n=12) and remained stable in BDhigh (2.9 [1.6] vs 2.9 [1.9]; n=21) and BDnorm (0.0 [0.5] vs –0.03 [0.97]; n=23) patients. In 47 of 56 patients with BTM assessments, normalization from baseline versus last visit was observed in mean PINP (135.6 ng/mL vs 63.1 ng/mL) and mean TRAcP-5b (1.4 U/L vs 2.0 U/L). In the overall safety population (N=107), frequent (≥20% of patients) treatment-related adverse events (TRAEs) were (any Grade, Grade ≥3) periorbital edema (41%, 6%), thrombocytopenia (40%, 21%), peripheral edema (38%, 2%), and anemia (32%, 16%). In total, 83 (78%) patients had dose reductions, 69 (64%) had dose interruptions, and 20 (19%) discontinued treatment due to TRAEs. With longer exposure, no new intracranial bleeds or safety concerns were identified versus prior reports. Conclusion: With a median follow-up of ~4 years, avapritinib showed durable effects including prolonged OS as 1L therapy regardless of AdvSM subtype. Improved effects on bone, including BD in the BDlow group and BTM normalization were observed. These results and the well-characterized and favorable benefit-risk profile, highlight the disease-modifying effects of avapritinib and support its long-term use for AdvSM, particularly as a 1L treatment.