PURPOSE: Most patients with gastrointestinal stromal tumor (GIST) have 
activating mutations in KIT/PDGFRA and are initially responsive to tyrosine 
kinase inhibitors (TKI). The acquisition of secondary mutations leads to 
refractory/relapsed disease. This study reports the results of an analysis from 
the phase III INVICTUS study (NCT03353753) characterizing the genomic 
heterogeneity of tumors from patients with advanced GIST and evaluating 
ripretinib efficacy across KIT/PDGFRA mutation subgroups.
PATIENTS AND METHODS: Tumor tissue and liquid biopsy samples that captured 
circulating tumor DNA were collected prior to study enrollment and sequenced 
using next-generation sequencing. Subgroups were determined by KIT/PDGFRA 
mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status 
was assessed.
RESULTS: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; 
placebo, n = 44). The most common primary mutation subgroup detected by combined 
tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 
77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving 
ripretinib demonstrated progression-free survival (PFS) benefit versus placebo 
regardless of mutation status (HR 0.16) and in all assessed subgroups in 
Kaplan-Meier PFS analysis (exon 11, P < 0.0001; exon 9, P = 0.0023; exon 13, P < 
0.0001; exon 17, P < 0.0001). Among patients with wild-type KIT/PDGFRA by tumor 
tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months 
for placebo.
CONCLUSIONS: Ripretinib provided clinically meaningful activity across mutation 
subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits 
a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were 
previously treated with three or more TKIs.