FDA Will Split NDA For Avapritinib Into Two Separate Submissions


The NDA for Blueprint Medicines' agent avapritinib will be split into two separate submissions for patients with GIST.

The FDA has informed Blueprint Medicines that it intends to split the proposed indications for its agent avapritinib into two separate new drug applications (NDAs) for patients with gastrointestinal stromal tumor (GIST): one for patients with PDGFRA exon 18—mutant disease regardless of prior therapy, and one for fourth-line GIST.1

Additionally, the FDA has requested topline findings from the phase III VOYAGER trial (NCT03465722) of avapritinib versus regorafenib (Stivarga) in the third or fourth-line setting for patients with GIST; the data are slated to become available in the second quarter of 2020. The agency stated that the results would be informative in its review for the fourth-line indication and in determining avapritinib’s clinical benefit through response rates and safety in this patient population.

In August 2019, the FDA granted a priority review designation to the NDA for avapritinib for the treatment of adult patients with PDGFRA exon 18—mutant GIST, regardless of prior therapy, as well as for patients with GIST in the fourth-line setting.2 The initial action date for the FDA was February 14, 2020.

Blueprint Medicines stated in a press release that there will likely be an extended review period for the NDA for avapritinib in fourth-line GIST, in order to provide the FDA with the topline VOYAGER results.

"Throughout the development of avapritinib, we have had a productive and collaborative dialogue with the FDA about the potential of avapritinib to address important medical needs in subsets of patients with advanced GIST," Jeff Albers, chief executive officer of Blueprint Medicines, stated in the press release.

The company also announced that it has completed patient screening in the VOYAGER trial; patient enrollment is expected to be completed by the end of November 2019. Blueprint Medicines added that it plans to prioritize completion of the VOYAGER trial, yet delay initiation of the phase III COMPASS-2L trial, which is evaluating avapritinib in second-line GIST.

Should avapritinib receive initial approval, Blueprint Medicines plans to submit a supplemental NDA to the FDA for avapritinib for third-line GIST in the second half of 2020.

In the ongoing, international, open-label, randomized phase III VOYAGER trial, patients with locally advanced unresectable or metastatic GIST, who previously received imatinib (Gleevec) and 1 or 2 other TKIs, receive oral avapritinib at 300 mg daily or oral regorafenib at 160 mg daily on a 3-weeks-on/1-week-off schedule.

The primary endpoint is progression-free survival (PFS); secondary endpoints include objective response rate (ORR), overall survival, and European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30).

Avapritinib has been evaluated in the open-label, dose-escalation/dose-expansion phase I NAVIGATOR (NCT02508532) trial, which explored the clinical activity of avapritinib at the recommended phase II dose of 300 mg once daily and the maximum-tolerated dose of 400 mg daily in patients with GIST who had PDGFRA exon 18 mutations (n = 43) or in in the fourth-line setting (n = 121).3

Patients must have had metastatic GIST following ≥2 prior lines of TKI therapy and had a mutation in KIT or PDGFRA to be eligible for enrollment. The median ages in the PDGFRA exon 18—mutant and fourth-line cohort were 64 years and 59 years, respectively. Twenty-nine percent and 70% of patients were male in the PDGFRA exon 18—mutant and fourth-line groups, respectively.

The key endpoints were ORR, duration of response (DOR), and safety.

As of the data cutoff date of November 16, 2018, most patients were able to remain on treatment with dose modifications when needed. The relative dose intensity was 86% at 300 mg daily and 73% at 400 mg daily.

In the PDGFRA exon 18—mutant cohort, results showed that the ORR was 86.0% (95% CI, 72.1-94.7); this included 3 complete responses (CRs), 34 partial responses (PRs), and 1 patient with stable disease (SD). The clinical benefit rate (CBR) was 95.3%, while the median DOR (95% CI, 11.5–NE) and median PFS was not evaluable (NE; 95% CI, 13.4–NE). As of the data cutoff date, which was at a median follow-up of 10.9 months, 78% of patients in this cohort were still in response.

In the fourth-line cohort, data showed that the ORR was 22% (95% CI, 14.4-30.4), with 1 CR and 23 PRs; 52 patients had SD and 35 patients had progressive disease. The CBR was 41%, the median DOR was 10.2 months (95% CI, 7.2—NE) and the median PFS was 3.7 months (95% CI, 3.4-5.6) at a median follow-up of 10.8 months.

Regarding safety, most adverse events (AEs) were grade 1/2, with a higher incidence of commonly reported AEs in the 400-mg cohort versus the 300-mg group. Grade ≥3 treatment-related AEs included anemia (33%), fatigue (13%), cognitive effects (8%), increase in blood bilirubin (8%), and diarrhea (6%). No treatment-related grade 5 AEs were reported.

Moreover, 8.3% of patients discontinued avapritinib for a treatment-related toxicity overall, but 2.0% of patients discontinued therapy due to cognitive effects.

Enrollment for a second-line cohort in NAVIGATOR is complete, and an analysis is pending.

The FDA previously granted a breakthrough therapy designation to avapritinib for the treatment of patients with unresectable or metastatic GIST harboring PDGFRα D842V mutations. Moreover, the European Medicines Agency validated a marketing authorization application for avapritinib in adult patients with PDGFRα D842V mutant GIST, regardless of prior therapy, and in the fourth line setting of GIST.

A version of this article originally appeared on OncLive® as, “FDA Will Split Avapritinib GIST NDA Into Separate Submissions”.


  • Blueprint Medicines Announces FDA Intent to Split Avapritinib New Drug Application into Separate Submissions for PDGFRA Exon 18 Mutant GIST and Fourth-Line GIST. Blueprint Medicines Corporation. Published October 28, 2019. https://bit.ly/2NqcFLA. Accessed October 28, 2019.
  • Blueprint Medicines Announces FDA Acceptance of New Drug Application for Avapritinib for the Treatment of PDGFRA Exon 18 Mutant GIST and Fourth-Line GIST. Blueprint Medicines Corporation. Published August 7, 2019. https://bit.ly/2Kn4Ply. Accessed August 7, 2019.
  • Heinrich M, Jones RL, von Mehren M, et al. Clinical activity of avapritinib in ≥4th line (4L+) and PDGFRA exon 18 gastrointestinal stromal tumors (GIST). J Clin Oncol. 2019;37 (suppl; abstr 11022).

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