Clinical Activity of Ripretinib in Patients with Advanced Gastrointestinal Stromal Tumor Harboring Heterogeneous KIT/PDGFRA Mutations in the Phase III INVICTUS Study.

Abstract

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.

• Authors: Sebastian Bauer, Michael C Heinrich, Suzanne George, John R Zalcberg, César Serrano, Hans Gelderblom, Robin L Jones, Steven Attia, Gina D'Amato, Ping Chi, Peter Reichardt, Julie Meade, Ying Su, Rodrigo Ruiz-Soto, Jean-Yves Blay, Margaret von Mehren, Patrick Schöffski
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 23 Pg. 6333-6342 (12 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34503977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Naphthyridines
• Urea
• ripretinib
• Proto-Oncogene Proteins c-kit
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Gastrointestinal Stromal Tumors (drug therapy, genetics, pathology)
• Humans
• Mutation
• Naphthyridines (pharmacology)
• Proto-Oncogene Proteins c-kit (genetics)
• Receptor, Platelet-Derived Growth Factor alpha (genetics)
• Urea (analogs & derivatives, therapeutic use)