Avapritinib treatment of patients with advanced systemic mastocytosis: 4-year safety, effect on bone and first-line efficacy results of the pathfinder clinical study Free

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 (BD^low: <–1; BD^high: >1; BD^norm: ≥–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 BD^low (–2.4 [0.46] vs –1.65 [1.25]; P<0.05; n=12) and remained stable in BD^high (2.9 [1.6] vs 2.9 [1.9]; n=21) and BD^norm (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 BD^low 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.