Researchers investigating how well ripretinib performed in inhibiting resistance mutations found it offered clinically meaningful benefits across the various mutation subgroups when compared to the placebo. This supports its use as a fourth-line therapy in patients with advanced gastrointestinal stromal tumors (GISTs) that harbor a wide spectrum of mutations, according to a study published in Clinical Cancer Research.

Ripretinib is a drug that has gained US Food and Drug Administration (FDA) approval to treat patients with advanced GIST who had prior treatment with 3 or more tyrosine kinase inhibitors (TKIs). 

In addition, researchers set out to describe the genomic landscape of KIT-related resistance in GISTs using both liquid biopsies and tumor tissue from patients recruited in the phase 3 INVICTUS study. They discovered that liquid biopsy was a novel and noninvasive tool that, most importantly, showed promising signs of being highly useful in determining patients’ genotypes.


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GIST patients tend to have KIT/PDGRA mutations and respond well to TKIs. However, secondary mutations often occur. The researchers of this study decided to investigate the efficacy of both liquid biopsy and tumor tissue in identifying those mutations. In addition, they wanted to investigate the efficacy of ripretinib as a drug to inhibit these mutations. 

What is the INVICTUS study? The researchers explained, “INVICTUS is an international, multicenter, randomized, double-blind, placebo-controlled phase 3 trial in 129 patients who received at least 3 prior anticancer therapies for advanced GIST.” Researchers randomized patients 2:1 to receive ripretinib (150 mg) once daily or a placebo until disease progression. They collected liquid biopsies prior to ripretinib treatment as a baseline, as well as at the start of every 28-day cycle and at the conclusion of treatment. Fresh tumor tissue samples were also collected prior to ripretinib treatment. 

The findings of the study showed that while tissue biopsy remains the traditional gold standard in clinical practice, liquid biopsy is useful in determining patients’ genotypes while being noninvasive and therefore more comfortable for the patient. In addition, researchers concluded that “ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with 3 or more TKIs.” 

This study is unique in that it is “the first genomic characterization of baseline mutations using tissue and liquid biopsy in patients with advanced GIST with disease progression following imatinib, sunitinib, and regorafenib treatment,” according to the authors of the study. 

Conclusion

Bauer S, Heinrich MC, George S, et al. Clinical activity of ripretinib in patients with advanced gastrointestinal stromal tumor harboring heterogenous KIT/PDGFRA mutations in the phase 3 INVICTUS study. Clin Cancer Res. Published online September 9, 2021. doi:10.1158/1078-0432.CCR-21-1864