Targeting KIT in advanced systemic mastocytosis

During the MPN Hub Steering Committee Meeting on May 26, 2026, key opinion leaders met to discuss targeting KIT in advanced systemic mastocytosis (AdvSM). The session opened with a presentation by Andreas Reiter, University Hospital Mannheim, Mannheim, DE, and was followed by a discussion with MPN Hub Steering Committee Chair Jean-Jacques Kiladjian and Steering Committee member Steffen Koschmieder.  

In this presentation, Reiter discusses the rationale for KIT inhibition, and key efficacy and safety data for KIT-targeting therapies in AdvSM. The presentation highlights data from key trials, including the depth of molecular response with KIT-targeting therapies and its correlation with clinical benefit, and concludes with an overview of future directions in KIT inhibition for patients with AdvSM. The presentation was followed by a discussion in which the Steering Committee explored the clonal evolution of AdvSM, its implications for treatment, molecular indicators of response, and practical approaches to adverse event management. 

Key points 

• AdvSM is a hematologic neoplasm characterized by excessive proliferation and accumulation of mast cells, resulting in organ damage.¹ 
• KIT D816V is a central disease driver, present in ~95% of patients with AdvSM.² 
• Midostaurin is a first-generation KIT-targeting therapy that established the benchmark for the treatment of patients with AdvSM, although its efficacy is limited and treatment may be complicated by adverse events.³ 
• Avapritinib is a next-generation KIT inhibitor that is highly selective for KIT D816V. Other selective KIT D816V inhibitors in development include bezuclastinib and elenestinib.^2,4 
• Evidence supporting avapritinib in AdvSM comes from a clinical development program spanning early‑phase, registrational, pooled, and long‑term follow‑up studies, including the phase I EXPLORER trial (NCT02561988) and the phase II PATHFINDER trial (NCT03580655) (Figure 1).^1-3,5 
• In the PATHFINDER trial, 60% of patients receiving avapritinib achieved ≥50% reduction in KIT D816V VAF; greater reductions in KIT D816V VAF were associated with deeper clinical responses.^1,3 
• The 4-year follow-up of the PATHFINDER trial confirmed that these deep molecular responses translated into durable clinical benefit, with sustained responses and prolonged survival in patients with AdvSM.⁶ 
• Long-term follow-up demonstrated a manageable safety profile, with dose optimization improving treatment tolerability while maintaining durable clinical responses.⁶ 
  • Protocol amendments, including withholding treatment in patients with platelet counts ≤50 × 10⁹/L and optimized management of thrombocytopenia, substantially reduced intracranial bleeding events compared with earlier avapritinib studies.⁶ 
• In an adjusted comparative analysis, avapritinib was associated with significantly improved overall survival vs best available therapy (HR, 0.48; 95% CI, 0.29–0.79; p = 0.004) (Figure 2).⁷ 
• Next-generation KIT inhibitors aim to expand treatment options for patients with AdvSM while optimizing efficacy and tolerability.⁴ 
• Overall, the panel emphasized the importance of understanding clonal evolution, integrating molecular monitoring into clinical practice, and proactively managing adverse events to optimize long-term outcomes for patients with AdvSM. 

This educational resource is independently supported by Blueprint Medicines. All content is developed by SES in collaboration with an expert steering committee. Funders are allowed no influence.