Sorafenib, sold under the brand name Nexavar, is a

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (

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 ...

), FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma.

Mechanism of action

Sorafenib is a

protein kinase inhibitor A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that phosphorylate (add a phosphate, or PO4, group) to a protein and can modulate its function. The ph ...

with activity against many protein kinases, including VEGFR, PDGFR and RAF kinases. Of the RAF kinases, sorafenib is more selective for c-Raf than B-RAF. (See BRAF (gene)#Sorafenib for details the drug's interaction with B-Raf.) Sorafenib treatment induces

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

, which may suppress tumor growth. Based on its 1,3-disubstituted urea structure, sorafenib is also a potent soluble epoxide hydrolase inhibitor and this activity likely reduces the severity of its adverse effects.

Medical uses

Sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable

s (HCC) and thyroid cancer.

Kidney cancer

Clinical trial results, published January 2007, showed that, compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear cell renal cell carcinoma in whom previous therapy has failed. The median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group ( hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval I 0.35 to 0.55; P<0.01). In Australia this is one of two TGA-labelled indications for sorafenib, although it is not listed on the Pharmaceutical Benefits Scheme for this indication.

Liver cancer

At ASCO 2007, results from the SHARP trial were presented, which showed efficacy of sorafenib in

. The primary endpoint was median overall survival, which showed a 44% improvement in patients who received sorafenib compared to placebo ( hazard ratio 0.69; 95% CI, 0.55 to 0.87; p=0.0001). Both median survival and

time to progression Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is p ...

showed 3-month improvements; however, there was no significant difference in median time to symptomatic progression (''p''=0.77). There was no difference in quality of life measures, possibly attributable to toxicity of sorafenib or symptoms related to underlying progression of liver disease. Of note, this trial only included patients with Child-Pugh Class A (i.e. mildest) cirrhosis. Because of this trial sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007. In a randomized, double-blind, phase II trial combining sorafenib with doxorubicin, the median

was not significantly delayed compared with doxorubicin alone in patients with advanced hepatocellular carcinoma. Median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone. A prospective single-centre phase II study which included the patients with unresectable hepatocellular carcinoma (HCC) concluding that the combination of sorafenib and DEB- TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib. In Australia this is the only indication for which sorafenib is listed on the PBS and hence the only government-subsidised indication for sorafenib. Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib.

Thyroid cancer

On 22 November 2013, sorafenib was approved by the FDA for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment. The phase III DECISION trial showed significant improvement in progression-free survival but not in overall survival. However, as is known, the side effects were very frequent, specially hand and foot skin reaction.

Adverse effects

Adverse effects by frequency
''Note: Potentially serious side effects are in bold.''
Very common (>10% frequency)
* Lymphopenia * HypophosphataemiaLow blood phosphate levels * HaemorrhageBleeding; including serious bleeds such as intracranial and intrapulmonary bleeds *

Hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

High blood pressure * Diarrhea * Rash * Alopecia (hair loss; occurs in roughly 30% of patients receiving sorafenib) * Hand-foot syndrome * Pruritus (itchiness) * Erythema * Increased amylase * Increased

lipase Lipase ( ) is a family of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually tr ...

* Fatigue * PainIncluding abdominal pain, headache, tumour pain, etc. * Nausea * VomitingConsidered a low (~10-30%) risk chemotherapeutic agent for causing emesis) Common (1-10% frequency)
* LeucopeniaLow level of

white blood cell White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...

s in the blood * NeutropoeniaLow level of

neutrophils Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

in the blood * AnaemiaLow level of red blood cells in the blood * ThrombocytopeniaLow level of

plasma cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...

s in the blood * Anorexia (weight loss) * HypocalcaemiaLow blood calcium * HypokalaemiaLow blood potassium * Depression * Peripheral sensory neuropathy * TinnitusHearing ringing in the ears * Congestive heart failure * Myocardial infarctionHeart attack * Myocardial ischaemiaLack of blood supply for the heart muscle * Hoarseness * Constipation * StomatitisMouth swelling, also dry mouth and

glossodynia Burning mouth syndrome (BMS) is a burning, tingling or scalding sensation in the mouth, lasting for at least four to six months, with no underlying known dental or medical cause. No related signs of disease are found in the mouth. People with ...

* DyspepsiaIndigestion * DysphagiaNot being able to swallow * Dry skin * Exfoliative dermatitis * Acne * Skin desquamation * ArthralgiaSore joints *

Myalgia Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likel ...

Muscle aches * Kidney failureKidney failure * ProteinuriaExcreting protein sually plasma proteinsin the urine. Not dangerous in itself but it is indicative kidney damage *

Erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...

* Asthenia (weakness) * Fever * Influenza-like illness * Transient increase in transaminase Uncommon (0.1-1% frequency)
* Folliculitis * Infection * Hypersensitivity reactionsIncluding skin reactions and urticaria (hives) *

Hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...

Underactive thyroid * HyperthyroidismOveractive thyroid *

Hyponatraemia Hyponatremia or hyponatraemia is a low concentration of sodium in the blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symptoms can be abs ...

Low blood sodium * Dehydration * Reversible posterior leukoencephalopathy * Hypertensive crisis * RhinorrhoeaRunny nose * Interstitial lung disease-like events Pneumonitis, radiation pneumonitis, acute respiratory distress, etc. * Gastro-oesophageal reflux disease (GORD) * PancreatitisSwelling of the pancreas * GastritisSwelling of the stomach * Gastrointestinal perforationsFormation of a hole in the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...

, leading to potentially fatal bleeds * Increase in

bilirubin Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...

leading, potentially, to

jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...

Yellowing of the skin and eyes due to a failure of the liver to adequately cope with the amount of bilirubin produced by the day-to-day actions of the body * CholecystitisSwelling of the gallbladder * CholangitisSwelling of the bile duct * Eczema * Erythema multiformeA potentially fatal skin reaction * KeratoacanthomaA fairly benign form of skin cancer *

Squamous cell carcinoma Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...

* Gynaecomastia (swelling of the breast tissue in men) * Transient increase in blood alkaline phosphatase * INR abnormal * Prothrombin level abnormal * bulbous skin reaction Rare (0.01-0.1% frequency) *

QT interval The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...

prolongationA potentially fatal abnormality in the electrical activity of the heart * AngiooedemaSwelling of the skin and mucous membranes * Anaphylactic reactionA potentially fatal allergic reaction * HepatitisSwelling of the liver * Radiation recall dermatitis * Stevens–Johnson syndrome *

Leucocytoclastic vasculitis Cutaneous small-vessel vasculitis (CSVV), also known as hypersensitivity vasculitis, cutaneous leukocytoclastic vasculitis, hypersensitivity angiitis, cutaneous leukocytoclastic angiitis, cutaneous necrotizing vasculitis and cutaneous necrotizing v ...

* Toxic epidermal necrolysis *

Nephrotic syndrome Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy ...

Rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of th ...

The rapid breakdown of muscle tissue leading to the build-up of

myoglobin Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the cardiac and skeletal muscle tissue of vertebrates in general and in almost all mammals. Myoglobin is distantly related to hemoglobin. Compared to hemoglobin, myoglobi ...

in the blood and resulting in damage to the kidneys

History

Renal cancer

Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005, and received European Commission marketing authorization in July 2006, European Commission – Enterprise and industry
Nexavar
. Retrieved 24 April 2007. both for use in the treatment of advanced renal cancer.

Liver cancer

The European Commission granted marketing authorization to the drug for the treatment of patients with

(HCC), the most common form of liver cancer, in October 2007, and FDA approval for this indication followed in November 2007. In November 2009, the UK's National Institute of Clinical Excellence declined to approve the drug for use within the NHS in England, Wales and Northern Ireland, stating that its effectiveness (increasing survival in primary liver cancer by 6 months) did not justify its high price, at up to £3000 per patient per month. In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason. In March 2012, the Indian Patent Office granted a domestic company, Natco Pharma, a license to manufacture generic sorafenib, bringing its price down by 97%. Bayer sells a month's supply, 120 tablets, of Nexavar for. Natco Pharma will sell 120 tablets for , while still paying a 6% royalty to Bayer. The royalty was later raised to 7% on appeal by Bayer. Under the Patents Act, 1970 and the World Trade Organisation TRIPS Agreement, the government can issue a compulsory license when a drug is not available at an affordable price.

Society and culture

Nexavar controversy

In January 2014, Bayer's CEO Marijn Dekkers allegedly stated that Nexavar was developed for "Western patients who can afford it, not for Indians". However, Dekkers actually never said this. In fact, his words were misquoted and the context was omitted. A kidney cancer patient would pay $96,000 (£58,000) for a year's course of the Bayer-made drug, whereas the cost of the Indian version of the

generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

would be around $2,800 (£1,700).

Research

Lung

In some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition to paclitaxel and carboplatin may be ''detrimental'' to patients.

Ovarian cancer

Sorafenib has been studied as maintenance therapy after ovarian cancer treatment and in combination with chemotherapy for recurrent ovarian cancer but did not show results that led to approval of the drug for these indications.

Brain (recurrent glioblastoma)

There is a phase I/II study at the Mayo Clinic of sorafenib and CCI-779 ( temsirolimus) for recurrent glioblastoma.

Desmoid tumor (aggressive fibromatosis)

A study performed in 2008 showed that Sorafenib is active against aggressive fibromatosis. This study is being used as justification for using sorafenib as an initial course of treatment in some patients with aggressive fibromatosis. A phase III clinical trial is testing the effectiveness of sorafenib to treat desmoid tumors (also known as aggressive fibromatosis), after positive results in the first two trial stages. Dosage is typically half of that applied for malignant cancers (400 mg vs 800 mg). NCI are sponsoring this trial.

Notes

References

External links

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