Regorafenib

Systematic (IUPAC) name
4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate
Clinical data
Trade names	Stivarga
Pregnancy category	AU: D US: D (Evidence of risk)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	69-83%
Protein binding	99.5%
Metabolism	Hepatic (UGT1A9-mediated)
Biological half-life	20-30 hours
Excretion	Faeces (71%), urine (19%)
Identifiers
CAS Number	755037-03-7
ATC code	L01XE21 (WHO)
PubChem	CID: 11167602
ChemSpider	28295228
KEGG	D10138
ChEBI	CHEBI:68647 Y
ChEMBL	CHEMBL1946170
Synonyms	BAY 73-4506
Chemical data
Formula	C21H17ClF4N4O4
Molecular mass	482.82 g mol
SMILES CNC(=O)c1cc(ccn1)Oc2ccc(c(c2)F)NC(=O)Nc3ccc(c(c3)C(F)(F)F)Cl.O
InChI InChI=1S/C21H15ClF4N4O3.H2O/c1-27-19(31)18-10-13(6-7-28-18)33-12-3-5-17(16(23)9-12)30-20(32)29-11-2-4-15(22)14(8-11)21(24,25)26;/h2-10H,1H3,(H,27,31)(H2,29,30,32);1H2 Key:ZOPOQLDXFHBOIH-UHFFFAOYSA-N

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

Regorafenib demonstrated to increase the overall survival of patients with metastatic colorectal cancer 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.

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.

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 (mucousitis), weight loss, infection, high blood pressure, and changes in voice volume or quality (dysphonia).