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Bauer S , Heinrich MC , George S , Zalcberg JR , Serrano C , Gelderblom H , Jones RL , Attia S , D'Amato G , Chi P , Reichardt P , Meade J , Su Y , Ruiz-Soto R , Blay JY , von Mehren M , Schöffski P
Clinical activity of ripretinib in patients with advanced gastrointestinal stromal tumor harboring heterogenous KIT/PDGFRA mutations in the phase 3 INVICTUS study
Clin Cancer Res. 2021 Sep 9
PMID: 34503977   
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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.
1557-3265 Bauer, Sebastian Orcid: 0000-0001-5949-8120 Heinrich, Michael C Orcid: 0000-0003-3790-0478 George, Suzanne Zalcberg, John R Orcid: 0000-0002-6624-0782 Serrano, César Orcid: 0000-0003-1416-8739 Gelderblom, Hans Orcid: 0000-0001-9270-8636 Jones, Robin L Orcid: 0000-0003-4173-3844 Attia, Steven D'Amato, Gina Chi, Ping Reichardt, Peter Meade, Julie Su, Ying Orcid: 0000-0003-0462-3865 Ruiz-Soto, Rodrigo Blay, Jean-Yves Orcid: 0000-0001-7190-120x von Mehren, Margaret Orcid: 0000-0001-6158-890x Schöffski, Patrick Orcid: 0000-0001-5980-030x Journal Article United States Clin Cancer Res. 2021 Sep 9:clincanres.1864.2021. doi: 10.1158/1078-0432.CCR-21-1864.