The U.S. Food and Drug Administration (FDA) has approved avapritinib (Ayvakit™; Blueprint Medicines, previously known as BLU-285) for the treatment adults patients with unresectable or metastatic gastrointestinal stromal tumor (GIST), a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine, harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.
The approval includes GIST that harbors a PDGFRA D842V mutation, which is the most common exon 18 mutation. Avapritinib is a kinase inhibitor, meaning it blocks a type of enzyme called a kinase and helps keeps the cancer cells from growing.
Each year, approximately 5,000 new cases of GIST are diagnosed in the United States. However, GISTs may be more common because small tumors, without clear signs or symptoms, often remain undiagnosed.
Gastrointestinal stromal tumors are caused by genetic changes in one of several genes
About 80% of cases are associated with a mutation in the KIT gene, and about 10 percent of cases are associated with a mutation in the PDGFRA gene. Mutations in the KIT and PDGFRA genes are associated with both familial and sporadic GISTs. A small number of affected individuals have mutations in other genes.
GISTs arise from specialized nerve cells found in the walls of the gastrointestinal tract. One or more mutations in the DNA of one of these cells may lead to the development of GIST. These cells aid in the movement of food through the intestines and control various digestive processes.
More than half of GISTs start in the stomach. Most of the others start in the small intestine, but GISTs can start anywhere along the gastrointestinal tract. The activating mutations in PDGFRA have been linked to the development of GISTs, and up to approximately 10% of GIST cases involve mutations of this gene.
Response to PDGFRA
“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies for GIST. However, today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” noted Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.
“Clinical trials showed a high response rate with almost 85% of patients experiencing tumor shrinkage with this targeted drug,” Pazdur added.
The FDA approved avapritinib based on the results of a clinical trial involving 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with PDGFRA D842V mutation.
In this trial, patients received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity. The recommended dose was determined to be 300 mg once daily.
The trial measured how many patients experienced complete or partial shrinkage of their tumors during treatment, referred to as overall response rate or ORR. For patients harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response (CR) and 77% having a partial response (PR).
For the subgroup of patients with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response. While the median duration of response was not reached, 61% of the responding patients with exon 18 mutations had a response lasting six months or longer (31% of patients with an ongoing response were followed for less than six months).
“The full approval of [avapritinib] is based on robust data from our Phase I NAVIGATOR study. This is an incredibly exciting milestone for our company and, more importantly, for GIST patients with a PDGFRA exon 18 mutation, who have been waiting for a new treatment option,” explained Jeff Albers, Chief Executive Officer at Blueprint Medicines.
“[Avapritinib] is the first of what we hope will be many approved medicines enabled by our research platform. Now, as we begin to deliver [avapritinib] to patients and their healthcare providers, we aim to fortify our leadership in the field of precision medicine and build a foundation for our broader portfolio by pairing our strong research and development capabilities with an equally talented commercial organization focused on addressing patient needs, accelerating diagnostic testing and enabling access,” Albers added.
Common side effects for patients taking avapritinib were edema (swelling), nausea, fatigue/asthenia (abnormal physical weakness or lack of energy), cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation (secretion of tears), abdominal pain, constipation, rash and dizziness.
Avapritinib can cause intracranial hemorrhage (bleeding that occurs inside the skull) in which case the dose should be reduced, or the drug should be discontinued. The newly approved agent can also cause central nervous system effects including cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders and hallucinations.
If this happens, the highlights of prescription information specifies that, depending on the severity, the drug should be withheld and then resumed at the same or reduced dose upon improvement or permanently discontinued.
The FDA granted this application Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious condition, when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies.
Avapritinib was also granted Fast Track designation, which expedites the review of drugs to treat serious conditions and fill an unmet medical need. Avapritinib received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
New Drug Application
As part of the approval process, the FDA administratively split the proposed indications for avapritinib under the initial New Drug Application (NDA) into two separate NDAs. These NDA’s include one for the indication for PDGFRA exon 18 mutant GIST, and one for fourth-line GIST.
The Prescription Drug User Fee Act (PDUFA) action date for the fourth-line GIST indication is currently February 14, 2020. For the NDA for fourth-line GIST an extension of up to three months for the PDUFA action date will likely be required to enable Blueprint Medicines to provide top-line data to the FDA from VOYAGER, a Phase III clinical trial evaluating avapritinib versus regorafenib (Stivarga®; Bayer) in third- or fourth-line GIST.
In addition to the approved indication in GIST, Blueprint Medicines is investigating avapritinib in the treatment of acute myeloid leukemia and systemic mastocytosis and systemic mastocytosis with an associated hematologic neoplasm and mast cell leukemia.
These studies are based on the understanding that mutations in two type-3 receptor tyrosine kinases, KIT and FLT3, are common in acute myeloid leukemia and systemic mastocytosis, leading to hyperactivation of key signalling pathways. 
Based on the structural similarity between FLT3 and KIT, researchers have found that tyrosine kinase inhibitors targeting either FLT3 or KIT offer significant clinical benefit. 
These benefits have been shown in the ongoing PIONEER study, a multicenter, randomized, double-blind, placebo-controlled, phase II study in patients with indolent or smoldering systemic mastocytosis whose symptoms are not adequately controlled by best supportive care. These patients typically have a single driver gain-of-function KIT mutation making them promising candidates for KIT D816V inhibitor therapy, including avapritinib.
Avapritinib is now being studies to help identify the recommended phase II dose (RP2D) in indolent systemic mastocytosis and to investigate efficacy of avapritinib vs. placebo in patients with indolent and smoldering systemic mastocytosis.
Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors (NAVIGATOR) – NCT02508532
Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST (VOYAGER) – NCT03465722
Early Access Program (EAP) for Avapritinib in Patients With Locally Advanced Unresectable or Metastatic GIST – NCT03862885
Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis (PATHFINDER) – NCT03580655
Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, Versus Placebo in Patients With Indolent and Smoldering Systemic Mastocytosis (PIONEER) – NCT03731260
 Weisberg E, Meng C, Case AE, et al. Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies. Br J Haematol. 2019;187(4):488–501. doi:10.1111/bjh.16092