Ripretinib demonstrated clinical benefit in gastrointestinal stromal tumors harboring KIT exon 11 and 17/18 mutations in exploratory ctDNA analysis from the phase 3 INTRIGUE trial.
Abstract: In the second-line setting, patients with KIT exon 11 + 17/18 mutations were found to be superior to sunitinib in objective response rate (ORR) and time-to-event analyses.
Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract. The estimated incidence rate is 1.5/100,000 per year, accounting for 1-2% of gastrointestinal tumors. About 75-80% of patients have KIT exons 9, 11, 13, and 14 as primary mutations, 5-10% have PDGFRA gene mutations, and the rest are wild-type GISTs. FDA approved a sequential treatment by tyrosine kinase inhibitors (TKIs) for GIST from first to fourth line setting, sequentially administering imatinib, sunitinib, regorafenib, and ripretinib. Ripretinib is a novel TKI that targets the KIT action loop and kinase switch pocket to stabilize KIT in an inactive conformation and block downstream signal transduction pathways. In a phase 3 INTRIGUE trial, ripretinib was compared to sunitinib in the second-line setting in patients with GIST after imatinib failure or intolerance. The result was reported at the 2022 ASCO Annual Meeting, ripretinib was not superior to sunitinib in the second-line setting. The median PFS with ripretinib was 8 months vs 8.3 months with sunitinib. An exploratory analysis was implemented to find the baseline of patient mutation and response to ripretinib and sunitunib. In patients with a KIT exon 11 primary mutations, 52 patients had co-occuring mutations in exon 17/18, 27 with ripretinib, and 25 with sunitinib. The patient who received ripretinib demonstrated superior mPFS (14.2 months), ORR (44.4%), and mOS (NE) to patients with sunitinb (1.5 months, 0%, and 17.5 months, respectively). Based on these extraordinary results, the pharmaceutical company plans to launch the phase 3 INSIGHT trial, which will further explore the safety and efficacy of second-line ripretinib vs sunitinib in this KIT exon 11 and 17/18 mutated population.
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