Gastrointestinal Stromal Tumor (GIST)

Ayvakit (avapritinib) is a medication indicated for individuals with gastrointestinal stromal tumors (GISTs) caused by platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutations, including the imatinib-resistant D842V mutation. Avapritinib was fully approved by the US Food and Drug Administration (FDA) on January 9, 2020. Prior to approval, researchers conducting the NAVIGATOR phase 1 clinical trial discovered that avapritinib was effective in treating unresectable or metastatic GIST cases resulting from PDGFRA exon 18 mutations.1 Additionally, on June 16, 2021, the FDA approved avapritinib for treatment of advanced systemic mastocytosis in adults.2

Avapritinib, or BLU-285, is a selective tyrosine kinase inhibitor of KIT and platelet derived growth factor receptor alpha indicated for the treatment of unresectable, metastatic gastrointestinal stromal tumors. Credit: PubChem

Mechanism of Action and Pharmacokinetics 

While around 80% of GISTs are associated with KIT gene mutations, 5% to 10% of GISTs are caused by PDGFRA gene mutations.3 The PDGFRA gene encodes the PDGFRA protein, which belongs to the same family of tyrosine kinase proteins as the KIT tyrosine kinase protein. Both proteins perform a similar function of signal transduction via phosphorylation. The ligand normally responsible for the activation of PDGFRA protein is platelet-derived growth factor. In the case of a PDGFRA gene mutation, the PDGFRA protein is ligand-independent, which means that this protein is constantly activated without binding to platelet-derived growth factor. Signal transduction pathways activated by PDGFRA protein promote abnormal cell proliferation and survival, leading to GIST formation.4

Avapritinib is a tyrosine kinase inhibitor (TKI) that targets such PDGFRA mutations, as well as several KIT gene exon mutations including exons 11, 11/17, and 17. The mechanism of action for this drug involves binding to the adenosine triphosphate (ATP)-binding site to prevent activation of dysfunctional PDGFRA and KIT proteins. Therefore, avapritinib inhibits GIST cancer growth and development by blocking the signal transduction pathway initiated by these continuously activated proteins. Avapritinib also blocks activation loop mutations that are related to the development of secondary resistance to existing TKI therapies for GIST such as the first-line imatinib.5 

Efficacy and Safety of Ayvakit

In the NAVIGATOR phase 1 trial, 43 patients with PDGFRA exon 18 mutant GIST had an overall response rate of 84%, with 7% of the patients maintaining a complete response (complete remission of GIST) and 77% having a partial response. In the subgroup of patients with the PDGFRA D842V mutation, 8% had a complete response and 82% had a partial response.6

While there are no contraindications for avapritinib, possible adverse effects include serious intracranial hemorrhage (ICH), cognitive adverse reactions, and fetal harm in pregnant women. 

Intracranial hemorrhaging occurred in 2.9% of 749 patients taking avapritinib, with fatal events in less than 1% of patients. It is critical for physicians to monitor patients with a medical history of vascular aneurysms, ICH, strokes, or thrombocytopenia occurring within the year prior to initiation of avapritinib therapy. If ICH of any degree occurs while on avapritinib, permanent discontinuation of the drug is advised.7 

Cognitive impairment occurred in 39% of 749 patients and in 41% of 601 GIST patients with around 5% labeled as a higher than grade 3 adverse event. Memory loss was reported in 21% of patients (<1% of these events were grade 3), cognitive disorders in 12% (1.2% of these events were grade 3), confusional state in 6%, amnesia in 3% (<1% of these events were grade 3), and somnolence and speech disorders in 2% (none of these events were grade 3).7

Doctors should warn pregnant women about the potential risk to the fetus while taking avapritinib. Physicians also should recommend that women of childbearing age use effective means of contraception while taking avapritinib and for at least 6 weeks following the administration of the last dose. Women are encouraged not to breastfeed while on avapritinib and to wait until 2 weeks following administration of the last dose.7 

Common side effects of avapritinib in more than 20% of cases include nausea, edema, fatigue, asthenia, pyrexia, cognitive impairments, diarrhea, constipation, abdominal pain, decreased appetite, emesis, dizziness, sleep and mood disorders, dyspnea, rash, alopecia, hair color changes, and increased lacrimation.5,7

It is recommended to avoid coadministration of avapritinib with strong and moderate CYP3A inhibitors and inducers due to drug interactions.7

Avapritinib is orally administered on an empty stomach 1 hour before or 2 hours following a meal. The recommended dose of avapritinib is 300 mg once daily. The drug is available in 100 mg, 200 mg, and 300 mg dose strengths.1 

Get detailed prescribing information on the Ayvakit monograph page at MPR.

Adjuvant and Neoadjuvant Therapies With Ayvakit

Avapritinib (formerly BLU-285) is considered a first-line adjuvant or neoadjuvant therapy for individuals with imatinib-resistant PDGFRA D842V mutations. Imatinib is still recommended over avapritinib as the first-line TKI therapy for individuals with PDGFRA exon 18 non-D842V mutations, as these mutations generally demonstrate sensitivity to imatinib.8 

The phase 3 VOYAGER clinical trial resulted in the failure of avapritinib to meet the goal of improving progression-free survival (PFS) in individuals with third- or fourth-line advanced GIST compared to regorafenib. Avapritinib showed a median PFS of 4.2 months compared to the 5.6-month median PFS of patients on regorafenib. Therefore, due to these results, patients should attempt regorafenib as the third- or fourth-line TKI adjuvant therapy prior to avapritinib.9


  1. Blueprint Medicines announces FDA approval of Ayvakit® (avapritinib) for the treatment of adults with unresectable or metastatic PDGFRA exon 18 mutant gastrointestinal stromal tumor. Blueprint Medicines Corp. January 9, 2020. Accessed August 11, 2021.
  2. Ayvakit | Home. Blueprint Medicines Corp. Accessed August 11, 2021.
  3. Gastrointestinal stromal tumors (GISTs), c-KIT mutation analysis with reflex to PDGFRA mutation analysis. Labcorp. Accessed August 11, 2021. 
  4. PDGFRA gene. MedlinePlus. Updated July 13, 2021. Accessed August 11, 2021.
  5. Ayvakit (avapritinib) for the treatment of gastrointestinal stromal tumour. Clinical Trials Arena. Accessed August 11, 2021.
  6. Simon S. FDA approves Ayvakit (avapritinib) for GIST. American Cancer Society. January 10, 2020. Accessed August 11, 2021.
  7. Ayvakit (avapritinib): FDA approved for GIST. Blueprint Medicines Corp. Accessed August 11, 2021.
  8. Smrke A, Gennatas S, Huang P, Jones RL. Avapritinib in the treatment of PDGFRA exon 18 mutated gastrointestinal stromal tumors. Future Oncol. 2020;16(22):1639-1646. doi:10.2217/fon-2020-0348
  9. Blueprint Medicines announces top-line results from phase 3 VOYAGER trial of avapritinib versus regorafenib in patients with advanced gastrointestinal stromal tumor. Blueprint Medicines Corp. April 28, 2020. Accessed August 11, 2021.

Reviewed by Debjyoti Talukdar, MD, on 8/17/2021.