Sorafenib

Last updated

Sorafenib
Sorafenib2DACS.svg
Sorafenib 3D 3gcs.png
Clinical data
Trade names Nexavar, others
Other namesSorafenib tosylate
AHFS/Drugs.com Monograph
MedlinePlus a607051
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 38–49%
Protein binding 99.5%
Metabolism Liver oxidation and glucuronidation (CYP3A4 & UGT1A9-mediated)
Elimination half-life 25–48 hours
Excretion Feces (77%) and urine (19%)
Identifiers
  • 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]
    phenoxy]-N-methyl-pyridine-2-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.110.083 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H16ClF3N4O3
Molar mass 464.83 g·mol−1
3D model (JSmol)
  • CNC(=O)c1cc(ccn1)Oc2ccc(cc2)NC(=O)Nc3ccc(c(c3)C(F)(F)F)Cl
  • InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)
  • Key:MLDQJTXFUGDVEO-UHFFFAOYSA-N
   (verify)

Sorafenib, sold under the brand name Nexavar, [3] 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.

Contents

Mechanism of action

Sorafenib is a protein kinase inhibitor with activity against many protein kinases, including VEGFR, PDGFR and RAF kinases. [4] [5] Of the RAF kinases, sorafenib is more selective for c-Raf than B-RAF. [6] (See BRAF (gene)#Sorafenib for details the drug's interaction with B-Raf.)

Sorafenib treatment induces autophagy, [7] 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. [8]

Medical uses

Sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinomas (HCC) and thyroid cancer. [9] [1] [10] [11]

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). [12]

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. [11] [13]

Liver cancer

At ASCO 2007, results from the SHARP trial [14] 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. [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 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. [5]

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. [15]

In Australia this is the only indication for which sorafenib is listed on the PBS and hence the only government-subsidised indication for sorafenib. [13] Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib. [11]

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. [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]

Adverse effects

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

Common (1-10% frequency)

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, [20] and received European Commission marketing authorization in July 2006, [21] 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, [22] and FDA approval for this indication followed in November 2007. [23]

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. [24] In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS 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$3,400). Natco Pharma will sell 120 tablets for ₹8,800 (US$110), while still paying a 6% royalty to Bayer. The royalty was later raised to 7% on appeal by Bayer. [25] [26] [27] 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. [28]

Society and culture

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). [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 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. [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]

See also

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. 1 2 3 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

Related Research Articles

<span class="mw-page-title-main">Hepatocellular carcinoma</span> Medical condition

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.

<span class="mw-page-title-main">Everolimus</span> Chemical compound

Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours.

<span class="mw-page-title-main">Sunitinib</span> Cancer medication

Sunitinib, sold under the brand name Sutent, is an anti-cancer medication. It is a small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) in January 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications.

<span class="mw-page-title-main">Tremelimumab</span> Monoclonal antibody

Tremelimumab, sold under the brand name Imjudo, is a fully human monoclonal antibody used for the treatment of hepatocellular carcinoma. Tremelimumab is designed to attach to and block CTLA-4, a protein that controls the activity of T cells, which are part of the immune system.

Pazopanib, sold under the brand name Votrient, is an anti-cancer medication marketed worldwide by Novartis. It is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide.

<span class="mw-page-title-main">Axitinib</span> Chemical compound

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

Ramucirumab is a fully human monoclonal antibody (IgG1) developed for the treatment of solid tumors. This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.

<span class="mw-page-title-main">Lenvatinib</span> Chemical compound

Lenvatinib, sold under the brand name Lenvima among others, is an anti-cancer medication for the treatment of certain kinds of thyroid cancer and for other cancers as well. It was developed by Eisai Co. and acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2 and VEGFR3 kinases.

Regorafenib, sold under the brand name Stivarga among others, is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Since 2009 it was studied as a potential treatment option in multiple tumor types. By 2015 it had two US approvals for advanced cancers.

<span class="mw-page-title-main">Tivozanib</span> Medication

Tivozanib, sold under the brand name Fotivda, is a medication used for the treatment of advanced renal cell carcinoma. It is an oral VEGF receptor tyrosine kinase inhibitor.

<span class="mw-page-title-main">Cabozantinib</span> Chemical compound

Cabozantinib, sold under the brand names Cometriq and Cabometyx among others, is an anti-cancer medication used to treat medullary thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. It is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and also inhibits AXL and RET. It was discovered and developed by Exelixis Inc.

JX-594 is an oncolytic virus is designed to target and destroy cancer cells. It is also known as Pexa-Vec, INN pexastimogene devacirepvec) and was constructed in Dr. Edmund Lattime's lab at Thomas Jefferson University, tested in clinical trials on melanoma patients, and licensed and further developed by SillaJen.

Onyx Pharmaceuticals Inc. has been a biopharmaceutical company headquartered in South San Francisco, California. The company developed and marketed medicines for the treatment of cancer. Onyx was founded in 1992 by Kevin J. Kinsella and Frank McCormick Ph.D., FRS. McCormick served as the chief scientific officer until 1998, while Kinsella was the firm's chairman. In 2009, the company acquired Proteolix, Inc., a private biotechnology company, for $276 million in cash plus additional milestone payments. In January 2012, the company was named "the top biotechnology takeover target in 2012" through an industry survey. Onyx president and chief executive officer (CEO) Tony Coles had said that Onyx liked its prospects as an independent company and was focused on bringing new therapies to patients. However, at the end of August 2013, Amgen announced it was acquiring Onyx in an agreed $10.4 billion deal.

<span class="mw-page-title-main">Brivanib alaninate</span> Chemical compound

Brivanib alaninate (INN/USAN) also known as BMS-582664 is an investigational, anti-tumorigenic drug for oral administration. The drug is being developed by Bristol-Myers Squibb for the treatment of hepatocellular carcinoma or HCC, the most common type of liver cancer. Brivanib is no longer in active development.

<span class="mw-page-title-main">Nivolumab</span> Anticancer medication

Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction cancer. It is administered intravenously.

Resminostat is an orally bioavailable inhibitor of histone deacetylases (HDACs), of which inhibitors are antineoplastic agents.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq among others, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

<span class="mw-page-title-main">Abemaciclib</span> Anti-breast cancer medication

Abemaciclib, sold under the brand name Verzenio among others, is a medication for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6.

<span class="mw-page-title-main">Erdafitinib</span> Chemical compound

Erdafitinib, sold under the brand name Balversa, is an anti-cancer medication. It is a small molecule inhibitor of fibroblast growth factor receptor (FGFR) used for the treatment of cancer. FGFRs are a subset of tyrosine kinases which are unregulated in some tumors and influence tumor cell differentiation, proliferation, angiogenesis, and cell survival. Astex Pharmaceuticals discovered the drug and licensed it to Janssen Pharmaceuticals for further development.

VEGFR-2 inhibitor, also known as kinase insert domain receptor(KDR) inhibitor, are tyrosine kinase receptor inhibitors that reduce angiogenesis or lymphangiogenesis, leading to anticancer activity. Generally they are small, synthesised molecules that bind competitively to the ATP-site of the tyrosine kinase domain. VEGFR-2 selective inhibitor can interrupt multiple signaling pathways involved in tumor, including proliferation, metastasis and angiogenesis.

References

  1. 1 2 "Nexavar (sorafenib) tablet, film coated [Bayer HealthCare Pharmaceuticals Inc.]". DailyMed. Bayer HealthCare Pharmaceuticals Inc. November 2013. Archived from the original on 20 September 2015. Retrieved 26 December 2013.
  2. ↑ "Nexavar EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 14 October 2021. Retrieved 18 September 2022.
  3. ↑ "FDA Approves Nexavar for Patients with Inoperable Liver Cancer" (Press release). FDA. 19 November 2007. Archived from the original on 2 January 2017. Retrieved 10 November 2012.
  4. ↑ 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". Molecular Cancer Therapeutics. 7 (10): 3129–3140. doi: 10.1158/1535-7163.MCT-08-0013 . PMID   18852116.
  5. 1 2 3 Keating GM, Santoro A (2009). "Sorafenib: a review of its use in advanced hepatocellular carcinoma". Drugs. 69 (2): 223–240. doi:10.2165/00003495-200969020-00006. PMID   19228077.
  6. ↑ Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, et al. (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.
  7. ↑ Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X (January 2014). "Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways". Molecular Medicine Reports. 9 (1): 83–90. doi: 10.3892/mmr.2013.1781 . PMID   24213221.
  8. ↑ Singh N, Hammock B (30 March 2020). "Soluble Epoxide Hydrolase". In Offermanns S, Rosenthal W (eds.). Encyclopedia of Molecular Pharmacology. Springer, Cham. doi:10.1007/978-3-030-21573-6. hdl:10138/346042. ISBN   978-3-030-21573-6. S2CID   171511522.
  9. ↑ "Nexavar (sorafenib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 27 December 2013. Retrieved 26 December 2013.
  10. ↑ "Nexavar 200mg film-coated tablets - Summary of Product Characteristics (SPC) - (eMC)". electronic Medicines Compendium. Bayer plc. 27 March 2013. Archived from the original on 27 December 2013. Retrieved 26 December 2013.
  11. 1 2 3 "PRODUCT INFORMATION NEXAVAR (sorafenib tosylate)" (PDF). TGA eBusiness Services. Bayer Australia Ltd. 12 December 2012. Archived from the original on 14 January 2016. Retrieved 26 December 2013.
  12. ↑ Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. (January 2007). "Sorafenib in advanced clear-cell renal-cell carcinoma". The New England Journal of Medicine. 356 (2): 125–134. doi: 10.1056/NEJMoa060655 . PMID   17215530.
  13. 1 2 "Pharmaceutical Benefits Scheme (PBS) -SORAFENIB". Pharmaceutical Benefits Scheme. Australian Government Department of Health. Archived from the original on 27 December 2013. Retrieved 27 December 2013.
  14. 1 2 Llovet 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. CiteSeerX   10.1.1.531.1130 . doi:10.1056/NEJMoa0708857. PMID   18650514.
  15. ↑ 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". Journal of Clinical Oncology. 29 (30): 3960–3967. doi:10.1200/JCO.2011.37.1021. PMC   4829081 . PMID   21911714.
  16. ↑ "FDA Approval for Sorafenib Tosylate". National Cancer Institute. 5 October 2006. Archived from the original on 6 April 2015. Retrieved 27 November 2013.
  17. ↑ "ASCO: Sorafenib Halts Resistant Thyroid Cancer". www.medpagetoday.com. 4 June 2013. Archived from the original on 23 March 2021. Retrieved 21 December 2018.
  18. ↑ "Chemotherapy-Induced Nausea and Vomiting Treatment & Management". Medscape Reference. WebMD. 3 July 2012. Archived from the original on 27 December 2013. Retrieved 26 December 2013.
  19. ↑ Hagopian B (August 2010). "Unusually Severe Bullous Skin Reaction to Sorafenib: A Case Report". Journal of Medical Cases. 1 (1): 1–3. doi: 10.4021/jmc112e .
  20. ↑ "FDA Approval letter for use of sorafenib in advanced renal cancer" (PDF). Archived (PDF) from the original on 30 March 2021. Retrieved 19 November 2009.
  21. ↑ "Nexavar". Enterprise and Industry. European Commission. Archived from the original on 1 February 2008. Retrieved 24 April 2007.
  22. ↑ "Nexavar (Sorafenib) Approved for Hepatocellular Carcinoma in Europe" (Press release). Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. 30 October 2007. Archived from the original on 6 February 2012. Retrieved 10 November 2012.
  23. ↑ "FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma" (PDF). Archived (PDF) from the original on 31 March 2021. Retrieved 19 November 2009.
  24. 1 2 "Liver drug 'too expensive'". BBC News. 19 November 2009. Archived from the original on 11 September 2017. Retrieved 10 November 2012.
  25. ↑ "» Supreme Court says no to Bayer, upholds compulsory license on Nexavar". Archived from the original on 17 February 2015.
  26. ↑ "Application for Compulsory Licence Under Section 84(1) of the Patents Act, 1970 in Respect of Patent No.215758" (PDF). Controller of Patents Mumbai. Archived from the original (PDF) on 21 March 2012. Retrieved 2 April 2012.
  27. ↑ "Indian generics". Nature. 483 (7389): 250–1. 9–15 March 2012. Bibcode:2012Natur.483..250.. doi: 10.1038/483250a .
  28. ↑ "India Patents (Amendment) Act, 2005". WIPO. Archived from the original on 16 January 2013. Retrieved 16 January 2013.
  29. ↑ Chittum R (29 January 2014). "Bloomberg's viral misquote". Columbia Journalism Review. Archived from the original on 10 February 2021. Retrieved 12 September 2019.
  30. ↑ Chustecka Z (25 April 2008). "Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients". MedScape. Archived from the original on 29 August 2021. Retrieved 29 October 2010.
  31. ↑ Ciccone MA, Maoz A, Casabar JK, Machida H, Mabuchi S, Matsuo K (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. PMC   7534810 . PMID   27101098. S2CID   28717797.
  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, et al. (June 2011). "Activity of Sorafenib against desmoid tumor/deep fibromatosis". Clinical Cancer Research. 17 (12): 4082–4090. doi:10.1158/1078-0432.CCR-10-3322. PMC   3152981 . PMID   21447727.
  34. ↑ "Sorafenib Tosylate in Treating Patients With Desmoid Tumors or Aggressive Fibromatosis". Clinicaltrials.gov. Archived from the original on 13 November 2014. Retrieved 12 November 2014.
  35. ↑ Gounder MM, Lefkowitz RA, Keohan ML, D'Adamo DR, Hameed M, Antonescu CR, et al. (June 2011). "Activity of Sorafenib against desmoid tumor/deep fibromatosis". Clinical Cancer Research. 17 (12): 4082–4090. doi:10.1158/1078-0432.ccr-10-3322. PMC   3152981 . PMID   21447727.
  36. ↑ Mangla A, Agarwal N, Schwartz G (February 2024). "Desmoid Tumors: Current Perspective and Treatment". Current Treatment Options in Oncology. 25 (2): 161–175. doi: 10.1007/s11864-024-01177-5 . PMC   10873447 . PMID   38270798.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.