Cetuximab

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Cetuximab ?
Cetuximab.png
Monoclonal antibody
Type Whole antibody
Source Chimeric (mouse/human)
Target EGF receptor
Clinical data
Trade names Erbitux
AHFS/Drugs.com monograph
Licence data EMA:Link, US FDA:link
Legal status
Routes intravenous
Pharmacokinetic data
Half-life 114 hrs
Identifiers
CAS number 205923-56-4 YesY
ATC code L01XC06
DrugBank DB00002
UNII PQX0D8J21J YesY
KEGG D03455 YesY
ChEMBL CHEMBL1201577 N
Chemical data
Formula C6484H10042N1732O2023S36 
Mol. mass 145781.6 g/mol
 N (what is this?)  (verify)

Cetuximab (International Nonproprietary Name (INN)) is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer [1] 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 Bristol-Myers Squibb and outside the U.S. and Canada by the drug company Merck KGaA. In Japan, Merck KGaA, Bristol-Myers Squibb and Eli Lilly have a co-distribution.

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)[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]

Medical uses[edit]

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.[citation needed]

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.[citation needed]

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.[3]

Colorectal cancer[edit]

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[5] and CRYSTAL,[6] 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[7] 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[edit]

Cetuximab was approved by the FDA in March 2006[8] 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.[9] 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.[10] 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[edit]

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.[11] 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[edit]

One of the more serious side effects of cetuximab therapy is the incidence of acne-like rash. This rash rarely leads to dose reductions or termination of therapy. It is generally reversible.[12]

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. [13]

Mechanism of action[edit]

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 Testing[edit]

The KRAS gene encodes a small G protein on the EGFR pathway. Cetuximab and other EGFR inhibitors only work on tumors that are not mutated.[6][14][14]

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.[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 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.[5] Recent data suggest that around 65% of mCRC patients have the KRAS wild-type gene.[6]

Biomarkers[edit]

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.[15][16][17]

History[edit]

Ester Hurwitz, Michael Sela, and co-workers published observations in 1988.[18] Yeda Research on behalf of the Weizmann Institute of Science in Israel,[19] challenged[20] 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.[21] 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.[22][23]

Manufacture, distribution and sales[edit]

Manufacture[edit]

  • 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, and Bristol-Myers Squibb purchases the API for commercial use from Eli Lilly.
  • Merck KGaA manufactures Erbitux for supply in its territory (outside the U.S. and Canada) as well as for Japan.[24]

Distribution[edit]

  • Erbitux is marketed in the U.S. and Canada by Bristol-Myers Squibb. Eli Lilly has the option to co-promote Erbitux in the U.S. and Canada. Eli Lilly receives royalties from Bristol-Myers Squibb.
  • Outside the U.S. and Canada, Erbitux is commercialized by Merck KGaA. Eli Lilly receives royalties from Merck KGaA.
  • A separate agreement grants co-exclusive rights among Merck, Bristol-Myers Squibb and Eli Lilly in Japan and expires in 2032.[25]

Sales[edit]

Cetuximab is given by intravenous therapy and costs up to $30,000 for eight weeks of treatment per patient.[26]

Merck KGaA 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.[27]

Erbitux is under the top 10 best-selling cancer drugs of 2013:[28]

No. 2013 Global Sales INN Trade names Companies Indications
1 $7.78 billion Rituximab Rituxan/MabThera Roche, Pharmstandard non-Hodgkin's lymphoma, CLL
2 $6.75 billion Bevacizumab Avastin Roche Colorectal, lung, ovarian and brain cancer
3 $6.56 billion Trastuzumab Herceptin Roche Breast, esophagus and stomach cancer
4 $4.69 billion Imatinib Gleevec Novartis Leukemia, GI cancer
5 $1.09 billion Lenalidomide Revlimid Celgene, Pharmstandard Multiple myeloma, mantle cell lymphoma
6 $2.7 billion Pemetrexed Alimta Eli Lilly Lung cancer
7 $2.6 billion Bortezomib Velcade Johnson & Johnson, Takeda, Pharmstandard Multiple myeloma
8 $1.87 billion Cetuximab Erbitux Merck KGaA, Bristol-Myers Squibb Colon and head and neck cancer
9 $1.73 billion Leuprorelin Lupron, Eligard AbbVie and Takeda; Sanofi and Astellas Pharma Prostate and ovarian cancer
10 $1.7 billion Abiraterone Zytiga Johnson & Johnson Prostate cancer

Biosimilars of cetuximab[edit]

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.[29] However biosimilars of Erbitux are not expected until 2018.[30]

Biosimilars of cetuximab in development:[31]

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

References[edit]

  1. ^ http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  2. ^ a b "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. ^ a b 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. ^ a b "Therascreen KRAS RGQ PCR Kit – P110030". Device Approvals and Clearances. U.S. Food and Drug Administration. 2012-07-06. 
  5. ^ a b 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. 
  6. ^ a b c 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. 
  7. ^ [1][dead link]
  8. ^ "Cetuximab Beneficial in Head and Neck Cancer - National Cancer Institute". Cancer.gov. Retrieved 2013-04-13. 
  9. ^ "Cetuximab (Erbitux®) Plus Chemo Extends Survival in Advanced Head and Neck Cancer". Cancer.gov. 16 September 2008. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 8. Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically
  14. ^ a b 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. 
  15. ^ Palmer E (2012-07-09). "BMS, Lilly's targeted drug Erbitux gets new FDA nod". FiercePharma. 
  16. ^ Edney A (2012-06-12). "Bristol-Myers Gets U.S. Approval for Wider Erbitux Use -". Bloomberg. 
  17. ^ "Erbitux (cetuximab) Prescribing information highlights". Package Inserts. ImClone LLC, Eli Lilly and Company, and Bristol-Myers Squibb Company. 2012-012-01. 
  18. ^ 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. doi:10.1093/jnci/80.20.1605. PMID 3193478. 
  19. ^ "Yeda Research and Development Company Ltd". "Technology Transfer Company of the Weizmann Institute of Science" 
  20. ^ 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. 
  21. ^ 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 
  22. ^ "Court ruling on Yeda vs Aventis/Imclone case". 
  23. ^ "ImClone goes up against patent dispute". USA Today. 2006-09-14. 
  24. ^ Eli Lilly and Company Form 10-K Annual Report 2013
  25. ^ Eli Lilly and Company Form 10-K Annual Report 2013
  26. ^ 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. 
  27. ^ Merck KGaA's Erbitux beats Avastin in bowel cancer trial, Reuters, Jun 1 2013
  28. ^ Top 10 best-selling cancer drugs of 2013; May 29, 2014
  29. ^ Bristol-Myers Squibb Company 2013 Form 10-K
  30. ^ Merck Serono Investor & Analyst Day 2014 - Belen Garijo’s presentation - Slide 41 - 18 Sept 2014
  31. ^ Generics and Biosimilars Initiative (GaBI) - Biosimilars of cetuximab - 14/08/2014

External links[edit]