PRO-AGGRESSIVE

• 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 PDGFRA D842V-mutant unresectable/metastatic GIST. Detection: PDGFRA D842V is detectable on targeted NGS, hotspot PCR, or PDGFRA-specific IHC (D842V antibody). Tissue or ctDNA-based molecular testing of all GIST at diagnosis is standard of care per NCCN GIST 2025. PDGFRA non-D842V exon 18 mutations (e.g., D842del, DI842-843IM): intermediate imatinib sensitivity — these are NOT covered by this RF. The RF fires exclusively on the D842V substitution. Non-D842V exon 18 PDGFRA mutations route to imatinib (ALGO-GIST-1L step 2 default path). RF-GIST-PDGFRA-D842V