Targeted KIT inhibitors: paradigm shift in the treatment of systemic mastocytosis

INTRODUCTION: The therapeutic landscape of systemic mastocytosis (SM) has undergone a remarkable transformation with the development of selective KIT D816V inhibitors, shifting the field from limited supportive care to multiple effective targeted therapies. AREAS COVERED: This review summarizes the importance of and emerging clinical data on targeted KIT inhibitors (KITi) in SM. Trials evaluating the efficacy of approved (midostaurin, avapritinib) and investigational (bezuclastinib, elenestinib) KITi in advanced SM (AdvSM) and NonAdvSM are overviewed herein. We searched PubMed and meeting proceedings (2016-2026) with emphasis on pivotal trials on KITi. EXPERT OPINION: Agents such as midostaurin, avapritinib, bezuclastinib and elenestinib demonstrated meaningful clinical activity and are redefining AdvSM and NonAdvSM treatment. However, important unmet needs remain. Patients may continue to experience persistent mediator-related symptoms despite reductions in MC burden, suggesting biological mechanisms beyond KIT signaling. Long-term effects on clonal evolution remain unclear. Questions persist regarding optimal treatment sequencing, risk of emergence of resistance mutations, and the role of combinations, while minimizing polypharmacy. Patients with severe thrombocytopenia remain particularly challenging to treat and are often underrepresented in trials. Finally, delayed diagnosis, often approaching 7 years, highlights the need for greater disease awareness, multidisciplinary care, and longitudinal registries to better define long-term outcomes and optimize patient management.