Dr Kuykendall on AEs With Midostaurin and Avapritinib in Advanced Systemic Mastocytosis

Andrew Kuykendall, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the occurrence and management of adverse effects (AEs) associated with midostaurin (Rydapt) and avapritinib (Ayvakit) in patients with advanced systemic mastocytosis.

Two KIT-targeted therapies, midostaurin and avapritinib, are FDA approved in advanced systemic mastocytosis, Kuykendall says. Midostaurin has a more general kinase inhibition profile than avapritinib, which is more selective for KIT mutations, Kuykendall notes. Although both agents are effective for treating patients with advanced systemic mastocytosis, they each have distinct AE profiles to consider, Kuykendall explains.

Midostaurin, which is also approved in FLT3-mutant acute myeloid leukemia (AML), is associated with gastrointestinal (GI) toxicities, such as nausea, vomiting, and diarrhea, which can be challenging to manage, especially at the high dose of 100 mg that is recommended for patients with advanced systemic mastocytosis, which is double the dose of 50 mg that is recommended for the FLT3-mutant AML population, Kuykendall says. However, these GI AEs can be managed with treatment pauses, dose reductions, and dose re-escalations, Kuykendall notes.

Avapritinib is associated with fewer GI toxicities than midostaurin, although some GI toxicities can arise with this agent. Additionally, periorbital edema, an on-target effect of the agent’s PDGFR inhibition, can be managed with dose reduction but is significant in some cases, Kuykendall explains.

Internal bleeding, including intracranial hemorrhage in a small subset of patients, is another toxicity concern associated with avapritinib that typically arises with higher doses of this agent, such as the 300 mg daily dose approved for patients with gastrointestinal stromal tumor harboring a PDGFRA exon 18 mutation, Kuykendall says. The recommended starting dose of avapritinib in advanced systemic mastocytosis is 200 mg daily, and dose reductions can be used to mitigate AEs. As this internal bleeding is typically seen in patients with platelet counts lower than 50,000, avapritinib should be used with caution or avoided in patients with severe thrombocytopenia or anemia, Kuykendall emphasizes.

Avapritinib treatment may also cause cognitive AEs, which were seen in 11% of patients in the phase 2 PATHFINDER trial (NCT03580655) and 30% of patients in the phase 1 EXPLORER trial (NCT02561988). These cognitive AEs were mostly mild and tolerable, although 2 patients in EXPLORER required treatment discontinuation because of these AEs. Patients receiving avapritinib should have their neurologic status assessed at baseline and be closely monitored for cognitive AEs throughout their treatment, Kuykendall concludes.