Sorafenib

Overview

Sorafenib, sold under the brand name Nexavar, 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.[1] WP

Uses, dosage and effects

Medical uses

Sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinomas (HCC), thyroid cancer and Acute Myeloid Leukaemia with FLT3-ITD mutation.[2–5] WP

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).[6] WP

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.[5][7] WP

Liver cancer

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; 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.[8][9] WP

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.[9] WP

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.[10] WP

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.[5][7] WP

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.[11] WP

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.[12] WP

Acute myeloid leukaemia

In patients with FLT3-ITD mutated AML, sorafenib can be used as a maintenance therapy post-Allogeneic haematopoietic stem-cell transplantation to target any residual disease that could remain in the bone marrow.[13] WP

Risks and side effects

Adverse effects

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

• Lymphopenia WP
• Hypophosphataemia[14] WP
• Haemorrhage[15] WP
• Hypertension[16] WP
• Diarrhea WP
• Rash WP
• Alopecia (hair loss; occurs in roughly 30% of patients receiving sorafenib) WP
• Hand-foot syndrome WP
• Pruritus (itchiness) WP
• Erythema WP
• Increased amylase WP
• Increased lipase WP
• Fatigue WP
• Pain[17] WP
• Nausea WP
• Vomiting[18][19] WP

Common (1-10% frequency) WP

• Leucopenia[20] WP
• Neutropoenia[21] WP
• Anaemia[22] WP
• Thrombocytopenia[23] WP
• Anorexia (weight loss) WP
• Hypocalcaemia[24] WP
• Hypokalaemia[25] WP
• Depression WP
• Peripheral sensory neuropathy WP
• Tinnitus[26] WP
• Congestive heart failure WP
• Myocardial infarction[27] WP
• Myocardial ischaemia[28] WP
• Hoarseness WP
• Constipation WP
• Stomatitis[29] WP
• Dyspepsia[30] WP
• Dysphagia[31] WP
• Dry skin WP
• Exfoliative dermatitis WP
• Acne WP
• Skin desquamation WP
• Arthralgia[32] WP
• Myalgia[33] WP
• Kidney failure[34] WP
• Proteinuria[35] WP
• Erectile dysfunction WP
• Asthenia (weakness) WP
• Fever WP
• Influenza-like illness WP
• Transient increase in transaminase WP

Uncommon (0.1-1% frequency) WP

• Folliculitis WP
• Infection WP
• Hypersensitivity reactions[36] WP
• Hypothyroidism[37] WP
• Hyperthyroidism[38] WP
• Hyponatraemia[39] WP
• Dehydration WP
• Reversible posterior leukoencephalopathy WP
• Hypertensive crisis WP
• Rhinorrhoea[40] WP
• Interstitial lung disease-like events[41] WP
• Gastro-oesophageal reflux disease (GORD) WP
• Pancreatitis[42] WP
• Gastritis[43] WP
• Gastrointestinal perforations[44] WP
• Increase in bilirubin leading, potentially, to jaundice[45] WP
• Cholecystitis[46] WP
• Cholangitis[47] WP
• Eczema WP
• Erythema multiforme[48] WP
• Keratoacanthoma[49] WP
• Squamous cell carcinoma WP
• Gynaecomastia (swelling of the breast tissue in men) WP
• Transient increase in blood alkaline phosphatase WP
• INR abnormal WP
• Prothrombin level abnormal WP
• bulbous skin reaction[50] WP

Rare (0.01-0.1% frequency) WP

• QT interval prolongation[51] WP
• Angiooedema[52] WP
• Anaphylactic reaction[53] WP
• Hepatitis[54] WP
• Radiation recall dermatitis WP
• Stevens–Johnson syndrome[48] WP
• Leucocytoclastic vasculitis WP
• Toxic epidermal necrolysis[48] WP
• Nephrotic syndrome WP
• Rhabdomyolysis[55] WP

Pharmacology

Mechanism of action

Sorafenib is a protein kinase inhibitor 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.)[9][56][57] WP

Sorafenib treatment induces autophagy, 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.[58][59] WP

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.[60] WP

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.[61] WP

Brain (recurrent glioblastoma)

There is a phase I/II study at the Mayo Clinic of sorafenib and CCI-779 (temsirolimus) for recurrent glioblastoma.[62] WP

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 the condition.[63] WP

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.[64][65][66] WP

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, both for use in the treatment of advanced renal cancer.[67][68] WP

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, and FDA approval for this indication followed in November 2007.[69][70] WP

In November 2009, the UK's National Institute for 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.[71] WP

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.[72–75] WP⚠ Part of this sentence could not be copied from the source. Open the source to read it in full.

Legal status

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". 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).[76] WP

Chemistry

Formula

C21H16ClF3N4O3 PC

CAS number

284461-73-0 PC

Molar mass (g/mol)

464.8 PC

IUPAC name (computed by PubChem)

4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide PC

SMILES

CNC(=O)C1=NC=CC(=C1)OC2=CC=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F PC

InChIKey

MLDQJTXFUGDVEO-UHFFFAOYSA-N PC

PubChem CID

216239

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency FDA Approves Nexavar for Patients with Inoperable Liver Cancer. 19 November 2007
2. Other Nexavar (sorafenib) dosing, indications, interactions, adverse effects, and more
3. Journal / agency Nexavar (sorafenib) tablet, film coated [Bayer HealthCare Pharmaceuticals Inc.]. November 2013
4. Other Nexavar 200mg film-coated tablets - Summary of Product Characteristics (SPC) - (eMC). 27 March 2013
5. Other PRODUCT INFORMATION NEXAVAR (sorafenib tosylate). 12 December 2012
6. Journal / agency 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. Sorafenib in advanced clear-cell renal-cell carcinoma. The New England Journal of Medicine. January 2007. doi:10.1056/NEJMoa060655 · PMID 17215530
7. Other Pharmaceutical Benefits Scheme (PBS) -SORAFENIB
8. Journal / agency Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J. Sorafenib in advanced hepatocellular carcinoma. The New England Journal of Medicine. July 2008. doi:10.1056/NEJMoa0708857 · PMID 18650514
9. Journal / agency Keating GM, Santoro A. Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs. 2009. doi:10.2165/00003495-200969020-00006 · PMID 19228077
10. Journal / agency Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF. Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. Journal of Clinical Oncology. October 2011. doi:10.1200/JCO.2011.37.1021 · PMID 21911714 · PMC4829081
11. Other FDA Approval for Sorafenib Tosylate. 5 October 2006
12. Other ASCO: Sorafenib Halts Resistant Thyroid Cancer. 4 June 2013
13. Other Data Show Sorafenib Maintenance Therapy After Allo-HSCT Improves Outcomes in FLT3-ITD-Positive AML. 29 July 2020
14. Other Low blood phosphate levels
15. Other Bleeding; including serious bleeds such as intracranial and intrapulmonary bleeds
16. Other High blood pressure
17. Other Including abdominal pain, headache, tumour pain, etc
18. Other Considered a low (~10-30%) risk chemotherapeutic agent for causing emesis)
19. Other Chemotherapy-Induced Nausea and Vomiting Treatment & Management. 3 July 2012
20. Other Low level of white blood cells in the blood
21. Other Low level of neutrophils in the blood
22. Other Low level of red blood cells in the blood
23. Other Low level of plasma cells in the blood
24. Other Low blood calcium
25. Other Low blood potassium
26. Other Hearing ringing in the ears
27. Other Heart attack
28. Other Lack of blood supply for the heart muscle
29. Other Mouth swelling, also dry mouth and glossodynia
30. Other Indigestion
31. Other Not being able to swallow
32. Other Sore joints
33. Other Muscle aches
34. Other Kidney failure
35. Other Excreting protein [usually plasma proteins] in the urine. Not dangerous in itself but it is indicative kidney damage
36. Other Including skin reactions and urticaria (hives)
37. Other Underactive thyroid
38. Other Overactive thyroid
39. Other Low blood sodium
40. Other Runny nose
41. Other Pneumonitis, radiation pneumonitis, acute respiratory distress, etc
42. Other Swelling of the pancreas
43. Other Swelling of the stomach
44. Other Formation of a hole in the gastrointestinal tract, leading to potentially fatal bleeds
45. Other 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
46. Other Swelling of the gallbladder
47. Other Swelling of the bile duct
48. Other A potentially fatal skin reaction
49. Other A fairly benign form of skin cancer
50. Journal / agency Hagopian B. Unusually Severe Bullous Skin Reaction to Sorafenib: A Case Report. Journal of Medical Cases. August 2010. doi:10.4021/jmc112e
51. Other A potentially fatal abnormality in the electrical activity of the heart
52. Other Swelling of the skin and mucous membranes
53. Other A potentially fatal allergic reaction
54. Other Swelling of the liver
55. Other The rapid breakdown of muscle tissue leading to the build-up of myoglobin in the blood and resulting in damage to the kidneys
56. Journal / agency Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Molecular Cancer Therapeutics. October 2008. doi:10.1158/1535-7163.MCT-08-0013 · PMID 18852116 · PMC12261297
57. Journal / agency Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. January 2009. doi:10.1038/onc.2008.362 · PMID 18794803 · PMC2898184
58. Journal / agency Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X. Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways. Molecular Medicine Reports. January 2014. doi:10.3892/mmr.2013.1781 · PMID 24213221
59. Journal / agency Singh N, Hammock B. Encyclopedia of Molecular Pharmacology. 30 March 2020. doi:10.1007/978-3-030-21573-6
60. Other Chustecka Z. Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients. April 25, 2008
61. Journal / agency Ciccone MA, Maoz A, Casabar JK, Machida H, Mabuchi S, Matsuo K. Clinical outcome of treatment with serine-threonine kinase inhibitors in recurrent epithelial ovarian cancer: a systematic review of literature. Expert Opinion on Investigational Drugs. July 2016. doi:10.1080/13543784.2016.1181748 · PMID 27101098 · PMC7534810
62. Other ClinicalTrialsGov NCT00329719 Sorafenib and Temsirolimus in Treating Patients With Recurrent Glioblastoma
63. Journal / agency Gounder MM, Lefkowitz RA, Keohan ML, D'Adamo DR, Hameed M, Antonescu CR, Singer S, Stout K, Ahn L, Maki RG. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clinical Cancer Research. June 2011. doi:10.1158/1078-0432.CCR-10-3322 · PMID 21447727 · PMC3152981
64. Other Sorafenib Tosylate in Treating Patients With Desmoid Tumors or Aggressive Fibromatosis
65. Journal / agency Gounder MM, Lefkowitz RA, Keohan ML, D'Adamo DR, Hameed M, Antonescu CR, Singer S, Stout K, Ahn L, Maki RG. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clinical Cancer Research. June 2011. doi:10.1158/1078-0432.ccr-10-3322 · PMID 21447727 · PMC3152981
66. Journal / agency Mangla A, Agarwal N, Schwartz G. Desmoid Tumors: Current Perspective and Treatment. Current Treatment Options in Oncology. February 2024. doi:10.1007/s11864-024-01177-5 · PMID 38270798 · PMC10873447
67. Journal / agency FDA Approval letter for use of sorafenib in advanced renal cancer
68. Other Nexavar
69. Journal / agency Nexavar (Sorafenib) Approved for Hepatocellular Carcinoma in Europe. 30 October 2007
70. Journal / agency FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma
71. Other Liver drug 'too expensive'. 19 November 2009
72. Other » Supreme Court says no to Bayer, upholds compulsory license on Nexavar
73. Other Application for Compulsory Licence Under Section 84(1) of the Patents Act, 1970 in Respect of Patent No.215758
74. Journal / agency Indian generics. Nature. 9–15 March 2012. doi:10.1038/483250a
75. Other India Patents (Amendment) Act, 2005
76. Other Chittum R. Bloomberg's viral misquote. 29 January 2014

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.