FDA Approval Sought for Avapritinib in Advanced Systemic Mastocytosis

December 18, 2020 - A supplemental new drug application has been submitted to the FDA for avapritinib for use as a treatment in adult patients with advanced systemic mastocytosis.

A supplemental new drug application has been submitted to the FDA for avapritinib (Ayvakit) for use as a treatment in adult patients with advanced systemic mastocytosis (SM), according to an announcement from Blueprint Medicines Corporation.1

The company has requested priority review for the selective inhibitor of D816V mutant KIT. If granted by the regulatory agency, the agent could undergo a 6-month review process. The FDA has a filing review period of 60 days, which they will use to evaluate whether the application is complete and satisfactory for filing.

“Today’s submission is an important step toward our goal of bringing [avapritinib] to patients with advanced SM, a debilitating and life-threatening rare disease,” Fouad Namouni, MD, president of Research & Development at Blueprint Medicines Corporation, stated in a press release.

“Our application is based on an unprecedented clinical dataset in this disease, which showed that patients receiving [avapritinib] had high overall response and complete remission rates, with prolonged survival, and the treatment was generally well tolerated,” Namouni added. “We look forward to working closely with the FDA during the review, as we seek to introduce the first precision therapy targeting the underlying cause of SM.”

Previously, results from a phase 1 trial showed that the selective KIT inhibitor elicited a high response rate with favorable tolerability in patients with advanced SM.2

The phase 1 trial was conducted in 2 parts; the first portion was dedicated to identifying the recommended phase 2 dose of the agent, while the second portion was to examine its preliminary activity.

Part 1 of the trial utilized a standard 3+3 dose-escalation design. To be eligible for participation, patients had to have advanced SM, which could include aggressive SM, SM with an associated hematologic neoplasm (SM-AHN) or mast cell leukemia (MCL), or other myeloid neoplasm.

Notably, no restrictions were in place with regard to previous treatments for both portions of the trial. Patients were, however, required to have a “C-finding” of organ damage based on World Health Organization criteria but not on modified International Working Group Myeloproliferative Neoplasms Research and European Competence Network on Mastocytosis response criteria.

In the trial, patients received oral avapritinib starting at a dose of 30 mg; patients received treatment once daily, continuously, in 28-day treatment cycles. Investigators evaluated for efficacy on day 1 of cycles 3, 7, 11, and 18 through the use of bone marrow biopsy and liver and spleen imaging for volume assessment; after cycle 18, these assessments were done every 6 months.

At the data cutoff of April 10, 2017, 37 patients received treatment in the first portion of the trial; 17 patients had aggressive SM, 9 had SM-AHN, 3 had MCL, 2 had smoldering SM, and 1 had other. Eighty-eight percent of these patients harbored a KIT D816V mutation, and 69% had received previous treatment for SM. Four patients and previously received midostaurin.

Participants received avapritinib at daily doses ranging from 30 mg to 400 mg. No maximum-tolerated dose of the agent had been reached, but the recommended phase 2 dose was determined to be 300 mg daily.

Efficacy results indicated that the overall response rate in all patients examined was 72%. Among the subgroups of patients, the highest ORR achieved with avapritinib was 86% in those with advanced SM, followed by 67% in those with MCL and 63% in those with SM-AHN.

Normalization, defined as a complete response, or at least a 50% reduction from baseline, defined as a partial response, was observed in bone marrow mast cells, at 58% (n = 15/26) and 23% (n = 6/26), respectively. With regard to tryptase, these rates were 60% (n = 15/25) and 40% (n = 10/25), respectively, and for splenomegaly these rates were 55% (n = 6/11) and 36% (n = 4/11), respectively.

Moreover, KIT D816V mutation allele frequency was reduced by at least 50% in 73% (n = 19/26) of patients, and 87% (n = 13/15) of patients experienced improvement in cutaneous mastocytosis.

The most frequently reported toxicities included periorbital edema (59%), fatigue (41%), peripheral edema (34%), nausea (28%), anemia (28%), and thrombocytopenia (28%). Only 1 grade 3 or 4 adverse effect was reported in at least 1 patient, and that was neutropenia (13%).

Forty-one percent of patients experienced dose reductions and 2 patients discontinued treatment. However, no treatment discontinuations were due to toxicity.

Previously, the FDA granted a breakthrough therapy designation to avapritinib for use in patients with advanced SM, including subtypes of aggressive SM, SM-AHN, and MCL. The kinase inhibitor has regulatory approval in the United States for use in adults with unresectable or metastatic gastrointestinal stromal tumor that harbors a PDGFRA exon 18 mutation; it is also approved for use in Europe for this indication.


1. Blueprint Medicines submits supplemental new drug application to FDA for AYVAKIT (avapritinib) for the treatment of advanced systemic mastocytosis. News release. Blueprint Medicines Corporation. December 17, 2020. Accessed December 18, 2020. http://prn.to/3mvRjMi.

2. Deininger MW, Gotlib J, Robinson WA, et al. Avapritinib (BLU-285), a selective KIT inhibitor, is associated with high response rate and tolerable safety profile in advanced systemic mastocytosis (ADVSM): results of a phase 1 study. Presented at 2018 EHA Congress; June 15, 2018. Poster PFS612. http://bit.ly/3aocPjF.