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Blueprint Medicines' Ayvakit Approved for Rare GIST With PDGFRA Mutation


The platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation occurs in close to 6% of patients with gastrointestinal stromal tumors (GIST), the most common being the D842V mutation, for which there is no effective, approved treatment. The drug previously received breakthrough therapy, fast track, and orphan drug designations.

The FDA has approved Blueprint Medicines’ oral kinase inhibitor Ayvakit (avapritinib) for rare unresectable or metastatic gastrointestinal stromal tumors (GIST) in adults with the platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation—making it the first precision therapy approved for GIST and the only one for this indication—as well as the subset of patients who harbor the PDGFRA D842V mutation. The drug previously received breakthrough therapy, fast track, and orphan drug designations.

“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies for GIST. However, today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” stated 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.

The approval was based on efficacy results from the phase 1 NAVIGATOR (NCT02508532) trial of 43 patients with GIST with the PDGFRA exon 18 mutation, including 38 with the PDGFRA D842V mutation, and safety results of 204 heavily pretreated patients who received a median of 3 prior kinase inhibitors (range, 0-7). Patients received either 300- or 400-mg Ayvakit once daily.

In the PDGFRA exon 18 mutation group, the overall response rate (ORR) was 84% (95% CI, 69%-93%), and there were complete responses (CRs) in 7% and partial responses (PRs) in 77%. In the subgroup, the ORR was 89% (95% CI, 75%-97%), with 8% CRs and 82% PRs. The median duration of response was not reached in either group (range, 1.9+ to-20.3+ months). In contrast, patients who received imatinib had an ORR of 0%.

The most common adverse reactions (>20%) were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash, and dizziness. Intracranial hemorrhage (IH) and central nervous system (CNS) disorders are also possible, but more rare, and Ayvakit should be permanently withheld or resumed at a lower (IH and CNS disorders) or the same (CNS disorders) dose, depending on severity.

Embryo-fetal toxicity is also possible while on Ayvakit, so pregnant women and men and women of reproductive potential should be warned of this risk. Effective contraception should be used during treatment and for up to 6 weeks after the final dose. And women who are breastfeeding should stop while on Ayvakit and for 2 weeks after the final dose.

"Building on our growing understanding of the molecular basis of GIST, this milestone ushers in a new era of precision medicine in this disease,” stated Michael Heinrich, MD, professor of medicine at Oregon Health & Science University and an investigator on the NAVIGATOR trial.

Ayvakit will come in 100-, 200-, and 300-mg strengths, and the average recommendation is 300 mg daily. It could cost an average $32,000 per month, but that depends on treatment duration and insurance coverage.

Blueprint hopes to make Ayvakit available in the United States in less than a week.

Fourth-line GIST

Blueprint also announced that the FDA split avapritinib’s proposed indications into 2 new drug applications: (1) PDGFRA exon 18 mutant GIST and (2) fourth-line GIST. The action date for fourth-line GIST, under the Prescription Drug User Fee Act, is expected to be February 14, although a 3-month extension is likely so Blueprint can provide the FDA with data from the phase 3 VOYAGER (NCT03465722) trial.

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