The INSIGHT study: a randomized, Phase III study of ripretinib versus sunitinib for advanced gastrointestinal stromal tumor with <i>KIT</i> exon 11 + 17/18 mutations
Creators: name: George, Suzanne
name: Blay, Jean-Yves
name: Chi, Ping
name: Jones, Robin L
name: Serrano, César
name: Somaiah, Neeta
name: Gelderblom, Hans
name: Zalcberg, John R
name: Reichmann, William
name: Sprott, Kam
name: Cox, Paulina
name: Sherman, Matthew L
name: Ruiz-Soto, Rodrigo
name: Heinrich, Michael C
name: Bauer, Sebastian
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Medicine
subject: Genetics
subject: FOS: Biological sciences
subject: Pharmacology
subject: Cancer
subject: Infectious Diseases
subject: FOS: Health sciences

description: Somatic <i>KIT</i> activating mutations drive most gastrointestinal stromal tumors (GISTs). Disease progression eventually develops with first-line imatinib, commonly due to <i>KIT</i> secondary mutations, and different kinase inhibitors have various levels of treatment efficacy dependent on specific acquired resistance mutations. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA tyrosine kinase inhibitor for patients with advanced GIST who received prior treatment with three or more kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA analysis from the second-line INTRIGUE trial determined that patients with advanced GIST previously treated with imatinib harboring primary <i>KIT</i> exon 11 mutations and secondary resistance mutations restricted to <i>KIT</i> exons 17/18 had greater clinical benefit with ripretinib versus sunitinib. We describe the rationale and design of INSIGHT (NCT05734105), an ongoing Phase III open-label study of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib exclusively harboring <i>KIT</i> exon 11 + 17/18 mutations detected by circulating tumor DNA. <b>Clinical Trial Registration:</b>NCT05734105 (ClinicalTrials.gov) Gastrointestinal stromal tumor (GIST) is rare, but it is the most common mesenchymal tumor (a type of tumor that develops from cells which give rise to soft tissues) of the gastrointestinal tract. The primary treatment for advanced GIST is medication that targets the abnormal mechanisms in cancer cells in order to block tumor growth and spread. Ripretinib is an inhibitor of a protein known as KIT, which is a member of the tyrosine kinase protein family and is involved in the growth of GIST. In a Phase III clinical trial called INTRIGUE, the effects of ripretinib and another receptor tyrosine kinase inhibitor, sunitinib, were compared in patients with advanced GIST previously treated with the drug imatinib. An exploratory analysis from the INTRIGUE trial that characterized baseline circulating tumor DNA in the blood showed a greater clinical benefit with ripretinib versus sunitinib in patients with gene mutations solely occurring in <i>KIT</i> exon 11 + 17 and/or 18 (exon 11 + 17/18). This article describes the rationale and design for a Phase III clinical trial called INSIGHT that will evaluate the benefit of ripretinib compared with sunitinib in patients with advanced GIST whose tumors have mutations in <i>KIT</i> exon 11 and <i>KIT</i> exon 17 and/or 18. Patients will receive ripretinib or sunitinib in 6-week cycles, and investigators will assess survival without cancer progression as the primary outcome, and overall survival, and response of the tumor to these two drugs as secondary outcomes. This article describes the rationale and design for the INSIGHT Phase III trial evaluating patients with second-line advanced GIST who harbor primary <i>KIT</i> exon 11 mutations and secondary resistance mutations restricted to the activation loop (<i>KIT</i> exons 17/18). Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma, with approximately 80% of cases driven by activating mutations in <i>KIT.</i> Sunitinib is a multitargeted tyrosine kinase inhibitor (TKI) approved as a second-line therapy for advanced GIST after disease progression on or intolerance to imatinib. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA TKI approved as a fourth-line therapy for advanced GIST. Exploratory baseline circulating tumor DNA (ctDNA) analysis from INTRIGUE determined that patients with <i>KIT</i> exon 11 + 13/14 mutations had improved progression-free survival (PFS) and objective response rate (ORR) with sunitinib versus ripretinib, while those with <i>KIT</i> exon 11 + 17/18 mutations had improved PFS, ORR and overall survival (OS) and a better safety profile with ripretinib versus sunitinib. INSIGHT is an international, Phase III, randomized, multicenter, open-label study evaluating the efficacy of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib and who have <i>KIT</i> exon 11 mutations and co-occurring mutations exclusively in <i>KIT</i> exons 17/18, as identified by ctDNA. Approximately 54 patients 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. Eligible patients must have a histologic diagnosis of advanced GIST and co-occurring <i>KIT</i> exon 11 + 17/18 mutations confirmed by central laboratory ctDNA analysis, as well as radiologic progression on imatinib. The primary outcome measure is PFS based on blinded independent radiologic review (IRR) using modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1), while key secondary outcome measures are ORR based on blinded IRR using mRECIST v1.1 and OS. A PDF version of this infographic is available as supplemental material.