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

ABSTRACT

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.

KEYWORDS:

• Sarcoma
• GI stromal tumor
• KIT
• PDGFRA
• VEGFR
• tyrosine kinase inhibitors

Declaration of interest

Funding has been received from a VA Merit Review Grant, the Life Raft Group and the GIST Cancer Research Fund. M Heinrich declares research funding from Ariad, Inhibikase, Blueprint Medicines, and Deciphera Pharmaceuticals, Consultancy for Molecular MD, Novartis, Ariad and Pfizer, Equity interest in Molecular MD, Patent Royalties from a patent licensed from OHSU to Novartis and an Expert Testimony role with Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.