# PDGFRA D842V-mutant GIST

Source: https://onco.cc/cancers/gist-pdgfra-d842v/  
OnCo record `gist-pdgfra-d842v` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: PDGFRA exon 18-mutant GIST; Imatinib-resistant PDGFRA GIST; Epithelioid gastric GIST
- Tags: subtype-page
- Group: gastrointestinal
- Burden: 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.
- Subtypes: PDGFRA D842V-mutant gastric GIST, epithelioid (imatinib-resistant, avapritinib); Other PDGFRA exon 18 mutations (avapritinib; some imatinib-sensitive); PDGFRA exon 12 and 14-mutant GIST (imatinib-sensitive); Localised PDGFRA D842V GIST (surgery alone, no adjuvant therapy); Advanced PDGFRA D842V GIST after avapritinib
- Biomarkers: PDGFRA exon 18 D842V mutation (defines the subtype and excludes imatinib); Weak or absent KIT (CD117) staining with positive DOG1; Epithelioid histology; Mitotic count and size (risk, though behaviour is often indolent); Secondary PDGFRA mutations at progression on avapritinib

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/gist-pdgfra-d842v/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/gist-pdgfra-d842v/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/gist-pdgfra-d842v/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/gist-pdgfra-d842v/#finding-it [5 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/gist-pdgfra-d842v/#treating-it [3 settings, 1 decision with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/gist-pdgfra-d842v/#evidence [2 trials, 2 key papers, 4 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/gist-pdgfra-d842v/#science [4 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/gist-pdgfra-d842v/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/gist-pdgfra-d842v/#living-with-it [15 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/gist-pdgfra-d842v/coming/ [4 medicines, 2 trials, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/gist-pdgfra-d842v/data/ [24 connected records]

## Standard of care

- Localised, resectable: Surgical resection; no adjuvant imatinib because the mutation is resistant to it. ([Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/), [PDGFRA](https://onco.cc/targets/pdgfra/))
- Advanced, first line: Avapritinib 300 mg daily (NAVIGATOR), with monitoring for cognitive effects and bleeding. ([Avapritinib](https://onco.cc/drugs/avapritinib/), [PDGFRA](https://onco.cc/targets/pdgfra/), [KIT](https://onco.cc/targets/kit/))
- Progression on avapritinib: No established therapy; clinical trials, surgery or embolisation for isolated progression; regorafenib and other kinase inhibitors have low activity. ([Regorafenib](https://onco.cc/drugs/regorafenib/), [VOYAGER](https://onco.cc/trials/voyager/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/))

## State of the art

- Avapritinib is the first effective drug for a mutation that had defeated every earlier kinase inhibitor.
- The failure of VOYAGER in unselected patients alongside NAVIGATOR's success is the clearest example of genotype-driven treatment in sarcoma.
- Mutation testing before any imatinib is now mandatory in GIST guidelines, largely because of this subtype.

## Open problems

- No proven therapy after progression on avapritinib.
- Cognitive side effects limit dose and quality of life for some patients.
- Whether indolent D842V tumours can be watched rather than resected.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Avapritinib
- NAVIGATOR (Lancet Oncology 2020): https://pubmed.ncbi.nlm.nih.gov/32615108/
- Wikipedia: https://en.wikipedia.org/wiki/Avapritinib

## Connected records

- cancers: [Gastrointestinal stromal tumour (GIST)](https://onco.cc/cancers/gist/), [Imatinib-resistant GIST](https://onco.cc/cancers/gist-imatinib-resistant/), [KIT exon 11-mutant GIST](https://onco.cc/cancers/gist-kit-exon-11/)
- terms: [GIST risk stratification (mitotic count, size, site; Miettinen and modified NIH criteria)](https://onco.cc/terms/gist-risk-stratification/)
- trials: [NAVIGATOR](https://onco.cc/trials/navigator/), [VOYAGER](https://onco.cc/trials/voyager/)
- key papers: [NAVIGATOR: avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour](https://onco.cc/key-papers/paper-navigator-avapritinib-heinrich-lancet-oncol-2020/), [PDGFRA activating mutations in gastrointestinal stromal tumours](https://onco.cc/key-papers/paper-heinrich-pdgfra-gist-science-2003/)
- targets: [KIT](https://onco.cc/targets/kit/), [PDGFRA](https://onco.cc/targets/pdgfra/)
- drugs: [Avapritinib](https://onco.cc/drugs/avapritinib/), [IDRX-42](https://onco.cc/drugs/idrx-42/), [Imatinib](https://onco.cc/drugs/imatinib/), [Regorafenib](https://onco.cc/drugs/regorafenib/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/)
- people: [Michael C. Heinrich](https://onco.cc/people/michael-heinrich/)
- biomarkers: [PDGFRA exon 18 mutation (D842V)](https://onco.cc/biomarkers/pdgfra-exon-18-d842v/)

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JSON: https://onco.cc/api/v1/entities/gist-pdgfra-d842v.json