Avapritinib — Drug Monograph
Brand names: Ayvakit, Ayvakyt
Drug class: Tyrosine Kinase Inhibitor
Mechanism of Action
Avapritinib is an oral, potent, selective type I tyrosine kinase inhibitor designed to bind the active (DFG-in) conformation of KIT and PDGFRA. Unlike type II inhibitors such as imatinib, sunitinib and regorafenib — which bind the inactive kinase conformation and are ineffective against activation-loop mutants — avapritinib potently inhibits KIT and PDGFRA activation-loop mutations, most notably PDGFRA exon 18 D842V, the classic imatinib-resistant driver in gastrointestinal stromal tumor (GIST). It is also active against KIT exon 17 mutants and the KIT D816V mutation that drives systemic…
FDA Indications
- Unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V — approved January 2020 (NAVIGATOR trial)
- Advanced systemic mastocytosis, including aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia — approved June 2021 (PATHFINDER/EXPLORER)
- Indolent systemic mastocytosis with moderate-to-severe symptoms inadequately controlled by symptomatic therapy — approved May 2023 (PIONEER)
Common Side Effects
- Edema / periorbital and peripheral edema (up to 72%)
- Nausea (32-64%)
- Fatigue (up to 61%)
- Cognitive effects — memory impairment, confusion (up to 48%)
- Diarrhea (up to 42%)
- Vomiting (up to 37%)
- Decreased appetite (up to 40%)
- Hair color changes / hair loss
- Increased lacrimation
- Anemia, neutropenia, thrombocytopenia
Clinical Pearl
Avapritinib is the one setting in GIST where imatinib must NOT be used first line: PDGFRA exon 18 D842V is intrinsically imatinib-resistant, and avapritinib achieved an objective response rate above 90% in D842V-mutant GIST in NAVIGATOR. Its distinguishing toxicity is neurologic — cognitive effects and intracranial hemorrhage — so platelet monitoring and prompt evaluation of any CNS symptom are essential, and thrombocytopenia should trigger dose holds. In contrast, the VOYAGER trial did not…
Related Therapies & Mechanisms
- Ripretinib (Qinlock) — Tyrosine Kinase Inhibitor · GIST
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- Alpelisib (Piqray) — Tyrosine Kinase Inhibitor