Dr Kuykendall on Emerging Therapies in Systemic Mastocytosis

Andrew Kuykendall, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses agents currently in development for patients with systemic mastocytosis and how these investigational therapies may fit into the overall treatment paradigm for this disease.

The 2 KIT inhibitors currently FDA approved in systemic mastocytosis are midostaurin (Rydapt) and avapritinib (Ayvakit). Two novel KIT inhibitors in development, bezuclastinib and BLU-263, are building upon the benefits seen with midostaurin and avapritinib in patients with systemic mastocytosis, Kuykendall says. Both bezuclastinib and BLU-263 appear to have less central nervous system penetration than the currently approved agents, meaning they may cause fewer neurologic toxicities, cognitive adverse effects, and intracranial hemorrhages, particularly in patients with associated hematologic neoplasms, Kuykendall explains.

A total of 1.6% and 13% of patients who received avapritinib experienced intracranial bleeding in the phase 2 PATHFINDER (NCT03580655) and phase 1 EXPLORER trials (NCT02561988), respectively, many of whom had thrombocytopenia at baseline. If the investigational agents do not cross the blood-brain barrier, they may be safer options for patients with systemic mastocytosis who have associated hematologic neoplasms that result in low platelet counts, Kuykendall says. Bezuclastinib and BLU-263 may also be favorable agents for combination therapies in this population, as they would not contribute to low platelet counts, Kuykendall notes.

The safety and efficacy of bezuclastinib are being investigated in patients with advanced systemic mastocytosis in the phase 2 APEX trial (NCT04996875), which showed that all 11 patients treated with the agent had a more than 50% reduction in serum tryptase levels. The safety and efficacy of BLU-263 are being evaluated in patients with advanced systemic mastocytosis in the phase 1/2 AZURE trial (NCT05609942).

If these trials and additional research with these investigational agents demonstrate bezuclastinib and BLU-263 to be more tolerable than avapritinib and midostaurin but just as potent, these agents may expand the options for KIT-targeted therapy in patients with systemic mastocytosis, Kuykendall concludes.