PDGFRA D842V substitution mutation in advanced or metastatic GIST. The PDGFRA D842V varia...

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ID	`RF-GIST-PDGFRA-D842V`
Tipo	Sinal de alerta
Estado	reviewed 2026-05-08 \| pending_clinical_signoff
Doenças	`DIS-GIST`
Fontes	`SRC-NAVIGATOR` `SRC-NCCN-GIST-2025` `SRC-VOYAGER`

Origem da bandeira vermelha

Definição	PDGFRA D842V substitution mutation in advanced or metastatic GIST. The PDGFRA D842V variant accounts for approximately 6-7% of all GIST and is the most common PDGFRA exon 18 mutation (~65-70% of PDGFRA-mutant GIST). D842V confers primary resistance to imatinib, sunitinib, and regorafenib due to steric interference with drug binding at the activation loop. The type I kinase inhibitor avapritinib binds the active conformation of PDGFRA D842V and achieves ORR ~88% (NAVIGATOR phase 1; Heinrich CANCER DISCOV 2020) and confirmed ORR ~91% in the phase 3 NAVIGATOR expansion cohort. Imatinib is ineffective (historical ORR <10% for D842V) and must not be used as 1L for confirmed D842V-mutant GIST. Fires to route ALGO-GIST-1L step 1 to avapritinib (IND-GIST-1L- AVAPRITINIB-PDGFRA-D842V) instead of imatinib (IND-GIST-1L-IMATINIB). NCCN GIST 2025 Category 1 preferred: avapritinib 300 mg PO QD for PD...
Direcção clínica	intensificar
Categoria	high-risk-biology
Algoritmo de deslocamentos	ALGO-GIST-1L

Lógica de Desencadeamento

{
  "any_of": [
    {
      "finding": "BIO-PDGFRA",
      "value": "D842V"
    },
    {
      "finding": "pdgfra_mutation",
      "value": "D842V"
    },
    {
      "finding": "pdgfra_exon18_mutation",
      "value": "D842V"
    },
    {
      "finding": "pdgfra_mutation_codon",
      "value": "D842V"
    },
    {
      "finding": "pdgfra_d842v",
      "value": "true"
    }
  ],
  "type": "biomarker_status"
}

Notas

W5c RF authoring. Converts free-text `{condition: "PDGFRA D842V mutation positive"}` in ALGO-GIST-1L step 1 into a formal RF entity. Clinical rationale: PDGFRA D842V confers primary resistance to all approved TKIs except avapritinib. NAVIGATOR phase 3 expansion cohort (Heinrich et al, CANCER DISCOV 2020; trial NCT02508532) demonstrated ORR 88-91% with avapritinib 300 mg QD; median PFS not reached at data cutoff. VOYAGER (NCT03465722) was designed as avapritinib vs regorafenib in 3L+ GIST (mixed genotype); primary endpoint (PFS) did not meet statistical significance but was confounded by inclusion of non-D842V GIST. NAVIGATOR remains the key evidence base for D842V 1L. Trigger: uses BIO-PDGFRA/D842V pattern consistent with BMA entity bma_pdgfra_d842v_gist.yaml (ESCAT IA). Legacy finding name variants retained for backward engine compatibility until biomarker normalization pass completes. PDGFRA non-D842V exon 18 mutations (D842del, DI842-843IM, N659K, etc.) are NOT within this RF scope — those have intermediate imatinib sensitivity and route via ALGO-GIST-1L step 2 imatinib path. Source stubs: SRC-NAVIGATOR and SRC-VOYAGER are auto-stubs with pending citation verification (PMID + D...

Usado por

Algoritmos

ALGO-GIST-1L - ALGO-GIST-1L
ALGO-GIST-2L - ALGO-GIST-2L