Abstract

Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven by the KIT D816V mutation in approximately 95% of patients and characterized by proliferation and accumulation of mast cells causing debilitating symptoms and end-organ damage. Advanced SM (AdvSM) consists of aggressive SM (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Avapritinib, an oral, highly potent and selective inhibitor of KIT D816V, is approved in the USA and in Europe (after ≥1 systemic therapy) for treatment of adult patients with AdvSM with platelet counts of ≥50×109/L, and midostaurin is also approved in this indication. SM-AHN, the main AdvSM subtype seen in about 75% of cases, has a high degree of genetic heterogeneity and some patients with high-risk and very high-risk AHNs require additional AHN-specific therapeutic agents, such as hypomethylating agents (HMAs). Patients with SM with high-risk and very high-risk AHNs have not been studied for treatment with midostaurin or avapritinib alone due to the aggressive course of their disease. Many of these patients may benefit from combination therapy of a selective KIT D816V inhibitor with an HMA. Low central nervous system (CNS) penetration may allow safer dosing, especially in combination with HMAs with a reduced risk of CNS adverse events. BLU-263 is an investigational, novel, orally administered tyrosine kinase inhibitor (TKI) with high potency and selectivity towards the KIT D816V mutation and high in vitro potency in both the biochemical (dissociation constant, Kd=0.24 nM) and cellular (half-maximal inhibitory concentration, IC50=4.3 nM) settings. BLU-263 has a high degree of selectivity for KIT D816V with minimal CNS penetration, as demonstrated in preclinical studies and two phase 1 studies in healthy volunteers. Overall, the results from the preclinical as well as clinical studies in volunteers indicate a benefit/risk profile that allows the clinical evaluation of BLU-263 alone and in combination with azacitidine in patients with AdvSM, including high- and very high-risk SM-AHN. AZURE (NCT05609942) is an international, phase 1/2, open-label, 2-arm study designed to evaluate the safety and efficacy of BLU-263 as monotherapy and in combination with azacitidine in patients with AdvSM, including those with high-risk and very high-risk SM-AHN in whom HMAs, including azacitidine, are the standard of care. The study has 2 arms: Arm 1 will evaluate BLU-263 monotherapy in all patients with AdvSM, while Arm 2 will evaluate BLU-263 in combination with azacitidine in a selected population of high- and very high-risk SM-AHN patients. Key endpoints for the monotherapy include the recommended dose, safety, and tolerability, while for the combination therapy key endpoints include the ORR for AdvSM, per modified IWG-MRT-ECNM, PK, Time-to-response, OS, DOR, PFS. AZURE, a phase 1/2 study, will evaluate the safety and efficacy of BLU-263 given orally as monotherapy in patients with AdvSM, as well as in combination with azacitidine in a selected population of patients with SM-AHN. BLU-263 is also being studied in HARBOR, a phase 2/3 study comparing the efficacy and safety of BLU-263 + best supportive care (BSC) with placebo + BSC in patients with indolent SM whose symptoms are not adequately controlled by BSC.