Clinical activity of ripretinib in patients with advanced gastrointestinal stromal tumor harboring heterogenous KIT/PDGFRA mutations in the phase 3 INVICTUS study.
von Mehren, M
MetadataShow full item record
Purpose Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKIs). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase 3 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 vs placebo regardless of mutation status (hazard ratio 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 2-23 months for ripretinib vs 0.9-10.1 months for placebo Conclusions: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with 3 or more TKIs.
Sarcoma Clinical Trials (R Jones)
License start date
Clinical cancer research : an official journal of the American Association for Cancer Research, 2021