The FDA has extended the Prescription Drug User Fee Act deadline for a new drug application (NDA) for avapritinib (Ayvakit) as a treatment for adult patients with fourth-line gastrointestinal stromal tumor (GIST). The deadline, which was initially February 14, 2020, has been extended by 3 months to May 14, 2020, according to BluePrint Medicines, the developer of avapritinib.
The FDA has extended the Prescription Drug User Fee Act deadline for a new drug application (NDA) for avapritinib (Ayvakit) as a treatment for adult patients with fourth-line gastrointestinal stromal tumor (GIST). The deadline, which was initially February 14, 2020, has been extended by 3 months to May 14, 2020, according to BluePrint Medicines, the developer of avapritinib.1
The FDA previously requested topline data from the company’s ongoing phase III VOYAGER trial (NCT03465722) evaluating avapritinib and regorafenib (Stivarga) in third- or fourth-line GIST, which is slated to inform the pending action on the application for the fourth-line setting. BluePrint Medicines stated that it plans to provide the topline data to the FDA in the second quarter of 2020, so the agency will be able to decide on the application by the new deadline.
Additionally, the company announced that the National Comprehensive Cancer Network updated its Clinical Practice Guidelines in Oncology for Soft Tissue Sarcoma to include avapritinib as a recommended category 2A treatment for patients with unresectable or metastatic GIST with a PDGFRA exon 18 mutation, which includes PDGPRA D842V mutations, and fourth-line GIST.
The announcements follow the January 2020 FDA approval of avapritinib for the treatment of adult patients with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations.
The agency had initially granted a priority review designation to an NDA for avapritinib in August 2019 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 In October 2019, the FDA informed Blueprint Medicines that it intended to split the proposed indications for its agent avapritinib into 2 separate NDAs for patients with GIST: one for patients with PDGFRA exon 18—mutant disease regardless of prior therapy, and one for fourth-line GIST.3
The PDGFRA exon 18—mutant GIST approval is based on efficacy results from the phase I NAVIGATOR trial (NCT02508532), as well as combined safety data from multiple studies of avapritinib. In the specific PDGFRA exon 18–mutant patient population, avapritinib elicited an 84% overall response rate (ORR; 95% CI, 69%-93%), which included a 7% complete response (CR) rate and a 77% partial response (PR) rate.4 Specifically in patients with PDGFRA D842V mutations, the ORR was 89% (95% CI, 75%-97%), which included an 8% CR rate and an 82% PR rate. The median duration of response (DOR) was not reached in either patient population (range, 1.9+ months to 20.3+ months).
In the open-label, dose-escalation/dose-expansion phase I NAVIGATOR trial, investigators 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).5
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 fourth-line cohort, 71.1% of patient were white, 90.9% of patients had a KIT mutation, the median 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.
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%).
The key endpoints were ORR, 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 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.
In the PDGFRA exon 18—mutant cohort, previous 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.
The safety profile of avapritinib in patients with unresectable or metastatic GIST was evaluated in 204 patients who received avapritinib at 300 mg or 400 mg once daily in the NAVIGATOR trial.
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. 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).
1. Blueprint Medicines announces PDUFA date extension for new drug application of avapritinib for the treatment of adults with fourth-line gastrointestinal stromal tumor [news release]: Cambridge, MA. Published February 6, 2020. https://prn.to/2GWW92C. Accessed February 6, 2020.
2. 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.
3. 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.
4. Blueprint Medicines announces FDA approval of Ayvakit (avapritinib) for the treatment of adults with unresectable or metastatic PDGFRA exon 18 mutant gastrointestinal stromal tumor [news release]. Blueprint Medicines Corporation. Published January 9, 2020. https://bit.ly/2sTz3GX. Accessed January 9, 2020.
5. 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). doi: 10.1200/JCO.2019.37.15_suppl.11022.
This article originally appeared on OncLive as, "FDA Extends Review Period for Avapritinib in Fourth-Line GIST."