June 16, 2021 – Avapritinib (AYVAKIT, Blueprint Medicines) for adult patients with advanced systemic mastocytosis (AdvSM), including patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

June 16, 2021


On June 16, 2021, the Food and Drug Administration approved avapritinib (AYVAKIT, Blueprint Medicines Corp.) for adult patients with advanced systemic mastocytosis (AdvSM), including patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

Efficacy was evaluated in EXPLORER (NCT02561988) and PATHFINDER (NCT03580655), two multi-center, single-arm, open-label clinical trials enrolling patients with AdvSM. The main efficacy outcome measure was overall response rate (ORR) per modified IWG-MRT-ECNM criteria, as adjudicated by a central committee. Additional efficacy measures were duration of response (DOR), time to response, and changes in individual measures of mast cell burden. Fifty-three patients received daily doses of avapritinib, up to 200 mg.

The ORR in all evaluable patients in both trials combined was 57% (95% CI: 42, 70) (n=53), with 28% complete remissions and 28% partial remissions. The median duration of response was 38.3 months (95% confidence interval: 19, not estimable) and the median time to response was 2.1 months.

The most common adverse reactions (incidence ≥ 20%) in patients with AdvSM were edema, diarrhea, nausea, and fatigue/asthenia.

Avapritinib is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 X 109/L.

The recommended avapritinib dose is 200 mg orally once daily for patients with AdvSM.

View full prescribing information for Ayvakit.

This application was granted priority review, breakthrough designation and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email This email address is being protected from spambots. You need JavaScript enabled to view it..

January 9, 2020


On January 9, 2020 the U.S. Food and Drug Administration approved Avapritinib (Ayvakit) for the treatment of adults with unresectable (unable to be removed with surgery) or metastatic (when cancer cells spread to other parts of the body) 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. This approval includes GIST that harbors a PDGFRA D842V mutation, which is the most common exon 18 mutation. Ayvakit is a kinase inhibitor, meaning it blocks a type of enzyme called a kinase and helps keeps the cancer cells from growing.

“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,” said 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.”

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.

The FDA approved Ayvakit 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. Patients received Ayvakit 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 (by a certain amount) of their tumors during treatment (overall response rate). For patients harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response and 77% having a partial response. 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).

Common side effects for patients taking Ayvakit 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. Ayvakit can cause intracranial hemorrhage (bleeding that occurs inside the skull) in which case the dose should be reduced, or the drug should be discontinued. Ayvakit can also cause central nervous system effects including cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders and hallucinations. If this happens, depending on the severity, Ayvakit should be withheld and then resumed at the same or reduced dose upon improvement or permanently discontinued.

Health care professionals should advise pregnant women that Ayvakit may cause harm to a developing fetus or newborn baby. Additionally, the FDA advises health care professionals to tell females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with Ayvakit and for six weeks after the final dose.

View full prescribing information here: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212608s000lbl.pdf

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. Ayvakit was also granted Fast Track designation, which expedites the review of drugs to treat serious conditions and fill an unmet medical need. Ayvakit received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Ayvakit to Blueprint Medicines Corporation.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Pharmacist’s Applications to Practice

Avapritinib (Ayvakit) for Adults with Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST) with a PDGFRA Exon 18 Mutation, Including PDGFRA D842V Mutations

Author: Mary Walters, PharmD BCOP
Clinical Pharmacist
Advocate Aurora Health Care
Milwaukee, WI

What is the potential role for avapritinib in the treatment of GIST?

  • Avapritinib has a niche role as a novel therapy for patients with unresectable/metastatic GIST harboring a PDGFRA exon 18 mutation, including a PDGFRA D842V mutation.1
  • These mutations decrease the ability of tyrosine kinase inhibitors like imatinib to bind to the receptor’s activation loop in the tyrosine kinase domain, thus imparting resistance.2
    • These mutations occur in 5%–10% of the 3,000–5,000 patients diagnosed with GIST per year in the United States.3
  • Response rates with avapritinib were 84% for patients with PDGFRA exon 18 mutations and even higher for patients with the D842V mutation (objective response rate = 89%). The mean duration of response was not reached in both subgroups after median follow-up of 10.6 months. No overall or progression-free survival data are available currently.1,2
    • For comparison, a study by Yoo and colleagues4 demonstrated that imatinib produced a significantly different objective response rate between patients with the D842V mutation and those with non-D842V mutations (0% vs. 71%, p = .03). Patients with the D842V mutation also had poorer overall survival (OS) than those with non-D842V PDGFRA mutations: median 25.2 months (95% confidence interval [CI], 12.7 to 37.8) versus 59.8 months (95% CI, 43.0 to 76.5) (p = .02).
      • These results highlight the D842V variant’s resistance to treatment with imatinib and the need for a therapeutic alternative.
      • The relatively long OS even in the D842V population illustrates the indolent disease course of PDGFRA-mutated GIST.
  • Based on these data, avapritinib was approved on Fast Track with Breakthrough Therapy and Orphan Drug designations and adopted by the National Comprehensive Cancer Network (NCCN) guidelines:
    • First-line therapy in patients with unresectable recurrent or metastatic GIST harboring PDGFRA exon 18 mutations, including PDGFRA D842V mutations5
    • GIST progressing after imatinib, sunitinib, and regorafenib5
  • Potential benefits of avapritinib will have to be weighed with the physiologic and financial toxicity of the agent discussed below.

What role can the pharmacist play in the management of patients on avapritinib?

  • Assist in monitoring for toxicity:
    • 58% of patients experienced central nervous system (CNS) toxicities (cognitive impairment: mood, speech, or sleep disorders; dizziness; hallucinations) with 3% of patients experiencing intracranial hemorrhage.1,2
    • CNS effects may require therapy interruption, dose reduction, or permanent discontinuation (based on severity of the toxicity).1
  • Verify medication doses:
    • In vitro modeling suggests that avapritinib is a CYP3A4 substrate.1
      • Avoid concomitant use with moderate or strong CYP3A4 inhibitors or inducers. If coadministration with a moderate CYP3A inhibitor cannot be avoided, reduce dose to 100 mg once daily.1
    • There are no hepatic or renal dose adjustments recommended, but avapritinib has not been studied in patients with severe organ disfunction.1,2
  • Counsel on appropriate administration:
    • Standard dosing: 300 mg (one tablet) by mouth once daily on an empty stomach, at least 1 hour before or 2 hours after a meal until disease progression or unacceptable toxicity.1
    • Missed doses should be skipped if within 8 hours of the next scheduled dose. If vomiting occurs, do not take an additional dose; resume dosing with the next scheduled daily dose.1
  • Confirm appropriate supportive care is prescribed:
    • Avapritinib is associated with a moderate to high emetic potential; scheduled and as-needed antiemetics are recommended.6
  • Facilitate drug acquisition:

Clinical Pearls

  • Tablets are available in 100-mg, 200-mg, and 300-mg strengths. Each tablet’s average wholesale price is $1,280 per tablet. Therefore, treatment for a year would cost approximately $467,200.
  • Avapritinib is teratogenic. In addition to counseling individuals of reproductive potential to use effective contraception, pharmacists should take appropriate precautions for receiving, handling, storage, preparation, dispensing, administration, and disposal per National Institute for Occupational Safety and Health recommendations.1,7
  • No companion diagnostic was approved with the drug. PDGFRA exon 18 mutations were identified by local or central assessment using a polymerase chain reaction assay or next-generation sequencing–based assay in the studies informing its approval.2


  1. Ayvakit (avapritinib) [prescribing information]. Cambridge, MA: Blueprint Medicines Corporation; January 2020.
  2. Heinrich M, Jones RL, Von Mehren M, et al. Clinical response to avapritinib by RECIST and Choi Criteria in ≥4th line and PDGFRA exon 18 gastrointestinal stromal tumors (GIST). Connective Tissue Oncology Society Annual Meeting, Tokyo, Japan, November 15, 2019.
  3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma. Version 2.2020. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf (Accessed on June 4, 2020).
  4. Yoo C, Ryu MH, Jo J, Park I, Ryoo BY, Kang YK. Efficacy of imatinib in patients with platelet-derived growth factor receptor alpha–mutated gastrointestinal stromal tumors. Cancer Res Treat. 2016;48(2):546-552.
  5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma. Version 2.2020. Available at https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed June 3, 2020.
  6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version 2.2020. Available at https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed June 3, 2020.
  7. United States Pharmacopeia and National Formulary. Chapter <800>. Hazardous Drugs—Handling in Healthcare Settings. (USP 43-NF 38). Rockville, MD: United States Pharmacopeia Convention; 2020:74-92.