Abstract
Regorafenib shows activity in patients with TKI-refractory metastatic GIST.
Major finding: Regorafenib shows activity in patients with TKI-refractory metastatic GIST.
Approach: A phase II trial evaluated the safety and efficacy of the multi-kinase inhibitor regorafenib.
Impact: Regorafenib may be a third-line treatment for patients with advanced GIST.
Gastrointestinal stromal tumor (GIST), the most common form of sarcoma, is caused by activating mutations in either of the receptor tyrosine kinase genes KIT or PDGFRA. Treatment with the targeted first- and second-line tyrosine kinase inhibitors (TKI) imatinib and sunitinib, respectively, has dramatically improved the prognosis of patients with GIST. However, TKI resistance, which is usually mediated by secondary KIT mutations, eventually develops in advanced disease, and no third-line agents currently exist for the treatment of TKI-refractory metastatic GIST. Given the limited treatment options for advanced GIST, George and colleagues investigated the efficacy and safety of regorafenib, an oral multikinase inhibitor with activity against KIT, PDGFR, and multiple other targets, in 33 patients with metastatic GIST after failure of both imatinib and sunitinib. In this multicenter phase II trial, 75% of the patients achieved a clinical response, which included 4 partial responses and 22 instances of stable disease, with a median progression-free survival of 10 months. Importantly, analysis of patient biopsies from tumors that harbored KIT resistance mutations showed decreased levels of KIT activation and other downstream targets during treatment with regorafenib, suggesting that regorafenib is active against secondary KIT mutations. Although it remains unclear whether the clinical activity of regorafenib is solely due to inhibition of KIT, a compensatory signaling pathway, or both, these findings suggest that regorafenib may represent an effective third-line agent in patients with TKI-resistant GIST. A phase III trial further evaluating the efficacy of regorafenib is currently in progress.
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