Sorafenib, sold under the brand nameNexavar,[3] is akinase inhibitor drug approved for the treatment of primary kidney cancer (advancedrenal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma.
Sorafenib treatment inducesautophagy,[7] which may suppress tumor growth. Based on its 1,3-disubstituted urea structure, sorafenib is also a potentsoluble epoxide hydrolase inhibitor and this activity likely reduces the severity of its adverse effects.[8]
Clinical trial results, published January 2007, showed that, compared with placebo, treatment with sorafenib prolongsprogression-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).[12]
AtASCO 2007, results from the SHARP trial[14] were presented, which showed efficacy of sorafenib inhepatocellular carcinoma. The primary endpoint was medianoverall 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 andtime to progression 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 withChild-Pugh Class A (i.e. mildest) cirrhosis.[14] Because of this trial sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.[5]
In a randomized, double-blind, phase II trial combining sorafenib withdoxorubicin, the mediantime to progression was not significantly delayed compared with doxorubicin alone in patients with advanced hepatocellular carcinoma. Median durations of overall survival andprogression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone.[5]
A prospective single-centre phase II study which included the patients with unresectable hepatocellular carcinoma (HCC) concluding that the combination of sorafenib andDEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib.[15]
In Australia this is the only indication for which sorafenib is listed on thePBS and hence the only government-subsidised indication for sorafenib.[13] Along with renal cell carcinoma, hepatocellular carcinoma is one of theTGA-labelled indications for sorafenib.[11]
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.[16]
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.[17]
Sorafenib was approved by the U.S.Food and Drug Administration (FDA) in December 2005,[20] and receivedEuropean Commission marketing authorization in July 2006,[21] both for use in the treatment of advanced renal cancer.
The European Commission granted marketing authorization to the drug for the treatment of patients withhepatocellular carcinoma(HCC), the most common form of liver cancer, in October 2007,[22] and FDA approval for this indication followed in November 2007.[23]
In November 2009, the UK'sNational Institute for Clinical Excellence declined to approve the drug for use within theNHS 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.[24] In Scotland the drug had already been refused authorization by theScottish Medicines Consortium for use withinNHS Scotland, for the same reason.[24]
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$3,300). Natco Pharma will sell 120 tablets for₹8,800 (US$100), while still paying a 6% royalty to Bayer. The royalty was later raised to 7% on appeal by Bayer.[25][26][27] Underthe Patents Act, 1970 and the World Trade Organisation TRIPS Agreement, the government can issue acompulsory license when a drug is not available at an affordable price.[28]
In January 2014, Bayer's CEOMarijn Dekkers allegedly stated that Nexavar was developed for "Western patients who can afford it, not for Indians". 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 thegeneric drug would be around $2,800 (£1,700).[29]
In some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition topaclitaxel andcarboplatin may bedetrimental to patients.[30]
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.[31]
A study performed in 2008 showed that sorafenib is active againstaggressive fibromatosis. This study is being used as justification for using sorafenib as an initial course of treatment in some patients with the condition.[33]
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.[34][35][36]
^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
^abLlovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. (July 2008). "Sorafenib in advanced hepatocellular carcinoma".The New England Journal of Medicine.359 (4):378–390.CiteSeerX10.1.1.531.1130.doi:10.1056/NEJMoa0708857.PMID18650514.
^Chittum R (29 January 2014)."Bloomberg's viral misquote".Columbia Journalism Review.Archived from the original on 10 February 2021. Retrieved12 September 2019.
