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ERBITUX (Cetuximab) | Health and Medical Directory healthexcite.com | patients' adverse reactions to... mesotheliomaweb.org | FDA APPROVES ERBITUX? (CETUXIMAB) FOR TREATMENT OF spohnc.org |
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.
[edit] DevelopmentThis agent is based on Dr. John Mendelsohn's 1980s hypothesis that monoclonal antibodies against EGFR could block receptor activation. Cetuximab was developed by Dr. Esther Pirak, Dr. Esther Hurwitz, and Prof. Michael Sela, one of the developers of Copaxone, of the Weizmann Institute of Science, Rehovot, Israel, as a chimeric human-mouse monoclonal antibody which was derived from the original anti-EGFR mouse monoclonal antibody 225 generated by Dr. Mendelsohn. [edit] DistributionCetuximab 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 costs approximately €4,300 for eight weeks of treatment per patient. It is given by intravenous therapy and costs up to $30,000 for eight weeks of treatment per patient.[1] [edit] IndicationsCetuximab 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. Cetuximab (Erbitux) is indicated for the treatment of patients with squamous cell cancer 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 (SPC). [edit] BiomarkersIn 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. [edit] Clinical uses[edit] Colorectal cancerCetuximab 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. It is best to refer to updated Prescription Information. 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 significant improves response rates and disease free survival rates in mCRC patients with KRAS wild-type tumors. [edit] Head and neck cancerCetuximab 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. [edit] Side effectsOne of the side effects of Cetuximab therapy is the incidence of, possibly severe, acne-like rash. This rash rarely leads to dose reductions or termination of therapy. It is generally reversible after treatment is finished and may also be associated with a good response to therapy. 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, hypomagnesaemia due to magnesium wasting, and less commonly pulmonary and cardiac toxicity. [5] [edit] KRAS TestingThe 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][7] 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.[8] 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] [edit] References
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