FDA Denies Approval of Avapritinib in Fourth-Line GIST

The FDA has issued a complete response letter (CRL) to Blueprint Medicines, Inc regarding the New Drug Application (NDA) for avapritinib (Ayvakit) as treatment of adult patients with unresectable or metastatic fourth-line gastrointestinal stromal tumor (GIST). The CRL denies approval of the application.¹

The NDA for this indication was submitted to the FDA in June of 2019.² The NDA was accepted by the FDA in August 2019 along with a separate NDA for treatment of PDGFRA Exon 18-mutant GIST³, which was approved by the FDA in January 2020.

Recent data around avapritinib in unresectable or metastatic fourth-line GIST as seen in the phase III VOYAGER study showed that the agent failed to improve progression-free survival (PFS) in third- and fourth-line patients, missing the primary end point of the study. The topline results were released in April.⁴

The international, multicenter, open-label, randomized study included 476 patients total, including 240 patients in the avapritinib arm and 236 in the regorafenib comparator arm.

The median PFS observed was 4.2 months in the avapritinib arm and 5.6 months in the regorafenib (Stivarga) arm, which was not considered to be a statistically significant difference. The overall response rate (ORR) observed with avapritinib was 17% versus 7% with regorafenib.

Avapritinib was well-tolerated in the study population, according to the topline safety analysis. Adverse events (AEs) were predominantly grades 1 and 2. Overall, the safety profile was similar to previously reported data for avapritinib with no new safety signals.

The secondary end points of VOYAGER included ORR, overall survival, and quality of life. These outcomes were assessed in patients with histologically confirmed disease, who received imatinib and 1 or more other tyrosine kinase inhibitors as prior therapy, and an ECOG performance status of 0 to1.

Despite poor outcomes in third- and fourth-line patients, clinical activity was observed with the agent in patients with KIT- and PDGFRA-mutant GIST treated in the phase I NAVIGATOR study (NCT02508532). In the 43 evaluable patients, the ORR was 86%, including 3 complete responses (CRs), 34 partial responses (PRs) with 1 response pending, and 53 cases of stable disease (SD). Seventy-eight percent had ongoing responses at the time of data cutoff, but the median duration of response (DOR) was not reached.⁵

In the subgroup of patients treated in the fourth-line setting, the ORR was 22%, which included 1 CR, 23 PRs with 2 responses pending, and 5 patients with SD. The median DOR was 10.2 months with a median follow-up of 10.8 months.

Similar to the safety results seen with avapritinib in VOYAGER, the safety analysis in NAVIGATOR showed that patients tolerated the 300 mg and 400 mg doses of avapritinib well, and most AEs were grades 1 and 2. In terms of treatment-emergent AEs, 25% of patients experienced them, and they were most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (29%).

Two percent of patients experienced grade 3/4 AEs, with the most common being anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. AEs led to treatment discontinuation in 8.3% of patients altogether.

The NAVIGATOR study laid the groundwork for VOYAGER by leading to the hypothesis that avapritinib could change the standard-of-care.

Avapritinib is under ongoing development despite the FDA denial of approval for the indication in unresectable or metastatic fourth-line GIST. The VOYAGER will discontinue treating patients for any indication other than PDGFRA Exon 18-mutant GIST.

_Reference:

_{1. Blueprint Medicines receives complete response letter from FDA for avapritinib new drug application for the treatment of fourth-line gastrointestinal stromal tumor [news release]. Cambridge, Massachusetts: Blueprint Medicines, Inc. May 15, 2020. https://bit.ly/2yZehIP. Accessed May 15, 2020.}

_{2. Blueprint Medicines submits New Drug Application to U.S. Food and Drug Administration for avapritinib for the treatment of PDGFRA exon 18 mutant gist and fourth-line gist [news release]. Cambridge, Massachusetts: Blueprint Medicines, Inc. June 14, 2019. https://bit.ly/3dPsBm4.Accessed May 15, 2020.}

_{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 [news release]. Cambridge, Massachusetts: Blueprint Medicines, Inc. October 28, 2019. https://bit.ly/3cBoYQq. Accessed May 15, 2020.}

_{4. Blueprint Medicines announces top-line results from phase 3 VOYAGER trial of avapritinib versus regorafenib in patients with advanced gastrointestinal stromal tumor [news release]. Cambridge, Massachusetts: Blueprint Medicines, Inc; April 28, 2020. https://bit.ly/2zDRORC. Accessed May 15, 2020.}

_{5. Heinrich MC, Jones EL, von Mehren M, et al. Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST). J Clin Oncol. 2020; 38 (4). Abstract 826.}