Cetuximab

Compound Name:CetuximabMolecular Target:EGF (Epidermal Growth Factor) receptorMolecular Structure:chimeric monoclonal antibodyLicensed Indication:metastatic colorectal cancer, head and neck cancerManufacturer and/or Distributor:Imclone & Bristol-Meyers Squibb (North America); Merck KGaA (other areas)Initial FDA Approval2004SummaryCetuximab (Erbitux) is a chimeric IgG1k monoclonal antibody directed against the epidermal growth factor receptor (EGFR; also known as ErbB-1 and Her1). EGFR is present on normal epithelial tissues, as well as human cancers such as those of the head and neck, colon and rectum. Cetuximab competitively inhibits the binding of ligands (EGF, TGFa, amphiregulin and others) to EGFR, and thereby blocks its signaling cascade. This leads to inhibition of cell growth, induction of apoptosis, and decreased pro-inflammatory cytokine and vascular growth factor production. The K-Ras gene is downstream of EGFR in the signaling cascade. Patients with a mutated K-Ras gene therefore do not respond to cetuximab, such that the presence of such mututations needs to be excluded before treating with cetuximab. The drug is administered intravenously every two weeks. Cetuximab was approved in 2004 by the FDA for the treatment of metastatic carcinomas of the colon and rectum. For this indication, it improves overall progression-free survival and preserves the quality of life in patients who have not responded to chemotherapy. The use of cetuximab to treat head and neck cancer was approved in 2011. The FDA granted in 2012 approval to cetuximab for use in combination with FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) for treatment of patients with K-ras mutation-negative, EGFR-expressing metastatic colorectal cancer. Recently presented results from CAPRI-GOIM study demonstrated the efficacy of cetuximab plus FOLFOX chemotherapy as second-line treatment for patients withmetastatic colorectal cancer. The most serious adverse reactions observed in clinical trials of cetuximab, alone or in combination with irinotecan, were infusion reactions, dermatologic toxicity, interstitial lung disease, fever, sepsis, renal dysfunction, pulmonary embolism, dehydration, and diarrhea.References

Package Insert: http://packageinserts.bms.com/pi/pi_erbitux.pdf

1. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-345.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15269313


2. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005 Dec 1;23(34):8646-8654.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16314626


3.    Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-1765.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18946061

4. Watanabe T, Kobunai T, Yamamoto Y, Matsuda K, Ishihara S, Nozawa K, et al. Heterogeneity of KRAS status may explain the subset of discordant KRAS status between primary and metastatic colorectal cancer. Dis Colon Rectum. 2011 Sep;54(9):1170-1178.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21825899


5. Peeters M, Price T. Biologic therapies in the metastatic colorectal cancer treatment continuum - Applying current evidence to clinical practice. Cancer Treat Rev. 2012 Aug;38(5):397-406.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21899955


6. Gomez D, De Rosa A, Addison A, Brooks A, Malik H, Cameron I. Cetuximab therapy in the treatment of metastatic colorectal cancer: The future frontier? International journal of surgery (London, England). 2013;11(7):507-513.

http://dx.doi.org/10.1016/j.ijsu.2013.04.014


7. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75.
http://www.ncbi.nlm.nih.gov/pubmed/25088940

8. Normanno N, Rachiglio AM, Lambiase M, Martinelli E, Fenizia F et al. Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial. Ann Oncol. 2015 Aug;26(8):1710-4. doi: 10.1093
http://www.ncbi.nlm.nih.gov/pubmed/25851630

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