The FDA has approved avapritinib (AyvakitTM, Blueprint Medicines) for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) with platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutations, including D842V mutations, the most common type of exon 18 mutation. Up to 10% of patients with GIST harbor PDGFRA mutations, which have been linked to GIST development.
"GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies for GIST," commented 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. "Today's approval provides patients with the first drug specifically approved for GIST harboring this mutation."
The approval was based on data from the multi-center, single-arm phase 1 NAVIGATOR trial (NCT02508532), led by Michael C. Heinrich, MD, Professor of Medicine at Oregon Health & Science University. The trial enrolled 43 patients with GIST carrying PDGFRA exon 18 mutations, including 38 patients with D842V mutations. For the dose-finding portion of the study, patients were assigned to receive either 300 mg or 400 mg avapritinib orally once daily; upon findings of toxicity, the recommended dose was set at 300 mg. The trial's primary end point was overall response rate based on disease assessment by independent radiological review per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, with a secondary end point of response duration.
Avapritinib produced an overall response rate of 84%, including 7% complete responses and 77% partial responses, among all patients with PDGFRA exon 18 mutations. In the subgroup of patients with D842V mutations, avapritinib produced an overall response rate of 89%, including 8% complete responses and 82% partial responses. Among all patients, 61% of those who responded experienced a response of at least six months' duration; 31% of patients with ongoing responses were followed for less than six months. At a median follow-up of 10.6 months, the median response duration had not yet been reached.
Adverse reactions occurring in at least 20% of patients included 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 discontinued. It can also impact the central nervous system, causing cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations. Avapritinib may harm a developing fetus or newborn infant. Women of reproductive potential and male partners of women of reproductive potential should be advised to use effective contraception during avapritinib treatment and for six weeks following the last dose.
The recommended dose of avapritinib is 300 mg orally once daily, at least one hour before or two hours after a meal.
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