On September 25, 2020 Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported that the European Commission (EC) has granted conditional marketing authorization to AYVAKYT (avapritinib) as a monotherapy for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring the platelet-derived growth factor receptor alpha (PDGFRA) D842V mutation. For the first time in Europe, there is an approved therapy for patients with PDGFRA D842V mutant GIST specifically designed to target the underlying molecular driver of their disease (Press release, Blueprint Medicines, SEP 25, 2020, View Source [SID1234565614]).

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The EC approval is based on efficacy results from the Phase 1 NAVIGATOR trial as well as combined safety results from the NAVIGATOR and Phase 3 VOYAGER trials. AYVAKYT demonstrated deep and durable clinical activity and was generally well-tolerated in patients with PDGFRA D842V mutant GIST with or without prior therapy. In 38 NAVIGATOR trial patients with PDGFRA D842V mutant GIST at a starting dose of 300 mg or 400 mg once daily, AYVAKYT had an overall response rate (ORR) of 95 percent (95% CI: 82.3%, 99.4%), with 13 percent of patients achieving a complete response, and the median duration of response (DOR) was 22.1 months (95% CI: 14.1 months, not estimable). The median progression-free survival (PFS) was 24 months, and the median overall survival (OS) was not reached. These efficacy data were reported earlier this month during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020. The most frequently reported adverse reactions (≥20 percent) were nausea, fatigue, anemia, periorbital edema, face edema, hyperbilirubinemia, diarrhea, vomiting, peripheral edema, increased lacrimation, decreased appetite and memory impairment.

GIST is a genomically driven sarcoma of the gastrointestinal (GI) tract, with PDGFRA D842V mutations implicated in a rare subset of patients. A retrospective study of patients with PDGFRA D842V mutant GIST showed that treatment with imatinib, the standard first-line GIST therapy, led to an ORR of 0 percent.2 ESMO (Free ESMO Whitepaper) guidelines recommend including mutational testing in the GIST diagnostic work-up as standard practice.

"There have historically been no treatments offering hope for patients with PDGFRA D842V mutant GIST. AYVAKYT represents the first major therapeutic breakthrough for patients with GIST harboring this mutation, defining a new standard of care," said Sebastian Bauer, M.D., medical oncologist at the West German Cancer Center in Essen, and an investigator on the NAVIGATOR trial. "The NAVIGATOR trial confirmed that almost all patients with PDGFRA D842V mutant GIST achieved tumor shrinkage and clinical responses were durable. These patients have lived longer than what is expected based on historical outcomes, and side effects have been well-tolerated in most patients. With this approval, it is more important than ever to conduct mutational testing prior to first-line treatment, so that patients with PDGFRA D842V mutant GIST may begin therapy with AYVAKYT, the only effective treatment for their tumor type."

"This year, Blueprint Medicines has received three marketing approvals globally, highlighting our commitment to rapidly advance a portfolio of transformative treatments and effectively deliver them to patients worldwide," said Jeff Albers, Chief Executive Officer at Blueprint Medicines. "AYVAKYT is the first highly active treatment option for PDGFRA D842V mutant GIST, offering much-needed hope for this rare patient population who have long been underserved by existing therapies. As we progress toward our AYVAKYT launches in Europe, we are focused on raising awareness about the therapy’s differentiated clinical profile and the importance of mutational testing, and working closely with health authorities to enable patient access to AYVAKYT as rapidly as possible."

In Europe, Blueprint Medicines plans to initiate its first commercial launch in Germany following the EC approval, and the timing of AYVAKYT availability will vary for other countries based on local reimbursement and access pathways. AYVAKYT will be available in 100 mg, 200 mg and 300 mg dose strengths, and the recommended starting dose is 300 mg once daily. As part of the conditional marketing authorization, Blueprint Medicines plans to conduct an observational, long-term study in patients with PDGFRA D842V mutant GIST treated with AYVAKYT.

"The introduction of a new targeted therapy, AYVAKYT, is an important milestone for patients with PDGFRA D842V mutant GIST, who have historically had no effective treatment options," said Markus Wartenberg, chair of Sarcoma Patients EuroNet Association (SPAEN). "We appreciate working with companies like Blueprint Medicines to advance treatment for those living with GIST, and empower the patient community through education and support."

About AYVAKYT (avapritinib)

AYVAKYT (avapritinib) is a kinase inhibitor approved in the EU for the treatment of adults with unresectable or metastatic GIST harboring the PDGFRA D842V mutation. AYVAKYT is the first precision therapy approved in Europe to treat a genomically defined population of patients with GIST. The EC previously granted orphan medicinal product designation for AYVAKYT for the treatment of GIST. This medicine was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations, under the brand name AYVAKIT.

This therapy is not approved for the treatment of any other indication in the U.S. or Europe, or for any indication in any other jurisdiction by any other health authority. It is being developed globally for the treatment of advanced and indolent systemic mastocytosis (SM). The FDA granted breakthrough therapy designation to AYVAKIT for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of avapritinib in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for avapritinib in the rest of the world.

About GIST

GIST is a sarcoma, or tumor of bone or connective tissue, of the GI tract. Tumors arise from cells in the wall of the GI tract and occur most often in the stomach or small intestine. Most patients are diagnosed between the ages of 50 to 80, and diagnosis is typically triggered by GI bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or GI obstruction.

About 5 to 6 percent of primary GIST cases are caused by a PDGFRA D842V mutation, the most common PDGFRA exon 18 mutation. Published data have shown poor outcomes in patients with PDGFRA D842V mutant GIST treated with imatinib and other approved therapies, including a median OS of 15 months, a median PFS of 3 months and an ORR of 0 percent.2