Cetuximab

Cetuximab ^?

Monoclonal antibody
Type	Whole antibody
Source	Chimeric (mouse/human)
Target	EGF receptor
Clinical data
AHFS/Drugs.com	monograph
Pregnancy cat.	?
Legal status	?
Routes	intravenous
Pharmacokinetic data
Half-life	114 hrs
Identifiers
CAS number	205923-56-4 Y
ATC code	L01XC06
DrugBank	BTD00071
UNII	PQX0D8J21J Y
KEGG	D03455 Y
ChEMBL	CHEMBL1201577 N
Chemical data
Formula	C6484H10042N1732O2023S36
Mol. mass	145781.6 g/mol
N(what is this?)  (verify)

Cetuximab (IMC-C225—marketed under the name Erbitux) is a chimeric (mouse/human) monoclonal antibody, an epidermal growth factor receptor (EGFR) inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer and head and neck cancer.

Distribution

Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers Squibb, while in the rest of the world distribution is by Merck KGaA. Cetuximab is given by intravenous therapy and costs up to $30,000 for eight weeks of treatment per patient.^[1]

Indications

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 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.^{[citation needed]}

Biomarkers

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, assessment for EGFR expression is required for the use of cetuximab (Erbitux) in Colorectal Cancer, but not in Head & Neck Cancer.

Clinical uses

Colorectal cancer

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^[2] and CRYSTAL,^[3] have recently been published, and have provided further evidence that cetuximab significantly improves response rates and disease free survival 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 [1] 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^[4] 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. 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.^[5]

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. ^[6] 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 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.^[7]

As well as severe infusion reactions including but 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. ^[8]

KRAS Testing

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.^[9][10]

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.^[11]

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.^[2] Recent data suggest that around 65% of mCRC patients have the KRAS wild-type gene.^[3]

References

1. ^ 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. http://content.nejm.org/cgi/content/extract/351/4/317. 
2. ^ ^{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. 
3. ^ ^{a b} Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (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. 
4. ^ Cetuximab Beneficial in Head and Neck Cancer - National Cancer Institute
5. ^ [http://www.cancer.gov/clinicaltrials/results/summary/2007/cetuximab-head-neck0607
6. ^ Yonesaka, K.; Zejnullahu, K.; Okamoto, I.; Satoh, T.; Cappuzzo, F.; Souglakos, J.; Ercan, D.; Rogers, A. et al. (2011). "Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab". Science Translational Medicine 3 (99): 99ra86–99ra86. doi:10.1126/scitranslmed.3002442. ISSN 1946-6234. 
7. ^ 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. ^ 8. Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically
9. ^ http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34491
10. ^ Cetuximab and chemotherapy as initial treatment for metastatic colorecal cancer, Eric Van Cutsem, et all, N Engl J Med 360:1408
11. ^ OncoGenetics.Org (July 2009). "FDA updates Vectibix and Erbitux labels with KRAS testing info". OncoGenetics.Org. http://www.oncogenetics.org/web/fda-updates-vectibix-and-erbitux-labels-with-kras-testing-info. Retrieved 2009-07-20. ^{[dead link]}

External links

• 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
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