Sorafenib
Encyclopedia
Sorafenib is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma
) and advanced primary liver cancer (hepatocellular carcinoma
).
of several Tyrosine protein kinase
s (VEGFR and PDGFR) and Raf kinase
s (more avidly C-Raf than B-Raf).
(Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous. These pathways include Raf
kinase, PDGF (platelet-derived growth factor
), VEGF
receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor
. )
Sorafenib is/was unique in targeting the Raf/Mek/Erk pathway
(MAP Kinase pathway).
Sorafenib inhibits some intracellular serine/threonine kinases (e.g. C-Raf
, wild-type B-Raf
and mutant B-Raf).
(FDA) in December 2005, and received European Commission
marketing authorization in July 2006, both for use in the treatment of advanced renal cancer.
(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.
for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01). A few reports described patients with stage IV renal cell carcinomas that were successfully treated with a multimodal approach including neurosurgical, radiation, and sorafenib.
2007, results from the SHARP trial were presented, which showed efficacy of sorafenib in hepatocellular carcinoma
. The primary endpoint was 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 showed 3-month improvements. 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. The results of the study appear in the July 24, 2008, edition of The New England Journal of Medicine. 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 time to progression 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.
.
and carboplatin
may be detrimental to patients.
) for recurrent glioblastoma.
s of sorafenib include skin rash, hand-foot skin reactions, diarrhea, and hypertension. A case of diffuse yellow discoloration of the skin has been reported. Sorafenib has also been implicated in the development of reversible posterior leukoencephalopathy syndrome and reversible erythrocytosis.
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
) and advanced primary liver cancer (hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
).
Pharmacology
Sorafenib (a bi-aryl urea) is a small molecular inhibitorEnzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of several Tyrosine protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s (VEGFR and PDGFR) and Raf kinase
Raf kinase
Raf kinases are a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes. The mouse sarcoma virus 3611 contains a Raf kinase-related oncogene that enhances fibrosarcoma induction...
s (more avidly C-Raf than B-Raf).
(Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous. These pathways include Raf
C-Raf
RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...
kinase, PDGF (platelet-derived growth factor
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
), VEGF
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor
Stem cell factor
Stem Cell Factor is a cytokine that binds to the c-Kit receptor . SCF can exist both as a transmembrane protein and a soluble protein...
. )
Sorafenib is/was unique in targeting the Raf/Mek/Erk pathway
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
(MAP Kinase pathway).
Sorafenib inhibits some intracellular serine/threonine kinases (e.g. C-Raf
C-Raf
RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...
, wild-type B-Raf
BRAF (gene)
Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene...
and mutant B-Raf).
Renal cancer
Sorafenib was approved by the U.S. Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) in December 2005, and received European Commission
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....
marketing authorization in July 2006, 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 hepatocellular carcinomaHepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
(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
National Health Service
The National Health Service is the shared name of three of the four publicly funded healthcare systems in the United Kingdom. They provide a comprehensive range of health services, the vast majority of which are free at the point of use to residents of the United Kingdom...
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
Scottish Medicines Consortium
The Scottish Medicines Consortium has the role of providing advice to NHS Boards and their Area Drug and Therapeutics Committees about all newly licensed medicines....
for use within NHS Scotland
NHS Scotland
NHS Scotland is the publicly funded healthcare system of Scotland. Although they are separate bodies the organisational separation between NHS Scotland and the other three healthcare organisations each commonly called the National Health Service in the United Kingdom tends to be hidden from its...
, for the same reason.
Kidney
An article in The New England Journal of Medicine, published January 2007, showed 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 ratioHazard ratio
In survival analysis, the hazard ratio is the ratio of the hazard rates corresponding to the conditions described by two sets of explanatory variables. For example, in a drug study, the treated population may die at twice the rate per unit time as the control population. The hazard ratio would be...
for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01). A few reports described patients with stage IV renal cell carcinomas that were successfully treated with a multimodal approach including neurosurgical, radiation, and sorafenib.
Liver
At ASCOAmerican Society of Clinical Oncology
The American Society of Clinical Oncology is the world's leading professional organization representing physicians of all oncology subspecialties who care for people with cancer. Founded in 1964 by Drs...
2007, results from the SHARP trial were presented, which showed efficacy of sorafenib in hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
. The primary endpoint was overall survival, which showed a 44% improvement in patients who received sorafenib compared to placebo (hazard ratio
Hazard ratio
In survival analysis, the hazard ratio is the ratio of the hazard rates corresponding to the conditions described by two sets of explanatory variables. For example, in a drug study, the treated population may die at twice the rate per unit time as the control population. The hazard ratio would be...
0.69; 95% CI, 0.55 to 0.87; p=0.0001). Both median survival and time to progression showed 3-month improvements. 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. The results of the study appear in the July 24, 2008, edition of The New England Journal of Medicine. 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
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
, the median time to progression 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.
Thyroid cancer
A phase 3 clinical trial has started recruiting (Nov 2009) to use sorafenib for non-responsive thyroid cancerThyroid cancer
Thyroid neoplasm is a neoplasm or tumor of the thyroid. It can be a benign tumor such as thyroid adenoma, or it can be a malignant neoplasm , such as papillary, follicular, medullary or anaplastic thyroid cancer. Most patients are 25 to 65 years of age when first diagnosed; women are more affected...
.
Lung
In some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition to paclitaxelPaclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
and carboplatin
Carboplatin
Carboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...
may be detrimental to patients.
Brain (Recurrent Glioblastoma)
There is a phase I/II study at the Mayo Clinic of Sorafenib and CCI-779 (TemsirolimusTemsirolimus
Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma , developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration in late May 2007, and was also approved by the European Medicines Agency on November 2007...
) for recurrent glioblastoma.
Adverse effects
Adverse effectAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s of sorafenib include skin rash, hand-foot skin reactions, diarrhea, and hypertension. A case of diffuse yellow discoloration of the skin has been reported. Sorafenib has also been implicated in the development of reversible posterior leukoencephalopathy syndrome and reversible erythrocytosis.
External links
- Nexavar.com – Manufacturer's website
- Prescribing Information – includes data from the key studies justifying the use of sorafenib for the treatment of kidney cancer (particularly clear cell renal cell carcinoma, which is associated with the von Hippel-Lindau geneVon Hippel-Lindau tumor suppressorThe Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that in humans is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease....
) - Patient Information from FDA
- Sorafenib in Treating Patients With Soft Tissue Sarcomas
- Sorafenib Sunitinib differences - diagram - Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
- Cipla launches Nexavar generic at 1/10 of Bayer's price