INSIGHT: A Phase 3, Randomized, Multicenter, Open-Label Study of Ripretinib Vs Sunitinib in Patients with Advanced Gastrointestinal Stromal Tumor Previously Treated with Imatinib Harboring KIT Exon 11+17 And/or 18 Mutations

TPS767 Background: Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma with approximately 80% of cases driven by KIT mutations. Most patients (pts) with advanced GIST experience disease progression following first-line treatment with imatinib due to KIT secondary resistance mutations occurring most commonly in the ATP-binding pocket (exons 13/14) and/or activation loop (exons 17/18). Sunitinib is approved as second-line therapy for advanced GIST. Ripretinib is a switch-control tyrosine kinase inhibitor approved for pts with GIST who received prior treatment with 3 or more kinase inhibitors, including imatinib. In the phase 3 INTRIGUE study (NCT03673501) in second-line advanced GIST, ripretinib was not superior to sunitinib in terms of progression-free survival (PFS); however, a more favorable safety profile was observed with ripretinib vs sunitinib. 1 Exploratory mutational analysis from INTRIGUE using baseline circulating tumor DNA (ctDNA) demonstrated that pts harboring primary KIT exon 11 mutations with secondary resistance mutations exclusively in KIT exons 17/18 derived PFS benefit with ripretinib vs sunitinib (median, 14.2 vs 1.5 months; HR, 0.22; 95% CI, 0.11 to 0.44; nominal P <0.0001). 2 Here, we describe a planned phase 3 study for pts with advanced GIST previously treated with imatinib harboring KIT exon 11 + 17/18 mutations. Methods: INSIGHT (NCT05734105) is a phase 3, randomized, open-label study aiming to evaluate the efficacy of ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib and who harbor KIT exon 11 + 17/18 mutations. Eligible pts must be ≥18 years old with histologically confirmed GIST and co-occurring KIT exon 11 + 17/18 mutations confirmed by ctDNA analysis. Pts must also have advanced disease with ≥1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, radiologic progression on imatinib, and an Eastern Cooperative Oncology Group performance status ≤2. Key exclusion criteria include a KIT exon 9, 13, or 14 mutation confirmed via ctDNA analysis at screening and prior treatment with another line of therapy in addition to imatinib for advanced GIST. A total of 54 pts will be randomized (2:1) to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. The primary endpoint is PFS by independent radiologic review (IRR) per mRECIST v1.1; key secondary endpoints are objective response rate by IRR using mRECIST v1.1 and overall survival. Safety and patient-reported outcome measures will also be assessed. Pts randomized to the sunitinib arm may cross over to the ripretinib arm upon disease progression. 1. Bauer S et al. J Clin Oncol. 2022. 2. Bauer S et al. J Clin Oncol. 2023; abstract 397784. Clinical trial information: NCT05734105 .