What type of study is this?

This is a Pre-Registered Trial study.

What question did this study set out to answer?

To evaluate the overall survival of advanced systemic mastocytosis patients treated with avapritinib versus midostaurin.

December 8, 2025

Improved overall survival in patients with advanced systemic mastocytosis treated with avapritinib versus real-world therapy based on mutation-adjusted risk score (MARS) stratification

Puntos clave

To evaluate the overall survival of advanced systemic mastocytosis patients treated with avapritinib versus midostaurin.
Compared overall survival between patients receiving 1L avapritinib and 1L midostaurin using IPTW-weighted Cox models.
Conducted MARS stratification to classify patients into risk groups based on clinical and mutation factors.
Estimated treatment outcomes from retrospective data and calendar follow-up of 38.0 months.
Patients treated with avapritinib showed significantly improved overall survival compared to midostaurin (HR 0.08).
Median OS was not reached in the avapritinib cohort compared to 26.8 months in the midostaurin cohort for 1L treatment.
In the 2L+ treatment subgroup, avapritinib patients had a median OS of 50.2 months compared to 14.8 months for best available therapy.

Resumen

Abstract Introduction Avapritinib (Ava) is a potent, selective KIT D816V inhibitor indicated for adult patients (pts) with advanced systemic mastocytosis (AdvSM) based on results from the PATHFINDER (NCT03580655) and EXPLORER (NCT02561988) studies. MARS is a prognostic tool classifying AdvSM pts into low-, intermediate-, and high-risk groups based on age (60 years), anemia (hemoglobin 10 g/dL), thrombocytopenia (platelet count 100x10⁹/L), and the presence and number of SRSF2, ASXL1, or RUNX1 (S/A/R) mutations. Prior retrospective analyses of overall survival (OS) showed a hazard ratio (HR) of 0.19 for Ava vs midostaurin (Mido) in frontline (1L) therapy and 0.34 for Ava vs best available therapy (BAT) in second or later-lines (2L+) of treatment in AdvSM, regardless of MARS (Reiter et al., ASH 2024). MARS-defined intermediate- and high-risk pts face particularly poor prognoses, making it essential to evaluate treatment outcomes in this underserved population. This analysis builds on the earlier work, comparing OS between intermediate- and high-risk MARS pts treated with Ava (200 mg/day starting dose) in the PATHFINDER trial and those treated with BAT in real-world (RW) clinical practice. Methods Data from the PATHFINDER trial (median follow-up: 38.0 months) and a RW retrospective chart review study (NCT04695431) conducted at six global sites, were used to compare OS between pts treated with 1L Ava vs 1L Mido, and 2L+ Ava vs 2L+ BAT, which was predominantly Mido and cladribine (Clad). Analyses were restricted to lines of therapy (LOTs) in the combined cohorts of MARS- intermediate- or high-risk (score 1) pts. Subgroup analyses were conducted among pts with SM with an associated hematologic neoplasm (SM-AHN). Inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences in key prognostic covariates; covariate balance was confirmed by standardized mean differences 0.1. IPTW-weighted Cox proportional hazards models were used to compare OS between cohorts. Results 1L analysis. Ava (n=24) vs Mido (n=43); mean age 70.3 vs 70.9 years; mean follow-up 33.1 vs 22.5 months. Before weighting, more Ava pts had anemia (75.0% vs 60.5%) and fewer had an elevated serum tryptase level at baseline (≥125 ng/mL: 62.5% vs 72.1%). Distributions of AdvSM subtypes were similar between the cohorts (SM-AHN: 79.2% vs 79.1%; Aggressive SM ASM: 12.5% vs 14%; Mast Cell Leukemia MCL: 8.3% vs 7.0%). IPTW-weighted median OS was not reached (NR) (95% confidence interval CI: not estimable NE, NE) in the Ava cohort, and 26.8 months (95% CI: 14.4, 49.8) in the Mido cohort. In IPTW-weighted Cox analysis, OS was significantly longer in Ava vs Mido pts (HR 95% CI: 0.08 0.02, 0.29; p0.001). 1L SM-AHN subgroup. Ava (n=19) vs Mido (n=34); IPTW-weighted median (95% CI) OS was NR (NE, NE) in the Ava cohort, and 22.1 months (13.0, 61.5) in the Mido cohort. After adjustment, OS was significantly improved in Ava vs Mido pts (HR 95% CI: 0.09 0.02, 0.36; p0.001). 2L+ analysis. Ava (n=41) vs BAT (n=55, 71 LOTs); mean age 71.0 vs 67.3 years; mean follow-up 28.4 vs 17.6 months. Common 2L+ BAT agents included Mido (47.5%), Clad (34.4%), and hydroxyurea (8.2%). Before weighting, more Ava vs BAT LOTs had elevated serum tryptase at baseline (78.0% vs 63.4%) and received prior treatment with tyrosine kinase inhibitors (85.4% vs 46.5%). Fewer Ava vs BAT LOTs had ≥1 S/A/R mutation (56.1% vs 66.2%); distributions of AdvSM subtypes were similar (SM-AHN: 70.7% vs 70.4%; ASM: 17.1% vs 14.1%; MCL: 12.2% vs 15.5%). IPTW-weighted median (95% CI) OS was 50.2 months (50.2, NE) in the Ava cohort, and 14.8 months (13.2, 32.6) in the BAT cohort. In IPTW-weighted Cox analysis, OS was significantly longer in Ava vs BAT pts (HR 95% CI: 0.28 0.13, 0.61; p=0.001). 2L+ SM-AHN subgroup. Ava (n=29) vs BAT (n=38, 50 LOTs); IPTW-weighted median (95% CI) OS was 50.2 months (23.0, NE) in the Ava cohort, and 13.2 months (7.7, 27.5) in the BAT cohort. After adjustment, OS was significantly improved in Ava vs BAT pts (HR 95% CI: 0.31 0.13, 0.74; p=0.008). ConclusionsAmong the combined cohort of MARS intermediate- and high-risk AdvSM pts, avapritinib was associated with significantly improved OS compared to midostaurin in the 1L setting and BAT in the 2L+ setting, including in the SM-AHN subgroup. This analysis further characterizes the survival benefit of avapritinib, and supports treatment decisions, in this traditionally underserved patient population.

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Cite This Study

Álvarez‐Twöse et al. (Mon,) studied this question.

synapsesocial.com/papers/69362f744fa91c937236e279 https://doi.org/https://doi.org/10.1182/blood-2025-5595

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