|ATC code||L01XE21 (WHO)|
|Biological half-life||20-30 hours|
|Excretion||Faeces (71%), urine (19%)|
|Chemical and physical data|
|Molar mass||482.82 g mol|
|3D model (Jmol)||Interactive image|
Regorafenib (BAY 73-4506, commercial name Stivarga) is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Since 2009 it was studied as a potential treatment option in multiple tumor types. By 2015 it had 2 US approvals for advanced cancers.
Approvals and indications
Metastatic colorectal cancer
After a manufacturer's appeal Regorafenib was restored to the list of treatments funded by the English Cancer Drugs Fund.
Advanced gastrointestinal stromal tumours
On February 25, 2013 the US FDA expanded the approved use to treat patients with advanced gastrointestinal stromal tumors that cannot be surgically removed and no longer respond to other FDA-approved treatments for this disease. In a clinical study with 199 patients regorafenib treated patients had a delay in tumor growth (progression-free survival) that was, on average, 3.9 months longer than patients who were given placebo.
Regorafenib is being approved with a Boxed Warning alerting patients and health care professionals that severe and fatal liver toxicity occurred in patients treated with regorafenib during clinical studies. Serious side effects, which occurred in less than one percent of patients, were liver damage, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks and perforations (holes) in the intestines. The most common side effects reported in patients treated with regorafenib include weakness or fatigue, loss of appetite, hand-foot syndrome (also called palmar-plantar erythrodysesthesia), diarrhoea, mouth sores (mucousitis), weight loss, infection, high blood pressure, and changes in voice volume or quality (dysphonia).
Regorafenib and at least one of its analogs, sorafenib, are potent inhibitors of Soluble epoxide hydrolase (sEH). sEH metabolizes, and in general thereby inactivates, epoxyeicosatrienoic acids (EETs), epoxydocosapentaenoic acids (EDPs), epoxyeicosatetraenoic acids (EEQs), and other epoxy polyunsaturated fatty acids that are made be various cytochrome P450 epoxygenases. EETs. EDPs, and EEQs have various effects in animals including vasodilation, anti-hypertensive, and anti-blood-clotting actions. However, EDPs, unlike EETs, inhibit the vascularization, growth, and metastasis of human cancer cells in vitro and in animal models. It is suggested that the inhibition of sEH and consequential increase in EDP levels contributes to the anti-cancer activity of regorafenib and related analogs, a possibility supported by studies showing that 1) DHA acted synergistically with regorafenib to increase EDP levels in and inhibit the growth of several human renal cancer cell lines in vitro and 2) dietary DHA likewise acted synergistically with regorafenib to inhibit the invasiveness and growth of a human renal cancer cell line while increasing its EPA levels in mice. These preclinical studies suggest that dietary supplementation with omega-3 fatty acids, particularly DHA, may be useful in enhancing the anti-cancer actions of regorafenib in humans.
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- CONSIGN, CONCUR Confirm Efficacy of Regorafenib in mCRC. 2015
- "FDA Prescribing Information" (PDF). 27 Sep 2012.
- Zhang, G; Kodani, S; Hammock, B. D. (2014). "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research. 53: 108–23. doi:10.1016/j.plipres.2013.11.003. PMC 3914417. PMID 24345640.
- Hwang, S. H.; Wecksler, A. T.; Zhang, G; Morisseau, C; Nguyen, L. V.; Fu, S. H.; Hammock, B. D. (2013). "Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors". Bioorganic & Medicinal Chemistry Letters. 23 (13): 3732–7. doi:10.1016/j.bmcl.2013.05.011. PMC 3744640. PMID 23726028.
- Kim, J; Ulu, A; Wan, D; Yang, J; Hammock, B. D.; Weiss, R. H. (2016). "Addition of DHA Synergistically Enhances the Efficacy of Regorafenib for Kidney Cancer Therapy". Molecular Cancer Therapeutics. 15 (5): 890–8. doi:10.1158/1535-7163.MCT-15-0847. PMC 4873345. PMID 26921392.