|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||D (AU) D (US)|
|Legal status||℞-only (US)|
|Metabolism||Hepatic oxidation and glucuronidation (CYP3A4-mediated)|
|Excretion||Fecal (77%) and renal (19%)|
|Mol. mass||464.825 g/mol|
| (what is this?)
Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar), is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma).
(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 was approved by the U.S. Food and Drug Administration (FDA) in December 2005, and received European Commission marketing authorization in July 2006, both for use in the treatment of advanced renal cancer.
The European Commission granted marketing authorization to the drug for the treatment of patients with hepatocellular carcinoma (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 280,000 (US$4,800). Natco Pharma will sell 120 tablets for 8,800 (US$150), while still paying a 6% royalty to Bayer. Under Indian Patents Act, 2005 and the World Trade Organisation TRIPS Agreement, the government can issue a compulsory license when a drug is not available at an affordable price.
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 ratio 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.
At ASCO 2007, results from the SHARP trial were presented, which showed efficacy of sorafenib in hepatocellular carcinoma. 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 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. A prospective single-center 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.
Brain (Recurrent Glioblastoma)
Adverse effects 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.
Licensing in India
In March 2012, Bayer was forced to license production of the drug to Natco Pharma. This brought down the cost of the drug from $5,500 a month to $175 a month under provisions in the Indian Patents Act and WTO TRIPS agreement.
- "FDA Approves Nexavar for Patients with Inoperable Liver Cancer" (Press release). FDA. November 19, 2007. Retrieved November 10, 2012.
- Keating GM, Santoro A (2009). "Sorafenib: a review of its use in advanced hepatocellular carcinoma". Drugs 69 (2): 223–40. doi:10.2165/00003495-200969020-00006. PMID 19228077.
- Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M (January 2009). "CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations". Oncogene 28 (1): 85–94. doi:10.1038/onc.2008.362. PMC 2898184. PMID 18794803.
- Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (October 2008). "Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling". Mol. Cancer Ther. 7 (10): 3129–40. doi:10.1158/1535-7163.MCT-08-0013. PMID 18852116.
- "Sorafenib Sunitinib differences". Retrieved August 15, 2007.[unreliable medical source?]
- FDA Approval letter for use of sorafenib in advanced renal cancer
- European Commission – Enterprise and industry. Nexavar. Retrieved April 24, 2007.
- "Nexavar® (Sorafenib) Approved for Hepatocellular Carcinoma in Europe" (Press release). Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. October 30, 2007. Retrieved November 10, 2012.
- FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma
- "Liver drug 'too expensive'". BBC News. November 19, 2009. Retrieved November 10, 2012.
- "Seven days: 9–15 March 2012". Nature 483 (7389): 250–1. 2012. doi:10.1038/483250a.
- "India Patents (Amendment) Act, 2005". WIPO. Retrieved 16 January 2013.
- Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM (January 2007). "Sorafenib in advanced clear-cell renal-cell carcinoma". N. Engl. J. Med. 356 (2): 125–34. doi:10.1056/NEJMoa060655. PMID 17215530.
- Walid MS, Johnston KW (2009). "Successful treatment of a brain-metastasized renal cell carcinoma". Ger Med Sci 7: Doc28. doi:10.3205/000087. PMC 2775194. PMID 19911072.
- http://www.nejm.org/doi/full/10.1056/NEJMoa0708857Llovet, et. al. (2008). "Sorafenib in Advanced Hepatocellular Carcinoma". NEJM 359: 378–90.
- Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF (October 2011). "Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma". J. Clin. Oncol. 29 (30): 3960–7. doi:10.1200/JCO.2011.37.1021. PMID 21911714.
- "Phase 3 Trial of Nexavar in Patients With Non-Responsive Thyroid Cancer"[dead link]
- "Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients"
- ClinicalTrials.gov NCT00329719 Sorafenib and Temsirolimus in Treating Patients With Recurrent Glioblastoma
- Dasanu CA, Alexandrescu DT, Dutcher J (March 2007). "Yellow skin discoloration associated with sorafenib use for treatment of metastatic renal cell carcinoma". South. Med. J. 100 (3): 328–30. doi:10.1097/SMJ.0b013e31802f01a9. PMID 17396743.
- Alexandrescu DT, McClure R, Farzanmehr H, Dasanu CA (August 2008). "Secondary erythrocytosis produced by the tyrosine kinase inhibitors sunitinib and sorafenib". J. Clin. Oncol. 26 (24): 4047–8. doi:10.1200/JCO.2008.18.3525. PMID 18711201.
- 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 gene)
- Patient Information from FDA
- Sorafenib in Treating Patients With Soft Tissue Sarcomas
- Sorafenib bound to proteins in the PDB
- Sorafenib Sunitinib differences – diagram
- ClinicalTrials.gov NCT00217399 – Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
- Cipla launches Nexavar generic at 1/10 of Bayer's price