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Ayvakyt for the treatment of adults with unresectable or metastatic PDGFRA D842V mutant gastrointestinal stromal tumors, approved by European Commission

The European Commission ( EC ) has granted conditional marketing authorization to Ayvakyt ( Avapritinib ) as a monotherapy for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors ( GIST ) harboring the platelet-derived growth factor receptor alpha ( PDGFRA ) D842V mutation.
This is the first approved therapy for patients with PDGFRA D842V mutant GIST specifically designed to target the underlying molecular driver of the disease.

The EC approval is based on efficacy results from the phase 1 NAVIGATOR trial as well as combined safety results from the NAVIGATOR and phase 3 VOYAGER trials.
Ayvakyt has demonstrated deep and durable clinical activity and was generally well-tolerated in patients with PDGFRA D842V mutant GIST with or without prior therapy.
In 38 NAVIGATOR trial patients with PDGFRA D842V mutant GIST at a starting dose of 300 mg or 400 mg once daily, Ayvakyt had an overall response rate ( ORR ) of 95% ( 95% CI: 82.3%, 99.4% ), with 13% of patients achieving a complete response, and the median duration of response ( DOR ) was 22.1 months ( 95% CI: 14.1 months, not estimable ).
The median progression-free survival ( PFS ) was 24 months, and the median overall survival ( OS ) was not reached.

The most frequently reported adverse reactions ( greater than or equal to 20% ) were nausea, fatigue, anemia, periorbital edema, face edema, hyperbilirubinemia, diarrhea, vomiting, peripheral edema, increased lacrimation, decreased appetite and memory impairment.

GIST is a genomically driven sarcoma of the gastrointestinal tract, with PDGFRA D842V mutations implicated in a rare subset of patients.
A retrospective study of patients with PDGFRA D842V mutant GIST has shown that treatment with Imatinib, the standard first-line GIST therapy, led to an ORR of 0%.
ESMO guidelines recommend including mutational testing in the GIST diagnostic work-up as standard practice.

GIST is a sarcoma, or tumor of bone or connective tissue, of the gastrointestinal tract. Tumors arise from cells in the wall of the gastrointestinal tract and occur most often in the stomach or small intestine.
Most patients are diagnosed between the ages of 50 to 80, and diagnosis is typically triggered by gastrointestinal bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or gastrointestinal obstruction.
About 5 to 6% of primary GIST cases are caused by a PDGFRA D842V mutation, the most common PDGFRA exon 18 mutation.
Published data have shown poor outcomes in patients with PDGFRA D842V mutant GIST treated with Imatinib and other approved therapies, including a median overall survival of 15 months, a median progression-free survival of 3 months and an overall response rate of 0%. ( Xagena )

Source: Blueprint Medicines, 2020