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PDGFRA D842V GIST is driven by a mutation in the PDGFRA receptor rather than KIT, and it does not respond to imatinib at all. Avapritinib, designed to fit the mutant activation loop, shrinks nearly nine in ten of these tumours and is the standard treatment for advanced disease; localised tumours are cured by surgery alone.
About 10 to 15 percent of GISTs carry mutations in PDGFRA, the platelet-derived growth factor receptor alpha, discovered by Heinrich in 2003; the commonest, the D842V substitution in the activation loop encoded by exon 18, accounts for around two thirds of them and about 5 percent of GISTs overall. These tumours are almost always gastric, have epithelioid or mixed histology, may stain weakly or not at all for KIT, and often behave indolently, with a lower rate of metastasis than KIT-mutant tumours of the same size. Mutation testing is essential because D842V confers complete primary resistance to imatinib, sunitinib and regorafenib: the mutation stabilises the active conformation that these type II inhibitors cannot bind.
Localised tumours are removed surgically, and because imatinib is ineffective, adjuvant therapy is not given whatever the risk score. In advanced disease, avapritinib, a type I inhibitor built to bind the active conformation of KIT and PDGFRA, produced responses in 88 percent of D842V patients in the NAVIGATOR trial (Lancet Oncology 2020) with responses lasting years, and was approved by the FDA in January 2020 for PDGFRA exon 18 mutations including D842V and by the EMA for D842V; it was the first drug to work in this group. Cognitive effects, memory impairment and, rarely, intracranial haemorrhage are its distinctive toxicities and require dose adjustment and monitoring.
VOYAGER, which compared avapritinib with regorafenib in unselected third-line GIST, was negative, a lesson in patient selection: the drug's benefit is confined to the mutation it was designed for. Other PDGFRA exon 18 mutations and exon 12 and 14 mutations remain imatinib-sensitive and are managed like KIT-mutant disease. Resistance to avapritinib eventually arises through secondary PDGFRA mutations, and the sequence after it is undefined.
About one in twenty gastrointestinal stromal tumours, almost always in the stomach, with epithelioid histology and often indolent behaviour; the D842V substitution in the activation loop makes the receptor untouchable by imatinib but exquisitely sensitive to avapritinib.
Squamous cancers sit in the upper and middle oesophagus, adenocarcinomas at the junction and in the stomach; the stomach wall also gives rise to GIST from its pacemaker cells.
Same organ: Gastric & gastro-oesophageal junction cancer, HER2-positive gastric cancer, Claudin 18.2-positive gastric cancer, PD-L1-high gastric cancer, Microsatellite-unstable (MSI-high) gastric cancer, Early gastric cancer, Oesophageal squamous cell carcinoma, Oesophageal and junctional adenocarcinoma, Oesophageal cancer, Gastrointestinal stromal tumour (GIST), KIT exon 11-mutant GIST, Imatinib-resistant GIST
Nothing recorded yet.
Nothing recorded yet.
Also on OnCo: Symptoms and red flags · Early detection roadmap.
Surgical resection; no adjuvant imatinib because the mutation is resistant to it.
Avapritinib 300 mg daily (NAVIGATOR), with monitoring for cognitive effects and bleeding.
No established therapy; clinical trials, surgery or embolisation for isolated progression; regorafenib and other kinase inhibitors have low activity.
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Avapritinib 300 mg is the standard first-line treatment for advanced PDGFRA D842V GIST, and mutation testing before starting imatinib is essential to identify these patients.
PDGFRA testing is part of standard GIST genotyping, and the imatinib resistance of D842V predicted here led to the development of avapritinib.
Query for this cancer: (TITLE:"PDGFRA D842V-mutant GIST" OR ABSTRACT:"PDGFRA D842V-mutant GIST" OR TITLE:"PDGFRA exon 18-mutant GIST" OR ABSTRACT:"PDGFRA exon 18-mutant GIST" OR TITLE:"Imatinib-resistant PDGFRA GIST" OR ABSTRACT:"Imatinib-resistant PDGFRA GIST" OR TITLE:"Epithelioid gastric GIST" OR ABSTRACT:"Epithelioid gastric GIST") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about PDGFRA D842V-mutant GIST, not a curated reading list.
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Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Take with a low-fat breakfast (under 30% fat).
Not recommended in severe impairment; hepatotoxicity is a boxed warning.
The shared side effects of drugs that block blood vessel growth (bevacizumab, ramucirumab and VEGFR kinase inhibitors): high blood pressure, protein leaking into the urine, nosebleeds and more serious bleeding, slow wound healing, and rarely holes in the bowel.
Redness, peeling, pain and cracking of the palms and soles caused by certain chemotherapy pills and by kinase inhibitors that block blood vessel growth. Rarely dangerous but can stop patients walking or using their hands.
See all on the product pages:AvapritinibRegorafenib·Printable cards in the navigator
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