Drug Name (Brand/Generic)
AYVAKIT™ (avapritinib) is the first precision therapy approved for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumour (GIST).
Developed by Blueprint Medicines, AYVAKIT is used to treat the genomically defined population of patients with GIST bearing a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.
Blueprint Medicines selected PANTHERx® Rare Pharmacy as a limited distribution partner for AYVAKIT (avapritinib).
Avapritinib’s suggested dose is 300mg once daily (QD) and the drug is available in 100mg, 200mg and 300mg strengths as white film-coated capsule-shaped or round tablets.
The US Food and Drug Administration (FDA) approved AYVAKIT for gastrointestinal stromal tumour (GIST) in January 2020.
A New Drug Application (NDA) for avapritinib was split by the FDA into two NDAs, one for PDGFRA exon 18 mutants GIST and another for fourth-line GIST.
The Prescription Drug User Fee Act (PDUFA) action date for the fourth-line GIST indication is currently set as 14 May 2020.
Blueprint Medicines is expected to receive regulatory approval alongside the launch of avapritinib in Europe in the third quarter of 2020.
Gastrointestinal stromal tumour or sarcoma (GIST) occurs in the walls of gastrointestinal tract (GIT) and ensues in the stomach and small intestine.
Cells in the GIT are known as the interstitial cells of Cajal (ICCs) or precursors to these cells. A tumour can be cancerous (malignant) or noncancerous (benign).
Symptoms include swelling or pain in the abdomen, loss of appetite, nausea and loss of weight, weakness, tiredness, bleeding of the intestinal tract, throat or stomach and vomiting of blood.
GIST is usually associated with a mutation in the KIT and PDGFRA gene that provides the instruction for the making of receptor proteins.
AYVAKIT is an inhibitor of tyrosine kinase that targets PDGFRA and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17 and 17 mutants.
The drug is the only FDA-approved type 1 GIST inhibitor that prevents KIT and PDGFRA mutations by binding to the ATP-binding site.
AYVAKIT inhibits a broad range of KIT and PDGFRA mutations associated with GIST, including potent clinical activity against activation loop mutations that are associated with resistance to currently approved therapies.
The other targets of avapritinib include wild type KIT, PDGFRB, and CSFR1.
The FDA approval of avapritinib comes from results of phase 1 NAVIGATOR, a multi-centre, single-arm, open-label clinical trial as well as combined safety results from multiple clinical trials for avapritinib.
NAVIGATOR clinical study enrolled 43 patients with GIST nurturing a PDGFRA exon 18 mutation, including 38 patients with PDGFRA D842V mutation.
A total of 204 patients received a starting dose of avapritinib, either 300mg or 400mg once daily (QD), heavily pre-treated with a median of three prior kinase inhibitors. A total of 56% of the patients received exposure for six months or more, while 44% received exposure for more than one year.
Efficacy data for avapritinib was evaluated by blinded, independent central radiology review, based on modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST 1.1 criteria) for GIST.
The drug indicated durable responses in patients with PDGFRA exon 18 mutations across multiple lines of treatment.
Patients with PDGFRA exon 18 mutations, the overall response rate (ORR) was 84%, including 7% complete responses (CR), and 77% partial responses (PR). In patients harbouring PDGFRA D842V mutations, the ORR was 89% (8% CR, 82% PR).
Neither patient population (range: 1.9 months or more, 20.3 months or longer) reached the median duration of response (DOR).
Common adverse reactions observed in patients during the NAVIGATOR study include oedema, asthenia, pyrexia, abdominal pain, dyspepsia, dizziness, sleep and mood disorders, decreased appetite, increased lacrimation, alopecia and dyspnoea.
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