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The FDA has granted a priority review designation to a new drug application for avapritinib for the treatment of adult patients with PDGFRA exon 18–mutant gastrointestinal stromal tumors, regardless of prior therapy, as well as for patients with GIST in the fourth-line setting.
The FDA has granted a priority review designation to a new drug application (NDA) for avapritinib for the treatment of adult patients with PDGFRA exon 18—mutant gastrointestinal stromal tumors (GIST), regardless of prior therapy, as well as for patients with GIST in the fourth-line setting.1
Under the Prescription Drug User Fee Act, the FDA must make a decision on the NDA by February 14, 2020.
"Patients with PDGFRA exon 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 developer of the investigational and highly selective KIT and PDGFRA inhibitor. "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 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).
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.
In the PDGFRA exon 18—mutant cohort, 67.4% of patients were white, 88.4% of patients harbored a PDGFRA D842V mutation, and the median number of prior therapies was 1. A total of 97.7% of patients had metastatic disease, 46.5% of patients had a target lesion ≤5 cm, and 86.0% of patients had prior surgical resection. Patients had an ECOG performance status of 0 (32.6%), 1 (60.5%), or 2 (7.0%).
In the fourth-line cohort, 71.1% of patient were white, 90.9% of patients had a KIT mutation, the number of prior therapies was 4, and 98.3% of patients had metastatic disease. A total of 47.1% of patients had a largest target lesion of >5 cm to ≤10 cm, and 88.4% of patients had surgical resection. Moreover, 32.2% of patients had an ECOG performance status of 0, compared with 64.5% who had a status­ of 1, and 3.3% of whom had a status of 2.
The key endpoints were overall response rate (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 progression-free survival (PFS) was not estimated (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 mostly 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.
The ongoing, international, open-label, randomized phase III VOYAGER trial (NCT03465722) is evaluating the safety and efficacy of avapritinib versus regorafenib (Stivarga) in patients with third- or fourth-line advanced GIST.