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

Molly M. Daughety, Michael Heinrich

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)1-12
    Number of pages12
    JournalExpert Opinion on Orphan Drugs
    DOIs
    StateAccepted/In press - May 9 2016

    Fingerprint

    Gastrointestinal Stromal Tumors
    Protein-Tyrosine Kinases
    Therapeutics
    Cytochrome P-450 CYP3A
    Expert Testimony
    Enzyme Inhibitors
    PubMed
    Disease-Free Survival
    Placebos
    Imatinib Mesylate
    sunitinib
    regorafenib
    Databases
    Neoplasms

    Keywords

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

    ASJC Scopus subject areas

    • Pharmacology (medical)
    • Health Policy
    • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

    Cite this

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    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.",
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    author = "Daughety, {Molly M.} and Michael Heinrich",
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