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Cetuximab (Erbitux) 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 manufactured and distributed in the United States by the drug companies Bristol-Myers Squibb and Eli Lilly and Company and in Europe by the drug company Merck KGaA.
In July 2009, the FDA approved Erbitux for treatment of KRAS wild type colon cancer, since Cetuximab had little or no effect in colorectal tumors harboring a KRAS mutation (this also applied to the EGFR antibody panitumumab) This was the first genetic test to guide treatment of cancer. In July 2012, the FDA approved a real time PCR companion diagnostic test for KRAS, the therascreen KRAS test.
Cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer (mCRC), 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 positive opinion from the European regulatory agency, the Committee for Medicinal Products for Human Use (CHMP), was received for mCRC 1st line use in May 2008.
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 positive CHMP opinion for this indication was received in October 2008.
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 or panitumumab, according to FDA guidelines. Unfortunately, there is evidence that immunohistochemical EGFR receptor testing does not predict response to either cetuximab or panitumumab, 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.
Cetuximab is indicated for the treatment of patients with EGFR expressing, KRAS wild-type metastatic colorectal cancer in combination with chemotherapy or as a single agent in patients who have failed in oxaliplatin- or irinotecan- base 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 & 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 KRAS, to predict tumor response to anti-EGFR therapies. Two large clinical trials of cetuximab, OPUS and CRYSTAL, have recently been published, and have provided further evidence that cetuximab significantly improves the odds of a response to treatment and in one study, reduced the risk of disease progression. However, cetuximab did not significantly affect overall survival (OS) rates in mCRC patients with KRAS wild-type tumors.
A study in June 2010 found that Erbitux failed to benefit patients with less advanced (non-metastasized) stages of colorectal cancer with no improvement in survival rates. Adding Erbitux instead increased the side effects of chemotherapy. Several recent studies showed:
Adding the targeted drug cetuximab to a three-drug chemotherapy regimen for first-line treatment of metastatic colorectal cancer does not improve response rate, progression-free survival or overall survival, researchers reported at the 35th Congress of the European Society for Medical Oncology (ESMO) in Milan, Italy
A second Phase III study (COIN) of cetuximab in combination with capecitabine and oxaliplatin versus chemotherapy alone in first-line mCRC, did not meet its primary endpoint of overall survival in K-ras wild type patients (17 months vs. 17.9 months; HR 1.038; 95% CI 0.90 - 1.20; p=0.68).
Head and neck cancer
Cetuximab was approved by the FDA in March 2006 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.
Two landmark studies have evaluated the benefits of cetuximab (Erbitux) in patients with SCCHN in both the locally advanced (Bonner trial) 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. 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. 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.
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. 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.
Further severe infusion reactions 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 30-60 min. before administration is standard of care. Other common side effects include photosensitivity, hypomagnesemia due to magnesium wasting, and less commonly pulmonary and cardiac toxicity. 
Mechanism of action
When growth factors bind to their receptors on the surface of the cell, the receptors give a signal that causes cells to divide. Some cancers are caused by mutated receptors that give a signal to divide even without growth factor. That causes the cells to divide uncontrollably. Cetuximab binds to such receptors and turns off that signal.
The EGFR sends a signal down a pathway (see MAPK) that includes another protein, KRAS (also spelled K-ras). In some cancers, the EGFR is mutated, and is present to a larger or smaller degree. In these cancers, the KRAS protein may either be "wild type" or mutated. If mutated, KRAS sends a signal to divide uncontrollably, even if EGFR has been blocked by cetuximab.
Cetuximab binds to EGFR and turns off the uncontrolled growth in cancers with EGFR mutations (although in practice, studies have shown that the effect of cetuximab does not actually depend on the amount of EGFR receptor protein found on the cancer cells). However, if the KRAS protein is mutated, cetuximab has been found not to work, because the mutated KRAS gene downstream is causing the problem by continuously sending a growth signal (the KRAS protein) and this mutated gene now does not respond to the EGFR receptor.
Therefore, before cetuximab is used, the standard of care is that the KRAS gene in the cancer cells is tested for mutation. If KRAS is normal (wild type), cetuximab might work. But if KRAS is mutated, indications are that cetuximab (and also panitumumab) will not work, because the mutated KRAS gene continuously sends a KRAS protein signal to divide, even when cetuximab has turned the earlier EGFR signal off.
KRAS mutational analysis is commercially available from a number of laboratories.
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. 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.
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 KRAS tumors have been shown to benefit from a response rate of over 60% and a decreased risk for progression of over 40% when treated with Erbitux as 1st-line therapy. Recent data suggest that around 65% of mCRC patients have the KRAS wild-type gene.
In mCRC, biomarkers, including KRAS, are indicative of response to cetuximab (Erbitux). 60% of patients express the KRAS wild-type tumor and data have shown that these patients are significantly more likely to benefit from treatment with cetuximab or a combination of cetuximab plus chemotherapy. Two recent studies demonstrated that patients with KRAS wild-type tumors demonstrated significantly increased response rates and disease free survival when treated with cetuximab and standard chemotherapy (OPUS AND CRYSTAL), compared to patients receiving chemotherapy alone.
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 EGFR antibodies is not illegal, but secondary payors often will not pay for drugs given outside of FDA indications. 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.
Joseph Schlessinger, Michael Sela, and co-workers published observations in 1988. Yeda Research on behalf of the Weizmann Institute of Science in Israel, challenged the Aventis-owned patent, 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. The court ruled that Yeda is sole owner of the patent in the U.S., while Yeda and Sanofi-Aventis co-own the patent's foreign counterparts.
Cetuximab is manufactured and distributed in North America by Bristol-Myers Squibb and Eli Lilly and Company. ImClone is a wholly owned subsidiary of Lilly. In the rest of the world distribution is by Merck KGaA.
Merck had 887 million euros ($1.15 billion) in Erbitux sales in 2012, from head and neck as well as bowel cancer, while Bristol-Myers Squibb generated $702 million in sales from the drug.
- "Class Labeling Changes to anti-EGFR monoclonal antibodies, cetuximab (Erbitux) and panitumumab (Vectibix): KRAS Mutations". U.S. Food and Drug Administration. 2010-01-11.
- 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.
- "Therascreen KRAS RGQ PCR Kit – P110030". Device Approvals and Clearances. U.S. Food and Drug Administration. 2012-07-06.
- Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (February 2009). "Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer". J. Clin. Oncol. 27 (5): 663–71. doi:10.1200/JCO.2008.20.8397. PMID 19114683.
- Van Cutsem E, et al. (April 2009). "Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer". N. Engl. J. Med. 360 (14): 1408–17. doi:10.1056/NEJMoa0805019. PMID 19339720.
- [dead link]
- "Cetuximab Beneficial in Head and Neck Cancer - National Cancer Institute". Cancer.gov. Retrieved 2013-04-13.
- "Cetuximab (Erbitux®) Plus Chemo Extends Survival in Advanced Head and Neck Cancer". Cancer.gov. 16 September 2008.
- Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (September 2008). "Platinum-based chemotherapy plus cetuximab in head and neck cancer". N. Engl. J. Med. 359 (11): 1116–27. doi:10.1056/NEJMoa0802656. PMID 18784101.
- Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli, et al. (September 2011). "Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab". Sci Transl Med 3 (99): 99ra86. doi:10.1126/scitranslmed.3002442. PMC 3268675. PMID 21900593.
- Nguyen A, Hoang V, Laquer V, Kelly KM (December 2009). "Angiogenesis in cutaneous disease: part I". J. Am. Acad. Dermatol. 61 (6): 921–42; quiz 943–4. doi:10.1016/j.jaad.2009.05.052. PMID 19925924.
- 8. Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically
- Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH (July 2012). "Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials". Eur. J. Cancer 48 (10): 1466–75. doi:10.1016/j.ejca.2012.02.057. PMID 22446022.
- Palmer E (2012-07-09). "BMS, Lilly's targeted drug Erbitux gets new FDA nod". FiercePharma.
- Edney A (2012-06-12). "Bristol-Myers Gets U.S. Approval for Wider Erbitux Use -". Bloomberg.
- "Erbitux (cetuximab) Prescribing information highlights". Package Inserts. ImClone LLC, Eli Lilly and Company, and Bristol-Myers Squibb Company. 2012-012-01.
- Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M. (1988-12-21). "Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice". J Natl Cancer Inst. 80 (20): 1605–11. PMID 3193478.
- "Yeda Research and Development Company Ltd". "Technology Transfer Company of the Weizmann Institute of Science"
- Groombridge N, Gearing BP (February 2008). "Practical lessons from a "made for TV" patent litigation: The trial of Yeda Research & Development Co. Ltd. v. ImClone Systems Inc. and Aventis Pharmaceuticals Inc.". The Federal Lawyer: 51–55.
- US patent 6217866, Sela M, Pirak E, Hurwitz E, "Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same", published 2001-04-17, assigned to Yeda Research & Development
- "Court ruling on Yeda vs Aventis/Imclone case".
- "ImClone goes up against patent dispute". USA Today. 2006-09-14.
- Schrag, D (July 2004). "The price tag on progress – chemotherapy for colorectal cancer". New England Journal of Medicine 351 (4): 317–319. doi:10.1056/NEJMp048143. PMID 15269308.
- Merck KGaA's Erbitux beats Avastin in bowel cancer trial, Reuters, Jun 1 2013
- FDA Erbitux (cetuximab) Information Page
- Erbitux site from Bristol-Myers Squibb, ImClone Systems, and Merck KGaA
- Anti EGFreceptor monoclonals and small molecules on the web
- HighBeam: Amgen licenses patent after Yeda court win over ImClone
- List of clinical labs performing KRAS mutation analysis
- KRAS information
- KRAS mutation testing information for clinical labs
- esmo.org, retrieves nothing January 2013
- Mixed results for cetuximab (Erbitux™) in first-line treatment of metastatic colorectal cancer.