FDA Grants Priority Review to Avapritinib in PDGFRA+ and Fourth-Line GIST


The FDA has granted a priority review to a New Drug Application for avapritinib as a treatment for adult patients with <em>PDGFRA</em> exon 18&ndash;mutant gastrointestinal stromal tumors, regardless of prior therapy, and in the fourth-line setting for GIST.

Andy Boral, MD, PhD

Andy Boral, MD, PhD

Andy Boral, MD, PhD

The FDA has granted a priority review to a New Drug Application (NDA) for avapritinib as a treatment for adult patients withPDGFRAexon 18—mutant gastrointestinal stromal tumors (GIST), regardless of prior therapy, and in the fourth-line setting for GIST.1

Under the Prescription Drug User Fee Act, the FDA has set an action date of February 14, 2020, for a decision on the NDA&rsquo;s approval.

"Patients withPDGFRAexon 18 mutant GIST and fourth-line GIST are in need of new treatment options that address the underlying drivers of the disease," Andy Boral, MD, PhD, chief medical officer at Blueprint Medicines, the company developing the KIT and PDGFRA inhibitor, said in a statement. "The FDA's acceptance of our application for priority review brings us closer to our goal of delivering avapritinib to patients with GIST, and we look forward to working closely with the FDA during the review process."

Avapritinib recently demonstrated notable clinical activity in patients with advanced GIST in updates to the phase I NAVIGATOR trial presented at the 2019 ASCO Annual Meeting.2These findings supported the NDA.

The NAVIGATOR trial was an open-label, first-in-human study of avapritinib in adult patients with unresectable GIST or other relapsed or refractory solid tumors, consisting of a dose-escalation and expansion phase. The trial enrolled 237 patients with GIST, including 172 patients harboringKITmutations and 62 withPDGFRAexon 18 mutations. A total of 111 patients were being treated in the fourth-line or beyond.

In the fourth-line and beyond population (n = 121), patients were a median of 59 years (range, 33-80) and had previously received a median of 4 (range, 3-11) prior tyrosine kinase inhibitors (TKIs). In thePDGFRAexon 18 population (n = 43), patients were a median of 64 years (range, 29-90) and had received a median of 1 (range 0-5) prior TKI.

In the fourth-line setting, the objective response rate (ORR) was 22.0% (95% CI, 14.4%-30.4%), consisting of 1 complete response (CR) and 23 partial responses (PRs), 1 of which was still pending. Additionally, 52 patients achieved stable disease (SD). The median duration of response (DOR) was 10.2 months (95% CI, 7.2—not evaluable [NE]) and the median progression-free survival (PFS) was 3.7 months (95% CI, 3.4-5.6).

In thePDGFRAexon 18 population, the ORR was 86.0% (95% CI, 72.1%-94.7%), consisting of 3 CRs and 34 PR with 1 still pending. Five other patients achieved SD. The median DOR and PFS were both not reached. As of the data cutoff, 78% of patients in thePDGFRAexon 18 population were still in response.

Of note, the ORR was 100% among 5 patients withPDGFRAexon 18 mutations who were treated in the frontline setting.

A majority of adverse events (AEs) were of grade 1/2, including most commonly nausea (64.2%), fatigue (55.4%), anemia (50%), cognitive effects (41.2%), periorbital edema (40.7%), vomiting (38.2%), decreased appetite (37.7%), diarrhea (37.3%), increased lacrimation (32.8%), and peripheral edema (30.9%). Grade &ge;3 treatment-related AEs included anemia (33%), fatigue (6.4%), cognitive effects (3.9%), blood bilirubin increase (3.9%), and diarrhea (2.9%). Ten percent of patients discontinued treatment due to an AE.

The FDA previously granted a breakthrough therapy designation to avapritinib for the treatment of patients with unresectable or metastatic GIST harboring aPDGFRAD842V mutation.

Avapritinib is also currently being investigated in the open-label, randomized phase III VOYAGER trial, which is investigating the KIT/PDGFRA inhibitor in comparison with regorafenib (Stivarga) in patients with advanced GIST in the third- or fourth-line setting (NCT03465722). The trial is expecting to enroll 460 patients who have previously received imatinib (Gleevec) and 1 to 2 other TKIs.


  1. Blueprint Medicines Announces FDA Acceptance of New Drug Application for Avapritinib for the Treatment of PDGFRA Exon 18 Mutant GIST and Fourth-Line GIST [news release]. Cambridge, MA: Blueprint Medicines Corporation; August 7, 2019. https://bit.ly/2Kn4Ply. Accessed August 7, 2019.
  2. Heinrich MC, Jones RL, von Mehren M, et al. Clinical activity of avapritinib in &ge; fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST).J Clin Oncol. 2019;37(suppl 15; abstr 11022). doi: 10.1200/JCO.2019.37.15_suppl.11022.
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