Ripretinib in advanced gastrointestinal stromal tumors: an overview of current evidence and drug approval

by Selleckchem | Aug 24 2023

Over the past 20 years, the management of gastrointestinal stromal tumors has acted as an important model in the advancement of molecularly targeted therapies for solid tumors. The success of imatinib has established it as a lasting therapy in the management of early-stage and advanced disease in the first-line setting. Imatinib resistance inevitably develops, resulting in the need for further lines of therapy. Ripretinib is an orally administered switch-control tyrosine kinase inhibitor, specifically developed to target both primary and secondary KIT and PDGFRα resistance mutations. Herein, the authors discuss the molecular rationale, the preclinical evidence and the clinical use of ripretinib in the treatment of gastrointestinal stromal tumors in the advanced stages of disease.

Comments:

The management of gastrointestinal stromal tumors (GISTs) has indeed served as a significant model for the advancement of molecularly targeted therapies for solid tumors over the past 20 years. One of the major breakthroughs in the field was the development of imatinib, which has established itself as a long-lasting therapy for both early-stage and advanced GIST in the first-line setting.

However, despite the effectiveness of imatinib, resistance to this drug eventually develops, necessitating the exploration of additional treatment options. This is where ripretinib comes into play. Ripretinib is an orally administered switch-control tyrosine kinase inhibitor that has been specifically designed to target both primary and secondary mutations in KIT and PDGFRα, which are known to confer resistance to imatinib.

The molecular rationale behind the use of ripretinib lies in its ability to inhibit the activity of mutated KIT and PDGFRα enzymes, which drive the growth and proliferation of GIST cells. Preclinical studies have provided evidence supporting the efficacy of ripretinib in suppressing the growth of GISTs harboring resistance mutations. These studies have demonstrated that ripretinib effectively inhibits the activity of mutant KIT and PDGFRα enzymes, leading to decreased cell proliferation and increased cell death in GIST cells.

In clinical practice, ripretinib has shown promising results in the treatment of advanced GISTs. In a Phase III clinical trial called INVICTUS, ripretinib demonstrated superior progression-free survival compared to placebo in patients with advanced GISTs who had previously received treatment with imatinib, sunitinib, and regorafenib. The trial showed that ripretinib significantly prolonged the time until disease progression or death in these patients, highlighting its potential as an effective therapy for GISTs resistant to multiple lines of treatment.

In conclusion, ripretinib represents a significant advancement in the management of advanced GISTs. Its ability to target both primary and secondary mutations in KIT and PDGFRα, which are associated with imatinib resistance, makes it a valuable treatment option for patients who have exhausted other lines of therapy. The preclinical and clinical evidence supports the use of ripretinib in the treatment of advanced GISTs and underscores its importance as a molecularly targeted therapy in the field of solid tumors.