Regorafenib for treatment of imatinib- and sunitinib-resistant metastatic gastrointestinal stromal tumors

Introduction: The treatment of gastrointestinal stromal tumors (GISTs) has been transformed by the use of small molecule KIT/PDGFRA tyrosine kinase inhibitors (TKIs). Unfortunately, most GIST tumors develop resistance to front-line (imatinib) and second-line (sunitinib) therapy. Regorafenib, a multi-targeted KIT/PDGFRA/VEGFR oral TKI, has been shown to improve progression-free survival in the third- or fourth-line setting. Areas covered: This review encompasses the pre-clinical and clinical studies of regorafenib for treatment of GIST. The reviewed studies were all those retrievable using the PubMed database as of December 2015. Expert opinion: Based on the results of a randomized, double-blind, placebo-controlled, phase III study, regorafenib is now firmly established as the only proven third-line therapy. Regorafenib's activity in this setting is believed to be due to its activity against oncogenic forms of KIT/PDGFRA. Side effects are common with this agent; however, they can be effectively managed with a combination of supportive care, dose interruptions and dose reductions. In frail patients, starting at a lower dose with subsequent dose escalation/de-escalation may improve tolerance and optimize treatment. Regorafenib's toxicity profile is similar to other oral TKIs with anti-VEGFR activity. Regorafenib is primarily metabolized by CYP3A4, and concomitant use of strong inducers/inhibitors of this enzyme should be avoided.