Talk:Cetuximab/Archive 1

some help for non-experts required
The article is quite good in its coverage, but makes no concession to non-experts - who are after all, the people Wikipedia is supposed to be written for. I know what a HR (hazard ratio) is, and also what confidence limits are, but there's no help here if you don't know what they are. Also there are references to "first line" treatment, and so on. Insertion of Wikilinks, or better definition of technical terms would greatly improve the readability of the article for non-experts.--148.177.128.82 (talk) 08:09, 1 August 2011 (UTC)

Requested update
Hi,

My name is Carole Welsch and i am Associate Director, Personalized Heathcare at QIAGEN Inc. I would like to contribute to this page and share some recent information that will help update the Erbitux (cetuximab) Wikipedia page to make it more accurate. In July 2012, the FDA approved a companion diagnostic KRAS test for the drug Erbitux. As a consequence, the drug label was updated to require the use of an FDA approved KRAS test prior to prescribing the drug. Therefore, i would like to suggest the following addition to the existing page. For your convenience, i have also referenced each statement with third party source.

a.	In the very first section, last paragraph which currently reads: “A genetic test for the KRAS mutation was approved by the FDA as an indication for Erbitux treatment of colon cancer in July, 2009 (this also applied to the EGFR antibody panitumumab)[1] This was the first genetic test to guide treatment of cancer.[2]”

I would like to suggest adding: “In July 2012, the FDA approved a real time PCR companion diagnostic test for KRAS, the therascreen KRAS test.”

[Reference: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm312055.htm]

b.	Under the “Biomarkers” section, the last paragraph reads: “There is increasing evidence to support the use of biomarkers in predicting tumor response to treatment, as this allows therapeutic approaches to be tailored or personalized to individual patients and results in improved outcomes and survival. While there remains some scientific controversy on this (see above), assessment for EGFR expression is required for the "FDA indicated" use of cetuximab (Erbitux) in colorectal cancer, but not in head & neck cancer. Without formal FDA indication, such off-label use of EGRF antibodies is not illegal, but secondary payors often will not pay for drugs given outside of FDA indications.”

I would like to suggest adding: “Similarly, in 2012, the Erbitux drug label was updated to require the use of an FDA approved KRAS test prior to prescribing the drug to metastatic colorectal cancer patients”

[References: http://www.fiercepharma.com/story/bms-lillys-targeted-drug-erbitux-gets-new-fda-nod/2012-07-09 http://www.bloomberg.com/news/2012-07-06/bristol-myers-gets-u-s-approval-for-wider-erbitux-use.html http://packageinserts.bms.com/pi/pi_erbitux.pdf]

c.	Finally, under the “KRAS testing” section, in the paragraph which starts with “In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.[20]”

I would like to suggest adding: “In 2012, the FDA also cleared QIAGEN’s therascreen KRAS test, which is a genetic test designed to detect the presence of seven mutations in the KRAS gene in colorectal cancer cells. This test is used to aid physicians in identifying patients with metastatic colorectal cancer for treatment with Erbitux. The presence of KRAS mutations in colorectal cancer tissue indicates that the patient may not benefit from treatment with Erbitux. If the test result indicates that the KRAS mutations are absent in the colorectal cancer cells, then the patient may be considered for treatment with Erbitux.”

[Reference: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm312055.htm]

I look forward to hearing from you. Best regards,

Carole Carolewelsch (talk) 20:06, 26 November 2012 (UTC)


 * ✅ Hi Carole. Thank you for your suggestions and for disclosing your connection to QIAGEN.  Per your request, I have added your suggestions to the article, although I have edited your third suggestion for brevity.  Cheers. Boghog (talk) 13:56, 5 January 2013 (UTC)

Untitled
I was wondering what has occurred to ref [6] for this article?? — Preceding unsigned comment added by 121.218.103.135 (talk) 04:15, 6 April 2014 (UTC)

Erbitux did not work the second 8 weeks as shown in a brain MRI. The doctor moved me on to somthing else. --Transonline (talk) 13:13, 28 May 2009 (UTC)

I have been on Erbitux for 8 weeks with a weekly infusions. The rash is true and was the main side effect. I really did ok with it. With experience I could add to the main article. Experience is a good teacher. I have experience and no strong views on this. It has stopped the progress of Basal Cell. --Transonline (talk) 10:46, 25 October 2008 (UTC)

I've reverted this edit by User talk:198.177.2.15. There may be some good information there, but it reads like a copyvio. I would be happy to be proven wrong, though. --Arcadian 15:24, 18 July 2006 (UTC)

Cetuximab versus Supplement IgG / IgG1, are they different at all? Cetuximab is worth 30K $ while if you get Immunoglobulin G of a reputable supplement brand, it's dirt cheap. How are they different? —Preceding unsigned comment added by 70.134.73.2 (talk) 10:25, 9 March 2008 (UTC) Err yes. Immunogolbulin G and Cetuximab are as different as chalk and cheese irrespective of the cost differences. --Leapy99 (talk) 02:25, 5 September 2008 (UTC)

Merck's claim that Erbitux also helps in non-EGFR+ cancer not supported by COIN study: (in German) Dysmorodrepanis (talk) 13:53, 23 September 2009 (UTC)

External links modified
Hello fellow Wikipedians,

I have just added archive links to 1 one external link on Cetuximab. Please take a moment to review my edit. If necessary, add after the link to keep me from modifying it. Alternatively, you can add to keep me off the page altogether. I made the following changes:
 * Added archive https://web.archive.org/20110726180458/http://industry-news.org/2010/06/06/lillys-erbitux-fails-in-study-to-stop-colon-cancer-before-it-has-spread/ to http://industry-news.org/2010/06/06/lillys-erbitux-fails-in-study-to-stop-colon-cancer-before-it-has-spread/

When you have finished reviewing my changes, please set the checked parameter below to true to let others know.

Cheers.—cyberbot II  Talk to my owner :Online 15:10, 10 January 2016 (UTC)

Updates for the article
Hi, I have one question concerning the updates we would like to implement. There are many modifications we would like to implment like erasing outdated information and bringing in new ones. Does it makes sense to upload the whole article here in this section or should set up a new version that it is easier for you to check ? Thanks in advance br, Florian Schaub at Merck KGaA (talk) 16:21, 22 January 2016 (UTC)
 * Decline, no specific edit was requested.  Florian, please don't abuse the tag by just trying to bring attention to a question - the tag is for actual proposed edits.   You can propose content here or you can create a draft in your user space and then link to it here, as you wish. Please be mindful of WP:MEDRS and WP:INDY in the sources you choose.  Thanks. Jytdog (talk) 16:25, 22 January 2016 (UTC)

Thanks Jytdog and sorry for misusing the tag. I implemented the updated article below. We updated the content and aligned it to the latest facts. Furthermore, there is a new section caleld "RAS Testing" and the global sales picture the numbers of 2014. You will find some new references, I marked them by implementing the link. Please let me know if there are concerns or whether we are allowed to upload the updated article. Br, Florian Schaub at Merck KGaA (talk) 17:00, 1 February 2016 (UTC)


 * Hm, thanks for this. No you cannot just upload it - it needs to reviewed by an un-conflicted editor, which I am happy to do. But ....
 * this is really unworkable as you don't make clear what you changed. Would you please mark the text that is changed?  You can just make the changed text bold by putting three apostrophes in front and behind it like this -- changed text is marked.
 * Also any new citations you add - we have standards for sourcing. Health and biomedical information needs to be sourced per WP:MEDRS (briefly, sourced to a review published in good journal, or a statement by a major medical or scientific body, or the drug label.  For non-medical information you can use any reliable source (see WP:RS) but please avoid press releases or information from company websites (sources should be independent).
 * would you please format the citations you add? You can the tools described in step 5 here to format them, or use examples from the article.  For a journal article please be sure to include the PMID.
 * thanks Jytdog (talk) 01:44, 2 February 2016 (UTC)

Cetuximab
Cetuximab (INN) is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal antibody given by intravenous infusion that is distributed under the trade name Erbitux in the U.S. and Canada by the drug company Eli Lilly and company and outside the U.S. and Canada by the drug company Merck KGaA. In July 2009, the FDA approved cetuximab (Erbitux) for treatment of colon cancer with wild-type KRAS, since it had little or no effect in colorectal tumors harboring a KRAS mutation (this also applied to the EGFR antibody panitumumab)[2] This was the first genetic test to guide treatment of cancer.[3] In July 2012, the FDA approved a real time PCR companion diagnostic test for KRAS, the therascreen KRAS test.[4] In December 2013, the European Commission approved updates to the cetuximab (Erbitux) label for the treatment of patients with EGFR-expressing RAS (KRAS and NRAS genes) wild-type mCRC in Europe .[5]

Contents

 * 1 Medical uses
 * 1.1 metastatic Colorectal cancer
 * 1.2 Head and neck cancer
 * 1.3 Resistance
 * 2 Side effects
 * 3 Mechanism of action
 * 4 KRAS Testing
 * 5 RAS Testing
 * 6 Biomarkers
 * 7 History
 * 8 Society and culture
 * 8.1 Manufacture
 * 8.2 Distribution
 * 8.3 Sales
 * 8.4 Biosimilars
 * 9 References
 * 10 External links

Medical uses
Cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer (mCRC) in the U.S. and Canada,[4] and RAS wild-type mCRC in Europe[5] – in combination with chemotherapy, and as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan. The European Commission approved cetuximab for the 1st line treatment of KRAS wild-type mCRC in July 2008.[6] '''In December 2013, the European Commission approved updates to the cetuximab (Erbitux) indication for the treatment of patients with EGFR-expressing RAS (KRAS and NRAS genes) wild-type mCRC in Europe. In July 2012, the FDA approved cetuximab for 1st line use in KRAS wild-type mCRC.[7]'''

Cetuximab (Erbitux) is indicated for the treatment of patients with squamous cell carcinoma of the head and neck in combination with platinum-based chemotherapy for the 1st line treatment of recurrent and/or metastatic disease and in combination with radiation therapy for locally advanced disease. The European Commission approved this indication in December 2008.[8] In November 2011, the FDA approved cetuximab for this indication.[9]

A diagnostic immunohistochemistry assay (EGFR pharmDx) can be used to detect EGFR expression in the tumor material. Approximately 75% of patients with metastatic colorectal cancer have an EGFR-expressing tumor and are therefore considered eligible for treatment with cetuximab.[10] There is evidence that immunohistochemical EGFR receptor testing does not predict response to cetuximab, so that this has been called a "misleading biomarker" that has nevertheless caused insurers and even health systems to deny payment for EGFR antibody treatment for patients who lack a positive tumor EGFR histochemical test.[3]

Colorectal cancer
Cetuximab is approved for the treatment of patients with EGFR expressing, KRAS wild-type metastatic colorectal cancer (mCRC) in the U.S. and Canada,[4] and RAS wild-type mCRC in Europe[5] – in combination with chemotherapy or as a single agent in patients who have failed in oxaliplatin- or irinotecan- based therapy and who are intolerant to irinotecan. While there remains some scientific controversy on this, assessment for EGFR expression is required for use in colorectal cancer, but not in head and neck cancer. Many clinical trials have been conducted to investigate the efficacy of cetuximab (Erbitux) in metastatic colorectal cancer (mCRC) and there is increasing evidence to support the use of biomarkers, such as RAS (including KRAS and NRAS genes), to predict tumor response to anti-EGFR therapies.

Retrospective analyses performed on data from large clinical trials of cetuximab in patients with RAS wild-type mCRC tumors, OPUS[11] and CRYSTAL,[12] demonstrated that cetuximab plus chemotherapy significantly improves the overall response rate (ORR) to treatment, '''compared with chemotherapy alone (CRYSTAL: 66.3 vs. 38.6%, respectively [p<0.0001];  OPUS: 57.9 vs. 28.6%, respectively [p=0.0084]). In addition, CRYSTAL showed that cetuximab, plus chemotherapy significantly improved overall survival (OS) and reduced the risk of disease progression, compared with chemotherapy alone (median progression free survival [PFS]: 11.4 vs. 8.4 months, respectively [p<0.01]; median OS: 28.4 vs. 20.2 months [p=0.0024]).[12] A retrospective analysis of the phase III FIRE-3 study, demonstrated an increase in median OS from 25.0 to 33.1 months (p=0.0059) in mCRC patients with RAS wild-type tumors receiving 1st line Erbitux plus FOLFIRI, compared with patients receiving bevacizumab plus FOLFIRI. Additionally, numerical differences in ORR and PFS were observed for patients treated with Erbitux plus FOLFIRI, compared with the patients treated with bevacizumab plus FOLFIRI arm (ORR: 65.3% vs. 58.7% respectively; p=0.18; PFS: 10.3 months vs. 10.2 months, respectively; p=0.77).[13] A study published in June 2010 found that Erbitux failed to demonstrate a clinical benefit for less advanced (non-metastasized) stages of colon cancer[14] when used adjuvantly, alongside chemotherapy in patients who had undergone complete surgical resection. Erbitux potentiated the side effects of chemotherapy. Several recent studies report the following:''' A Phase III study (Nordic VII; NCT00145314) presented at the 35th Congress of the European Society for Medical Oncology (ESMO) in 2010, in Milan, Italy, demonstrated that the addition of targeted therapy cetuximab to a doublet chemotherapy regimen for first-line treatment of mCRC does not improve response rate, progression-free survival or overall survival.[15] Another Phase III study (COIN) demonstrated that cetuximab in combination with either OxMdG (a FOLFOX-like regimen) or capecitabine and oxaliplatin (XELOX) versus the same chemotherapy alone in first-line mCRC, did not meet its primary endpoint of increasing OS in KRAS wild-type patients (median OS: 17.0 vs. 17.9 months, respectively; hazard ratio 1.04 [95% confidence interval 0.87–1.23; p=0.67]).[16]

Head and neck cancer
Cetuximab was approved by the FDA in March 2006[17] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapy. '''The European Commission approved this indication in April 2006.[18] In November 2011, the FDA approved cetuximab for the treatment of patients with squamous cell carcinoma of the head and neck in combination with platinum-based chemotherapy for the 1st line treatment of recurrent and/or metastatic disease and in combination with radiation therapy for locally advanced disease.[9] The European Commission approved this indication in December 2008.[8]''' Two landmark studies have evaluated the benefits of cetuximab (Erbitux) in patients with SCCHN in both the locally advanced (Bonner trial[19]) and the recurrent and/or metastatic (EXTREME trial) settings. The EXTREME trial is the first time in 30 years that a Phase III trial has demonstrated a survival benefit in 1st-line recurrent and/or metastatic disease. The survival benefit of adding cetuximab to standard chemotherapy was almost three months.[20] The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months, and increased median overall survival from 7.4 to 10.1 months.[21] Erbitux was granted approval by the European Commission in November 2008 for the treatment of 1st-line recurrent and/or metastatic SCCHN based on the results of the EXTREME study.

Resistance
In September 2011, researchers at the Dana-Farber Cancer Institute showed that resistance to cetuximab was likely to be mediated via signalling through the HER2/neu protein - either through upregulation of protein production or overexpression of the gene.[22] This opens up the possibility that combination therapy with HER2/neu-targeting drugs such as trastuzumab or lapatinib may prove effective, although as yet this is unproven.

Side effects
One of the frequent side effects of cetuximab therapy is the incidence of skin reactions, especially acne-like rash. This rash rarely leads to dose reductions or termination of therapy but is a characteristic effect of therapy with EGFR inhibitors, such as cetuximab.[23] It is typically reversible.[13] and prophylactic measures are advised for patients to better manage the skin rash.[24] Furthermore, severe infusion related reactions have been described, these  include but are not limited to: fevers, chills, rigors, urticaria, pruritis, rash, hypotension, N/V, HA, bronchospasm, dyspnea, wheezing, angioedema, dizziness, anaphylaxis, and cardiac arrest. Therefore, pretreatment with diphenhydramine and corticosteroids 30-60 min. before administration is standard of care and required according to the EU SPC. Other common side effects include photosensitivity, hypomagnesemia due to magnesium wasting, and less commonly pulmonary and cardiac toxicity.[25]

Mechanism of action
When growth factors bind with their receptors on the surface of the tumor cell, the receptors generate a signal that triggers cell division. Some cancers are driven or sustained by receptors with aberrant activity that signal to cells to divide in the absence of growth factor stimulation. The result is uncontrollable tumor cell division. One such receptor, the EGFR, initiates a signal using the so-called MAPK intracellular pathway. The MAPK pathway contains an important protein, '''RAS. Cetuximab is a monoclonal antibody that specifically binds to EGFR and turns off the signal to RAS.''' Cetuximab blocks the signal from the EGFR receptor and turns off the uncontrolled growth of certain cancers, '''e.g. colorectal cancer, and head and neck squamous cell carcinoma. Some studies have demonstrated that the detection of EGFR expression in the tumor of a patient is not a requisite for the cetuximab activity. However, in colorectal cancer expressing RAS (both KRAS and NRAS forms) with genetic errors in the MAPK kinase pathway, cetuximab has been found not to work, because mutated RAS continuously sends a growth signal to the cancer cell, even if the EGFR has been blocked upstream by cetuximab or any anti-EGFR monoclonal antibody.''' Therefore, before cetuximab is used, the standard of care is that the RAS gene family (including KRAS and NRAS) in the cancer cells are tested for mutation. If RAS is normal (wild type), cetuximab might work. But if RAS is mutated, indications are that cetuximab (and also panitumumab) will not work, because the mutated KRAS gene continuously sends a RAS protein signal to divide, even when cetuximab has turned the earlier EGFR signal off.

KRAS Testing
The KRAS gene encodes a small G (guanine nucleotide binding) protein on the EGFR pathway. Cetuximab and other EGFR inhibitors only work on tumors that are not mutated.[26][27] KRAS mutational tests is commercially available from a number of companies. In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.[2] In 2012, the FDA also cleared a genetic test designed to detect the presence of seven mutations in the KRAS gene in colorectal cancer cells. This test is used to screen patients with metastatic colorectal cancer for treatment with Erbitux. If the test result indicates that the KRAS mutations are absent in the colorectal cancer cells, then the patient may be considered for treatment with Erbitux.[4] Studies have indicated that detection of KRAS gene mutations helps physicians identify patients that are unlikely to respond to treatment with targeted EGFR inhibitors, including cetuximab and panitumumab. Accordingly, genetic testing to confirm the absence of KRAS mutations (and so the presence of the KRAS wild-type gene), is now clinically routine before the start of treatment with EGFR inhibitors. mCRC patients with wild-type RAS tumors have been shown to benefit from a response rate of over 60% and a by over 40% decreased risk of progression and a by 30% reduced risk of death when treated with Erbitux as a 1st-line therapy.[28] Recent data suggest that around 50% of mCRC patients have the RAS wild-type gene.[29]

RAS Testing
'''RAS is a group of genes (including ‘KRAS’ and ‘NRAS’) in a tumor that may be 'wild-type', or 'mutant'. Cetuximab and other EGFR inhibitors only work on RAS tumors that are not mutated.[30] The latest research demonstrates that identification of specific molecules (biomarkers) in certain cancer types can help physicians ensure that the most appropriate treatment for the given tumor characteristics, is selected from the outset.[31] For example, genes that are involved in the EGFR signaling pathway, such as RAS, have been identified as biomarkers in mCRC.[15] Evidence suggests that anti-EGFR monoclonal antibody therapies may improve outcomes in patients with tumors that carry no RAS gene mutations, named ‘wild-type RAS’ mCRC. [11][12][32][33][34] Research into further mCRC biomarkers that are associated with other signaling pathways is ongoing. In December 2013, the European Commission approved updates to the cetuximab (Erbitux) label for the treatment of patients with EGFR-expressing RAS (KRAS and NRAS genes) wild-type mCRC in Europe.[5] RAS mutational analysis is available from a number of diagnostic centers.'''

Biomarkers
'''There is increasing evidence to support the use of biomarkers in predicting tumor response to treatment, as this allows therapeutic approaches to be tailored or personalized to individual patients and results in improved outcomes and survival. Biomarkers have played a central role in the clinical management of mCRC since 2008,[6] when it was discovered that KRAS mutations contribute to tumor development. For example, two studies have shown that patients with KRAS wild-type tumors experience significantly increased response rates and disease free survival when treated with cetuximab and standard chemotherapy (OPUS AND CRYSTAL), compared to patients receiving chemotherapy alone. Today, biomarkers in mCRC, involve testing for the ‘RAS’ family of genes (of which KRAS and NRAS are members), as these''' are indicative of response to cetuximab. Around half of patients with mCRC will have RAS wild-type expressing tumors[29] and data have shown that these patients are significantly more likely to benefit from treatment with cetuximab plus chemotherapy '''than patients whose tumors have RAS mutations. [11][12][32][33][34] However, despite the evidence highlighted above there still remains differences in license indications. In the United States cetuximab is currently approved by the FDA; it is required that an FDA-approved KRAS test is performed prior to prescribing the drug to mCRC KRAS wild-type patients.[35][36][37] However, the National Comprehensive Cancer Network clinical guidelines in the United States recommend that all patients with mCRC undergo a RAS mutation status test before a 1st line anti-EGFR therapy is prescribed.[38] While in Europe, the European Commission approved updates to the cetuximab indication for patients tested positive for EGFR-expressing RAS (KRAS and NRAS genes) wild-type mCRC in December 2013.[5]'''

History
Michael Sela Esther Pirak and co-workers published observations on EGFR inhibition in 1988.[39] Yeda Research, on behalf of the Weizmann Institute of Science in Israel,[40] challenged the Aventis-owned patent,[41] licensed by Imclone, for the use of anti-epidermal growth factor receptor antibodies in combination with chemotherapy, to slow the growth of certain tumors which was filed in 1989 by Rhone-Poulenc-Rorer.[42] The court ruled that Yeda is the sole owner of the patent in the U.S., while Yeda and Sanofi-Aventis co-own the patent's foreign counterparts.[43][44][45]

Manufacture
• Eli Lilly and Company is responsible for the manufacture and supply of Erbitux in bulk-form active pharmaceutical ingredient (API) for clinical and commercial use in the U.S. and Canada,. • Merck manufactures Erbitux for supply in its territory (outside the U.S. and Canada).[46]

Distribution
• Erbitux is marketed in the U.S. and Canada by Eli Lilly. • Outside the U.S. and Canada, Erbitux is commercialized by Merck. Eli Lilly receives royalties from Merck.

Sales
Cetuximab is given by intravenous therapy and costs up to $30,000 for eight weeks of treatment per patient.[2747] Merck had 904 million euros in Erbitux sales in 2014, from head and neck as well as bowel cancer.[48] Erbitux is in the top 10 best-selling cancer drugs of 2014:[49]

No.	2014 Global Sales INN           Trade names	      Companies	                Indications
 * 1) 	$7.55 billion,	   Rituximab,     Rituxan/MabThera,   Roche, Pharmstandard,	non-Hodgkin's lymphoma, CLL
 * 2) 	$7.02 billion,	   Bevacizumab,   Avastin,	      Roche,	                Colorectal, lung, ovarian and brain cancer
 * 3) 	$6.86 billion,	   Trastuzumab,   Herceptin,	      Roche,	                Breast, esophagus and stomach cancer
 * 4) 	$4.98 billion,	   Lenalidomide,  Revlimid,	      Celgene, Pharmstandard,	Multiple myeloma, mantle cell lymphoma
 * 5) 	$4.75 billion,	   Imatinib,      Gleevec,	      Novartis,	                Leukemia, GI cancer
 * 6) 	$3.07 billion,	   Bortezomib,    Velcade,	      Johnson & Johnson, Takeda,Pharmstandard,             Multiple myeloma
 * 7) 	$2.79 billion,	   Pemetrexed,    Alimta,	      Eli Lilly,         	Lung cancer
 * 8) 	$2.24 billion,	   Abiraterone,   Zytiga,	      Johnson & Johnson,   	Prostate cancer
 * 9) 	$1.93 billion,	   Cetuximab,	  Erbitux,	      Merck KGaA, Bristol-Myers Squibb,	Colon and head and neck cancer
 * 10) 	$1.58 billion,	   Everolimus,    Afinitor,	      Novartis,	                Kidney cancer, breast cancer, pancreatic cancer

Biosimilars
Erbitux had 2013 worldwide sales of US$1.9 billion making it a lucrative target for biosimilars developers. Additionally the patent protection for Erbitux in Europe expired in June 2014, and in the U.S. and in Japan the protection will expire in 2016.[50] However biosimilars of Erbitux are not expected until 2018.[51] Biosimilars of cetuximab in development:[52] Company name	Stage of development Actavis/Amgen, USA Developing a biosimilar in collaboration BioXpress Therapeutics, Switzerland	Biosimilar in pipeline Oncobiologics/Viropro, USA	Biosimilar in development, one of six monoclonal antibody biosimilars for which the companies are collaborating Torrent Pharmaceuticals/Reliance Life Sciences Reliance Life Sciences will manufacture the biosimilar at its facility in Navi Mumbai and supply to Torrent Pharmaceuticals[53]

References

1.	www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

2.	"Class Labeling Changes to anti-EGFR monoclonal antibodies, cetuximab (Erbitux) and panitumumab (Vectibix): KRAS Mutations". U.S. Food and Drug Administration. 2010-01-11.

3.	Messersmith WA, Ahnen DJ (October 2008). "Targeting EGFR in colorectal cancer". N. Engl. J. Med. 359 (17): 1834–6. doi:10.1056/NEJMe0806778. (PMID) 18946069.

4.	"Therascreen KRAS RGQ PCR Kit – P110030". Device Approvals and Clearances. U.S. Food and Drug Administration. 2012-07-06.

'''5.	European medicines Agency (June 2014). “Erbitux® (cetuximab) Summary of Product Characteristics (PDF).” 2015-11-19. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000558/WC500029119.pdf'''

'''6.	“Merck Receives European Approval for Broader Use of Erbitux in Metastatic Colorectal Cancer Including First-Line Treatment.” 2015-11-19. http://www.cancernetwork.com/articles/erbitux-gains-expanded-approval-europe '''

'''7.	“Cetuximab in Combination with Folfiri / Therascreen”. Approved Drugs. U.S. Food and Drug Administration. 2015-11-19. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm310933.htm '''

8.	“Merck KGaA: European Commission Approves Erbitux for First-Line Use in Head and Neck Cancer” 2015-11-16 http://www.merck.de/de/presse/extNewsDetail.html?newsId=48F85EDEAFC75F41C125750F004BDE03&newsType=1

'''9.	“Cetuximab (Erbitux).” About the Center for Drug Evaluation and Research. U.S. Food and Drug Administration. 2015-11-16.  10.	Meropol, NJ, et al (March 2005). “Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer: It's Time to Get Back on Target”. J. Clin. Oncol. 23 (9): 1791-1793. doi: 10.1200/JCO.2005.10.951. (PMID) 15677698. http://jco.ascopubs.org/content/23/9/1791.full'''

'''11.	Bokemeyer C, et al (May 2014). “Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab”. J Clin Oncol. 32:5s (Suppl; abstr 3505).'''

'''12.	Van Cutsem E, et al (January 2015). “Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Treatment and RAS Mutations in Colorectal Cancer”. J Clin Oncol. 33 (7): 692–700. (PMID) 19339720.'''

'''13.	Stintzing S et al (September 2014). “Independent Radiological Evaluation of Objective Response, Early Tumor Shrinkage, and Depth of Response in FIRE-3 (AIO KRK-0306) in the Final RAS Evaluable Population.” Ann Oncol. 25 (Suppl 5) :v1–v41. doi:10.1093/annonc/mdu438.9. http://annonc.oxfordjournals.org/content/25/suppl_4/mdu438.9.full.pdf

'''14.	“Erbitux fails to stop colon cancer before it spreads”. 2015–11–19. http://www.bloomberg.com/news/articles/2010-06-06/lilly-s-erbitux-cancer-drug-fails-to-stop-colon-tumors-from-spreading  15.	Tveit K, et al (October 2010). “Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study.” Ann Oncol. 21 (supplement 8) viii1–viii12. doi:10.1093/annonc/mdq601. http://annonc.oxfordjournals.org/content/21/suppl_8/NP.full.pdf+html'''

16.	Maughan TS, et al (June 2011). “Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.” Lancet. 77 2103–14. DOI:10.1016/S0140-6736(11)60613-2. http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736%2811%2960613-2.pdf

17.	"Cetuximab Beneficial in Head and Neck Cancer - National Cancer Institute". Cancer.gov. Retrieved 2013-04-13.

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responses
First of all, I have to apologize to you because the current state of this article, is absolutely shit. It appears to have been heavily editing by conflcted editors who don't understand how we write about drugs. I am going to work over the article over the weekend so that it complies with our policies and guidelines. and then I will consider the new notions you want to add.

A couple of notes. Please learn how we format in-line citations. All you have to do is click "edit" on the actual article and you can see how we use to create footnotes. You can just copy the source (what you see, when you click the edit button) as well and work with that. But providing citations like you did above is a huge waste of your time and the time any volunteer who wants to help you.

And please make sure that any content you propose, is actually supported by the source you provide. You cite source #5 for: "In December 2013, the European Commission approved updates to the cetuximab (Erbitux) label for the treatment of patients with EGFR-expressing RAS (KRAS and NRAS genes) wild-type mCRC in Europe." But there is no date on that source, and that document says nothing about what is new. It is just the new label, with the old and new mixed together. Do you see what I mean? I cannot read the source and find what the content says in that document. Writing a Wikipedia article is a different kind of writing. Jytdog (talk) 08:18, 19 February 2016 (UTC)

Hello,

I have marked the things in bold that have been changed. Regarding the sources I am still waiting for feedback from the responsible person.Florian Schaub at Merck KGaA (talk) 15:58, 7 March 2016 (UTC)

External links modified
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