Sorafenib

Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar),[1] is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma.

Sorafenib
Clinical data
Trade namesNexavar
Other namesNexavar
Sorafenib tosylate
AHFS/Drugs.comMonograph
MedlinePlusa607051
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
    Routes of
    administration    		By mouth
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability38–49%
    Protein binding99.5%
    MetabolismHepatic oxidation and glucuronidation (CYP3A4 & UGT1A9-mediated)
    Elimination half-life25–48 hours
    ExcretionFaeces (77%) and urine (19%)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    PDB ligand
    CompTox Dashboard (EPA)
    ECHA InfoCard100.110.083
    Chemical and physical data
    FormulaC21H16ClF3N4O3
    Molar mass464.83 g·mol−1
    3D model (JSmol)
      (verify)

    Mechanism of action

    Sorafenib is a protein kinase inhibitor with activity against many protein kinases, including VEGFR, PDGFR and RAF kinases.[2][3] Of the RAF kinases, Sorafenib is more selective for c-Raf than B-RAF.[4] (See BRAF (gene)#Sorafenib for details the drug's interaction with B-Raf.)

    Sorafenib treatment induces autophagy,[5] 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.[6]

    Medical uses

    Sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinomas (HCC) and thyroid cancer.[7][8][9][10]

    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 [CI], 0.35 to 0.55; P<0.01).[11]

    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.[10][12]

    Liver cancer

    At ASCO 2007, results from the SHARP trial[13] 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; 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.[13] Because of this trial Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.[3]

    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.[3]

    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.[14]

    In Australia this is the only indication for which sorafenib is listed on the PBS and hence the only Government-subsidised indication for sorafenib.[12] Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib.[10]

    Thyroid cancer

    On November 22, 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.[15]

    The Phase 3 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.[16]

    Desmoid tumors

    A phase 3 clinical trial is under way 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.[17][18]

    Adverse effects

    Adverse effects by frequency
    Note: Potentially serious side effects are in bold.
    Very common (>10% frequency)

    Common (1-10% frequency)

    • Transient increase in transaminase

    Uncommon (0.1-1% frequency)

    Rare (0.01-0.1% frequency)

    History

    Renal cancer

    Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005,[21] and received European Commission marketing authorization in July 2006,[22] 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 carcinoma(HCC), the most common form of liver cancer, in October 2007,[23] and FDA approval for this indication followed in November 2007.[24]

    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.[25] In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason.[25]

    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$3,900). Natco Pharma will sell 120 tablets for ₹8,800 (US$120), while still paying a 6% royalty to Bayer. The royalty was later raised to 7% on appeal by Bayer.[26][27][28] 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.[29]

    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.[30]

    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.[31]

    Brain (recurrent glioblastoma)

    There is a phase I/II study at the Mayo Clinic[32] of sorafenib and CCI-779 (temsirolimus) for recurrent glioblastoma.

    Desmoid tumor (aggressive fibromatosis)

    A study performed in 2011 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.[33]

    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 would be around $2,800 (£1,700).>[34]

    Notes
    1. Low blood phosphate levels
    2. Bleeding; including serious bleeds such as intracranial and intrapulmonary bleeds
    3. High blood pressure
    4. Including abdominal pain, headache, tumour pain, etc.
    5. Considered a low (~10-30%) risk chemotherapeutic agent for causing emesis)
    6. Low level of white blood cells in the blood
    7. Low level of neutrophils in the blood
    8. Low level of red blood cells in the blood
    9. Low level of plasma cells in the blood
    10. Low blood calcium
    11. Low blood potassium
    12. Hearing ringing in the ears
    13. Heart attack
    14. Lack of blood supply for the heart muscle
    15. Mouth swelling, also dry mouth and glossodynia
    16. Indigestion
    17. Not being able to swallow
    18. Sore joints
    19. Muscle aches
    20. Kidney failure
    21. Excreting protein [usually plasma proteins] in the urine. Not dangerous in itself but it is indicative kidney damage
    22. Including skin reactions and urticaria (hives)
    23. Underactive thyroid
    24. Overactive thyroid
    25. Low blood sodium
    26. Runny nose
    27. Pneumonitis, radiation pneumonitis, acute respiratory distress, etc.
    28. Swelling of the pancreas
    29. Swelling of the stomach
    30. Formation of a hole in the gastrointestinal tract, leading to potentially fatal bleeds
    31. 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
    32. Swelling of the gallbladder
    33. Swelling of the bile duct
    34. A potentially fatal skin reaction
    35. A fairly benign form of skin cancer
    36. A potentially fatal abnormality in the electrical activity of the heart
    37. Swelling of the skin and mucous membranes
    38. A potentially fatal allergic reaction
    39. Swelling of the liver
    40. The rapid breakdown of muscle tissue leading to the build-up of myoglobin in the blood and resulting in damage to the kidneys
    gollark: And balloons. And xenowyrms. And aeons...
    gollark: I'd want a CB gold maybe to get coppers from it.
    gollark: They breed awfully. Don't count on gifting any.
    gollark: There's a balloon there too, so it's worth about three.
    gollark: It also has a vaguely meaningful code.

    References
    1. "FDA Approves Nexavar for Patients with Inoperable Liver Cancer" (Press release). FDA. November 19, 2007. Retrieved November 10, 2012.
    2. 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.
    3. 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.
    4. 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.
    5. Zhang Y (Jan 2014). "Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways". Mol Med Rep. 9 (1): 83–90. doi:10.3892/mmr.2013.1781. PMID 24213221.
    6. Singh, Nalin; Hammock, Bruce (March 30, 2020). "Soluble Epoxide Hydrolase". In Offermanns, Stefan; Rosenthal, Walter (eds.). Encyclopedia of Molecular Pharmacology. Springer, Cham. doi:10.1007/978-3-030-21573-6. ISBN 978-3-030-21573-6.
    7. "Nexavar (sorafenib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 26 December 2013.
    8. "Nexavar (sorafenib) tablet, film coated [Bayer HealthCare Pharmaceuticals Inc.]". DailyMed. Bayer HealthCare Pharmaceuticals Inc. November 2013. Retrieved 26 December 2013.
    9. "Nexavar 200mg film-coated tablets - Summary of Product Characteristics (SPC) - (eMC)". electronic Medicines Compendium. Bayer plc. 27 March 2013. Retrieved 26 December 2013.
    10. "PRODUCT INFORMATION NEXAVAR (sorafenib tosylate)" (PDF). TGA eBusiness Services. Bayer Australia Ltd. 12 December 2012. Retrieved 26 December 2013.
    11. 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". New England Journal of Medicine. 356 (2): 125–34. doi:10.1056/NEJMoa060655. PMID 17215530.
    12. "Pharmaceutical Benefits Scheme (PBS) -SORAFENIB". Pharmaceutical Benefits Scheme. Australian Government Department of Health. Retrieved 27 December 2013.
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    14. 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. PMC 4829081. PMID 21911714.
    15. "FDA Approval for Sorafenib Tosylate". National Cancer Institute. 5 October 2006.
    16. "ASCO: Sorafenib Halts Resistant Thyroid Cancer". www.medpagetoday.com. 4 June 2013.
    17. "Sorafenib Tosylate in Treating Patients With Desmoid Tumors or Aggressive Fibromatosis". Clinicaltrials.gov.
    18. Gounder, MM; Lefkowitz, RA; Keohan, ML; D'Adamo, DR; Hameed, M; Antonescu, CR; Singer, S; Stout, K; Ahn, L; Maki, RG (15 June 2011). "Activity of Sorafenib against desmoid tumor/deep fibromatosis". Clinical Cancer Research. 17 (12): 4082–90. doi:10.1158/1078-0432.ccr-10-3322. PMC 3152981. PMID 21447727.
    19. "Chemotherapy-Induced Nausea and Vomiting Treatment & Management". Medscape Reference. WebMD. 3 July 2012. Retrieved 26 December 2013.
    20. Hagopian, Benjamin (August 2010). "Unusually Severe Bullous Skin Reaction to Sorafenib: A Case Report". Journal of Medical Cases. 1 (1): 1–3. doi:10.4021/jmc112e.
    21. FDA Approval letter for use of sorafenib in advanced renal cancer
    22. European Commission – Enterprise and industry. Nexavar Archived 2008-02-01 at the Wayback Machine. Retrieved April 24, 2007.
    23. "Nexavar (Sorafenib) Approved for Hepatocellular Carcinoma in Europe" (Press release). Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. October 30, 2007. Archived from the original on February 6, 2012. Retrieved November 10, 2012.
    24. FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma
    25. "Liver drug 'too expensive'". BBC News. November 19, 2009. Retrieved November 10, 2012.
    26. http://www.lawyerscollective.org/updates/supreme-court-says-no-to-bayer-upholds-compulsory-license-on-nexavar.html
    27. "Archived copy" (PDF). Archived from the original (PDF) on 2012-03-21. Retrieved 2012-04-02.CS1 maint: archived copy as title (link)
    28. "Seven days: 9–15 March 2012". Nature. 483 (7389): 250–1. 2012. Bibcode:2012Natur.483..250.. doi:10.1038/483250a.
    29. "India Patents (Amendment) Act, 2005". WIPO. Retrieved 16 January 2013.
    30. "Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients". login.medscape.com.
    31. Ciccone, Marcia A.; Maoz, Asaf; Casabar, Jennifer K.; Machida, Hiroko; Mabuchi, Seiji; Matsuo, Koji (July 2016). "Clinical outcome of treatment with serine-threonine kinase inhibitors in recurrent epithelial ovarian cancer: a systematic review of literature". Expert Opinion on Investigational Drugs. 25 (7): 781–796. doi:10.1080/13543784.2016.1181748. ISSN 1744-7658. PMID 27101098.
    32. Clinical trial number NCT00329719 for "Sorafenib and Temsirolimus in Treating Patients With Recurrent Glioblastoma" at ClinicalTrials.gov
    33. Gounder, MM; Lefkowitz, RA; Keohan, ML; D'Adamo, DR; Hameed, M; Antonescu, CR; Singer, S; Stout, K; Ahn, L; Maki, RG (Jun 2011). "Activity of Sorafenib against desmoid tumor/deep fibromatosis". Clin Cancer Res. 17 (12): 4082–90. doi:10.1158/1078-0432.CCR-10-3322. PMC 3152981. PMID 21447727.
    34. "Bloomberg's viral misquote".
    • "Sorafenib". Drug Information Portal. U.S. National Library of Medicine.
    • "Sorafenib". National Cancer Institute.
    • Clinical trial number NCT00217399 for "Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer" at ClinicalTrials.gov
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