PDGFRA D842V-mutant GIST

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.