Regorafenib, sold under the brand name Stivarga among others, is an oral multi-kinase inhibitor developed by
Bayer
Bayer AG (, commonly pronounced ; ) is a German multinational corporation, multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of busi ...
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 two US approvals for advanced cancers.
Approvals and indications
Metastatic colorectal cancer
Regorafenib demonstrated to increase the overall survival of patients with metastatic
colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
and has been approved by the
US FDA on September 27, 2012.
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.
Advanced hepatocellular carcinoma
On November 29, 2018 the
National Institute for Health and Care Excellence (NICE) approved use of regorafenib in patients with advanced
hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in t ...
who were previously treated with
sorafenib
Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer ( hepatocellular carcinoma), FLT3-ITD positive AML and r ...
.
Clinical trials
MetastaticCRC: After the CORRECT trial, two phase 3 trials (CONSIGN, CONCUR) showed benefits compared to placebo. Regorafenib dosing was 150 or 160 mg/d for first 3 weeks of each 4 week cycle.
[CONSIGN, CONCUR Confirm Efficacy of Regorafenib in mCRC. 2015]
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Adverse effects
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 (mucositis), weight loss, infection, high blood pressure, and changes in voice volume or quality ( dysphonia).
Other actions
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 acid
The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of Cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicosa ...
s (EETs), epoxydocosapentaenoic acids (EDPs), epoxyeicosatetraenoic acids (EEQs), and other epoxy polyunsaturated fatty acids that are made by various cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
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.
Brand names
In Bangladesh under the trade name Regonix.,
Regora 40mg Tablet manufactured by Beacon Pharmaceuticals Ltd.
References
External links
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Receptor tyrosine kinase inhibitors
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