Overall Survival and Duration of Treatment in Patients with Advanced Systemic Mastocytosis Receiving Avapritinib Versus Midostaurin or Best Available Therapy in a Real-World Setting
Authors: Reiter Andreas , Gotlib Jason , Álvarez-Twose Iván , Radia Deepti H. , Luebke Johannes , Bobbili Priyanka J. , Wang Aolin , Dimitrijević Saša , Sullivan Erin , Schwaab Juliana , Galinsky Ilene A. , Perkins Cecelia , Sperr Wolfgang R. , Sriskandarajah Priya , Mohan Manasi , Badu Teshawna , Duh Mei Sheng , Valent Peter , DeAngelo Daniel J. 
Published: December 2024

Introduction
This retrospective study builds on prior work assessing the efficacy of avapritinib, a selective KIT D816V inhibitor, in adult patients (pts) with advanced systemic mastocytosis (AdvSM). We sought to compare overall survival (OS) and duration of treatment (DOT) between pts with AdvSM treated with avapritinib in the PATHFINDER study (NCT03580655) and a real-world (RW) retrospective chart review study conducted at six global sites (NCT04695431).
Methods
Data from the PATHFINDER study with a median follow-up of 26.3 months were used to compare OS and DOT between study pts treated with avapritinib 200mg/day starting dose and RW pts treated with best available therapy (BAT). In the first line (1L) setting, avapritinib was compared to multi-kinase/KIT inhibitor midostaurin, historically the most common 1L treatment for AdvSM. As there is no standard of care in second or later lines (2L+), avapritinib was compared to all 2L+ BAT used in RW clinical practice, including midostaurin and the purine analogue cladribine.
OS was defined as time from treatment initiation to death from any cause. DOT was defined as time from treatment initiation to last dose date (avapritinib pts) or discontinuation for any reason (RW pts). Inverse probability of treatment weighting (IPTW) was used to adjust for differences in key baseline covariates between treatment cohorts. IPTW-weighted Cox proportional hazards regression models were used to compare OS and DOT between cohorts.
Results
1L analysis. Mean age at treatment initiation was 68.3 and 67.4 years and mean duration of follow-up was 24.7 and 26.1 months in the avapritinib (n=38) and midostaurin (n=58) cohorts, respectively. Before weighting, a higher proportion of avapritinib vs. midostaurin pts had AdvSM subtype of associated hematologic neoplasm (SM-AHN) (73.7% vs. 69.0%) and ≥1 mutated gene in the SRSF2/ASXL1/RUNX1 (S/A/R) panel (60.5% vs. 53.8%). Elevated (&gt;125ng/mL) serum tryptase was similar between cohorts (71.1% of avapritinib pts vs. 69.0% of midostaurin pts).
IPTW-weighted median OS was not reached (NR) (95% confidence interval [CI]: not estimable [NE], NE) in the avapritinib cohort, and 32.2 months (95% CI: 20.0, 44.6) in the midostaurin cohort. In IPTW-weighted Cox analysis, OS was significantly longer in avapritinib vs. midostaurin pts (hazard ratio [HR] [95% CI]: 0.19 [0.06, 0.57]; p=0.003).
IPTW-weighted median (95% CI) DOT was 41.3 months (33.9, 41.3) in the avapritinib cohort, and 13.0 months (7.5, 25.5) in the midostaurin cohort. In IPTW-weighted Cox analysis, DOT was significantly longer in avapritinib vs. midostaurin pts (HR [95% CI]: 0.37 [0.19, 0.70]; p=0.002).
2L+ analysis. Mean age at treatment initiation was 66.6 and 65.5 years and mean duration of follow-up was 22.1 and 25.2 months, respectively, in the avapritinib (n=67) and BAT (n=73) cohorts; 73 BAT pts contributed data on 104 lines of therapy (LOTs). Agent-level information was available for 89 LOTs in the BAT cohort, and common 2L+ agents received were midostaurin (46.1%), cladribine (32.6%), and hydroxyurea (7.9%). Before weighting, a higher proportion of avapritinib vs. BAT LOTs had subtype SM-AHN (61.2% vs. 51.0%), elevated serum tryptase (80.6% vs. 65.4%), and received prior treatment with tyrosine kinase inhibitors (89.6% vs. 48.1%). Fewer avapritinib vs. BAT LOTs had ≥1 S/A/R mutation (35.8% vs. 46.2%).
IPTW-weighted median (95% CI) OS was NR (30.2 months, NE) in the avapritinib cohort, and 17.9 months (14.8, 36.5) in the BAT cohort. In IPTW-weighted Cox analysis, OS was significantly longer in avapritinib vs. BAT pts (HR [95% CI]: 0.34 [0.17, 0.75]; p=0.008).
IPTW-weighted median (95% CI) DOT was 21.3 months (10.5, NE) in the avapritinib cohort, and 5.4 months (3.5, 9.8) in the BAT cohort. In IPTW-weighted Cox analysis, DOT was significantly longer in avapritinib vs. BAT pts (HR [95% CI]: 0.35 [0.21, 0.58]; p&lt;0.001).
Conclusions
This study supports the use of avapritinib as 1L treatment for AdvSM, demonstrating significant OS and DOT benefits compared to pts treated with 1L midostaurin. The results from this study also affirm that AdvSM pts with prior treatment experienced significantly improved OS and DOT on avapritinib compared to pts treated with BAT in the real world. These data offer important insights on the superior efficacy of avapritinib as compared to available therapies for pts with AdvSM and may help inform treatment decisions.