FDA Approves Avapritinib (Ayvakit ) for GIST With Mutation

Some patients with gastrointestinal stromal tumors (GIST) will now have a new treatment option.

The US Food and Drug Administration (FDA) has approved avapritinib (Ayvakit, Blueprint Medicines Corp) for use in a subgroup of these patients — adults with unresectable or metastatic GIST that harbors a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.

About 6%-10% of GIST tumors harbor this mutation.

"GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies…today's approval provides patients with the first drug specifically approved for GIST harboring this mutation," said Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence.

"Clinical trials showed a high response rate with almost 85% of patients experiencing tumor shrinkage with this targeted drug," he added.

The agency noted that the data that led to the approval comes from the phase 1 NAVIGATOR clinical trial involving 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with the most common mutation, PDGFRA D842V.

These patients received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity. The recommended dose was determined to be 300 mg once daily, the FDA noted.

For patients harboring 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%, with 8% having a complete response and 82% having a partial response.

While the median duration of response was not reached, 61% of the responding patients with exon 18 mutations had a response lasting 6 months or longer (31% of patients with an ongoing response were followed for less than 6 months).

The FDA notes that common side effects for patients taking avapritinib include edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash and dizziness.

The drug may cause intracranial hemorrhage, in which case the dose should be reduced, or the drug should be discontinued. It can also cause central nervous system effects, including cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations. If this occurs, depending on the severity, the FDA recommends that the drug should be withheld and then resumed at the same or reduced dose upon improvement, or permanently discontinued.

Avapritinib represents "a new standard of care for patients with PDGFRA exon 18 mutant GIST, a genomically defined population that previously had very limited treatment options," commented Michael Heinrich, MD, professor of medicine at Oregon Health & Science University in Portland and an investigator on the NAVIGATOR trial.

"For the first time, we can offer these patients a highly effective treatment that targets the underlying genetic cause of their disease," he said in a statement.

Heinrich also issued a "call to action to conduct mutational testing in all patients with GIST before initiating kinase inhibitor therapy, as recommended by clinical guidelines, so appropriate patients may realize the benefits of this promising new medicine."

The FDA granted this application Breakthrough Therapy designation, Fast Track designation, and the Orphan Drug designation for rare diseases.

Blueprint Medicines noted that the wholesale acquisition cost or list price will be $32,000 for a 30-day supply (about $384,000 annually).

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Cite this: FDA Approves Avapritinib (Ayvakit ) for GIST With Mutation - Medscape - Jan 09, 2020.