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FDA Approves Ayvakit for Gastrointestinal Stromal Tumors

Kinase inhibitor targets tumors with a PDGFRA exon 18 mutation

The FDA has approved avapritinib (Ayvakit, Blueprint Medicines Corporation) for adults with unresectable or metastatic gastrointestinal stromal tumors (GISTs) that have a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.

“GISTs harboring a PDGFRA exon 18 mutation do not respond to standard therapies for GISTs,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. Avapritinib, he added, “provides patients with the first drug specifically approved for GISTs harboring this mutation.”

GISTs occur in the gastrointestinal tract, mostly in the stomach or small intestine. Mutations in the DNA of specialized nerve cells found in the walls of the gastrointestinal tract may lead to GISTs. Up to about 10% of GIST cases involve PDGFRA mutations. Avapritinib’s approval includes treatment of GISTs that harbors a PDGFRA D842V mutation, the most common exon 18 mutation.

The FDA approved avapritinib, a kinase inhibitor, based on a clinical trial involving 43 patients with GISTs harboring a PDGFRA exon 18 mutation, including 38 patients with PDGFRA D842V mutation. Patients received avapritinib 300 mg or 400 mg orally once daily until disease progression or unacceptable toxicity. The recommended dose was determined to be 300 mg once daily.

For patients with a PDGFRA exon 18 mutation, the overall response rate (ORR) was 84%, with 7% having a complete response and 77% having a partial response. For the subgroup of patients with PDGFRA D842V mutations, the ORR was 89% (8% complete, 82% partial). While the median duration of response was not reached, 61% of the responding patients with exon 18 mutations had a response lasting six months or longer.

Common side effects were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash, and dizziness. Avapritinib can cause intracranial hemorrhage, in which case the dose should be reduced or the drug should be discontinued. Avapritinib can also cause central nervous system effects; depending on the severity, avapritinib should be withheld and then resumed at the same or reduced dose upon improvement or permanently discontinued.

The FDA granted this application breakthrough therapy, fast track, and orphan drug designations.

Source: FDA, January 9, 2020

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