Abstract
Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in
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
mutation subgroups.
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
mutations and correlation of clinical outcomes and
mutational status was assessed.
Overall, 129 patients enrolled (ripretinib 150 mg once daily,
= 85; placebo,
= 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in
exon 11 (ripretinib, 61.2%; placebo, 77.3%) and
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,
< 0.0001; exon 9,
= 0.0023; exon 13,
< 0.0001; exon 17,
< 0.0001). Among patients with wild-type
by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo.
Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of
mutations in patients with advanced GIST who were previously treated with three or more TKIs.
