Avapritinib Approved for GIST Subgroup

The FDA has granted marketing authorization to avapritinib (Ayvakit; Blueprint Medicines) for the treatment of inoperable or metastatic gastrointestinal stromal tumors (GIST) with exon 18 mutations of platelet-derived growth factor receptor-alpha (PDGFRA).

GIST is a rare sarcoma of the digestive tract typically driven by mutations in KIT or PDGFRA. Approximately 6% of patients have PDGFRA exon 18 alterations, the most common of which is D842V. This mutation renders tumors insensitive to all previously approved GIST therapies—multikinase inhibitors such as imatinib (Gleevec; Novartis) that block a limited number of KIT- and PDGFRA-mutant forms.

Avapritinib was designed to have activity across a range of mutations like D842V that occur in the activation-loop domain of the target kinases (Sci Transl Med 2017;9:eaao1690). “It's a super-potent drug for the PDGFRA D842V mutation,” says Sebastian Bauer, MD, of the West German Cancer Center in Essen, who was involved in testing avapritinib. “In this previously completely refractory subtype of GIST, it's working miraculously well.”

In the phase I NAVIGATOR trial—the results of which formed the basis of avapritinib's approval—43 patients with PDGFRA exon 18 mutations (38 of whom had D842V-mutant disease) received the drug. Overall, 86% responded, with the median treatment benefit lasting at least 11 months. Neither median duration of response (DOR) nor median progression-free survival (PFS) had been reached at the data cutoff in November 2018. The most common severe side effects included anemia, diarrhea, abdominal pain, and cognitive impairment.

Jason Sicklick, MD, of the University of California, San Diego, who was not involved in the trial, expects avapritinib to prompt more molecular profiling of GIST tumors, testing that's currently uncommon. “We need to start thinking about these subsets of GIST in a more genomically directed fashion,” says Sicklick.

Lead investigator Michael Heinrich, MD, of the Portland VA Hospital and Oregon Health and Science University, agrees. “It will clearly make a difference [in treatment] to know what the mutation is,” he says. “We're hoping that this approval is really going to drive testing.”

In addition to patients with PDGFRA exon 18 mutations, the NAVIGATOR trial also enrolled 103 others with GIST who had at least three prior lines of treatment. In that group of patients, the majority of whom harbored KIT mutations, the overall response rate was 17% and the median DOR approximately 10 months.

Blueprint is also testing the drug against regorafenib (Stivarga; Bayer) in patients with GISTs of all mutational causes who previously received imatinib and one or two other tyrosine kinase inhibitors. However, results of that phase III trial, called VOYAGER, won't be available for several months—at which point another KIT/PDGFRA inhibitor may have beaten avapritinib to market for the treatment of non–mutationally defined GISTs resistant to all other approved therapies.

The FDA is evaluating ripretinib (Deciphera Pharmaceuticals) for this indication. In the phase III INVICTUS trial, which enrolled 129 patients with advanced GIST whose prior drug regimen included at least imatinib, sunitinib (Sutent; Pfizer), and regorafenib, 9.4% of those who received ripretinib responded, leading to a significant prolongation in median PFS—6.3 months, compared with 1 month among patients who received placebo. A regulatory decision is anticipated in May. –Elie Dolgin

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