On January 9, the U.S. Food and Drug Administration (FDA) approved avapritinib (Ayvakit) for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring platelet-derived growth factor receptor α (PDGFRA) exon 18 mutations. This approval includes GISTs with PDGFRA D842V mutations, the most common exon 18 mutation. Avapritinib is an investigational oral precision therapy that selectively inhibits KIT and PDGFRA mutant kinases.
Dr. Richard Pazdur, director of the FDA Center of Excellence in Oncology and acting director of the Office of Oncology Diseases of the Center for Drug Evaluation and Research, said: “Gastrointestinal stromal tumors with PDGFRA exon 18 mutations do not respond to standard therapies for gastrointestinal stromal tumors. However, today's approval provides patients with the first specially approved drug for gastrointestinal stromal tumors with this mutation. Clinical trials have shown that the response rate of this targeted drug is very high, and almost 85% of patients have tumor shrinkage. ”
NAVIGATOR test
The FDA approved Avapritinib based on the results of the PHASE I NAVIGATOR TRIAL, which involved 43 patients with gastrointestinal stromal tumors with PDGFRA exon 18 mutations, including 38 patients with PDGFRA D842V mutations. Patients take 300 mg or 400 mg of Avapritinib orally once a day until the disease progresses or unacceptable toxicity occurs. The recommended dose is 300 mg once a day. The trial measured how many patients experienced all or part of the tumor atrophy (a certain amount) during treatment (full remission rate).
For patients with PDGFRA exon 18 mutations, the overall response rate was 84%, with 7% achieving a complete response and 77% achieving a partial response. For the subgroup of patients with PDGFRA D842V mutations, the overall response rate was 89%, with 8% achieving a complete response and 82% achieving a partial response. Although the median duration of response was not reached, 61% of patients with exon 18 mutations maintained a response for 6 months or longer (31% of those with sustained responses had a follow-up period of less than 6 months).
Side effect
Common side effects in patients taking Avapritinib are edema, nausea, fatigue/fatigue, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color change, tears, 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, including cognitive impairment, dizziness, sleep disorders, mood disorders, language disorders, and hallucinations. If this happens, depending on the severity, Avapritinib should be discontinued, and then Avapritinib should be restored at the same or reduced dose when improving, or permanently discontinued.
Health care professionals should advise pregnant women that Avapritinib may cause harm to a developing fetus or newborn baby. In addition, the FDA recommends that medical staff tell women with reproductive ability, as well as men who are partners with reproductive ability women, to use effective contraceptive methods during treatment with Avapritinib and within 6 weeks after the final dose.
When initial clinical evidence showed that the drug might show substantial improvements to existing therapies, the FDA granted the application the title of “breakthrough therapy”, which can accelerate the development and review of drugs designed to treat serious diseases. Avapritinib has also received the titles of ”fast track“ and ”orphan Drug" to encourage and assist in the development of drugs for rare diseases.
