Cetuximab for the Treatment of Colorectal Cancer

University of Ottawa, Ottawa, Ontario, Canada
New England Journal of Medicine (Impact Factor: 54.42). 11/2007; 357(20):2040-8. DOI: 10.1056/NEJMoa071834
Source: PubMed

ABSTRACT Cetuximab, an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor (EGFR), has activity against colorectal cancers that express EGFR.
From December 2003 to August 2005, 572 patients who had colorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin or had contraindications to treatment with these drugs underwent randomization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care (287 patients) or best supportive care alone (285 patients). The primary end point was overall survival.
In comparison with best supportive care alone, cetuximab treatment was associated with a significant improvement in overall survival (hazard ratio for death, 0.77; 95% confidence interval [CI], 0.64 to 0.92; P=0.005) and in progression-free survival (hazard ratio for disease progression or death, 0.68; 95% CI, 0.57 to 0.80; P<0.001). These benefits were robust after adjustment in a multivariable Cox proportional-hazards model. The median overall survival was 6.1 months in the cetuximab group and 4.6 months in the group assigned to supportive care alone. Partial responses occurred in 23 patients (8.0%) in the cetuximab group but in none in the group assigned to supportive care alone (P<0.001); the disease was stable in an additional 31.4% of patients assigned to cetuximab and in 10.9% of patients assigned to supportive care alone (P<0.001). Quality of life was better preserved in the cetuximab group, with less deterioration in physical function and global health status scores (both P<0.05). Cetuximab treatment was associated with a characteristic rash; a rash of grade 2 or higher was strongly associated with improved survival (hazard ratio for death, 0.33; 95% CI, 0.22 to 0.50; P<0.001). The incidence of any adverse event of grade 3 or higher was 78.5% in the cetuximab group and 59.1% in the group assigned to supportive care alone (P<0.001).
Cetuximab improves overall survival and progression-free survival and preserves quality-of-life measures in patients with colorectal cancer in whom other treatments have failed. ( number, NCT00079066 [].).

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Available from: Timothy J Price, Jul 30, 2015
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    • "Neoplasia Vol. 15, No. 10, 2013 Sym004 Can Overcome Resistance to Cetuximab Iida et al. 1203 Discussion EGFR is one of the most highly targeted receptors in oncology due to its frequent overexpression and aberrant activation in numerous cancers. The anti-EGFR mAb therapy cetuximab is a Food and Drug Administration–approved treatment for mCRC [21] and HNSCC [22] and has shown efficacy in other tumor types such as NSCLC [23] [24]. While cetuximab has demonstrated clinical success, both intrinsic and acquired resistance is commonly observed. "
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    ABSTRACT: The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many patients treated with cetuximab don't respond or eventually acquire resistance. To determine how tumor cells acquire resistance to cetuximab, we previously developed a model of acquired resistance using the non-small cell lung cancer line NCI-H226. These cetuximab-resistant (Ctx(R)) cells exhibit increased steady-state EGFR expression secondary to alterations in EGFR trafficking and degradation and, further, retained dependence on EGFR signaling for enhanced growth potential. Here, we examined Sym004, a novel mixture of antibodies directed against distinct epitopes on the extracellular domain of EGFR, as an alternative therapy for Ctx(R) tumor cells. Sym004 treatment of Ctx(R) clones resulted in rapid EGFR degradation, followed by robust inhibition of cell proliferation and down-regulation of several mitogen-activated protein kinase pathways. To determine whether Sym004 could have therapeutic benefit in vivo, we established de novo Ctx(R) NCI-H226 mouse xenografts and subsequently treated Ctx(R) tumors with Sym004. Sym004 treatment of mice harboring Ctx(R) tumors resulted in growth delay compared to mice continued on cetuximab. Levels of total and phospho-EGFR were robustly decreased in Ctx(R) tumors treated with Sym004. Immunohistochemical analysis of these Sym004-treated xenograft tumors further demonstrated decreased expression of Ki67, and phospho-rpS6, as well as a modest increase in cleaved caspase-3. These results indicate that Sym004 may be an effective targeted therapy for Ctx(R) tumors.
    Neoplasia (New York, N.Y.) 10/2013; 15(10):1196-206. DOI:10.1593/neo.131584 · 5.40 Impact Factor
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    • "Amongst the most well established of these are the monoclonal antibodies cetuximab and panitumumab, which target the EGFR. Cetuximab has been shown to have efficacy both as monotherapy and in combination with chemotherapy for patients with pretreated metastatic CRC [Cunningham et al. 2004; Jonker et al. 2007; Saltz et al. 2004; Sobrero et al. 2008; Souglakos et al. 2007]. However, the situation is less clear in the first-line setting. "
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    ABSTRACT: Advances in the treatment of metastatic colorectal cancer have led to an improvement in survival from 12 months with fluorouracil monotherapy to approximately 2 years. This is partly as a result of the addition of irinotecan and oxaliplatin, but is also due to the use of monoclonal antibodies against the epidermal growth factor receptor (EGFR) and antiangiogenic drugs such as bevacizumab. However, there are significant molecular differences between tumours which can affect both prognosis and response to treatment. Personalized medicine aims to tailor treatment according to the characteristics of the individual patient and is now a clinical reality as testing for KRAS mutations to guide treatment with the anti-EGFR monoclonal antibodies cetuximab and panitumumab is now part of routine clinical practice. However, not all patients who are KRAS wild type respond to anti-EGFR therapy and a validated biomarker for antiangiogenic therapy is still lacking. Therefore, other biomarkers are needed to assist with predicting response to both existing drugs as well as to drugs currently under investigation. This review summarizes the molecular biology of colorectal cancer, focusing on the genetic features that are currently most clinically relevant. Current and emerging biomarkers are reviewed along with their roles in selecting patients for targeted treatment with currently licensed therapies and drugs being evaluated in clinical trials. The value of predictive biomarkers of chemosensitivity and potential future treatment strategies are also discussed.
    Therapeutic Advances in Gastroenterology 09/2013; 6(5):381-95. DOI:10.1177/1756283X13491797
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    • "0.62 10.3 [9–11.1] – – Overall response rate (% [95% CI]) 8 [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] 9 [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] 0.85 4 [1] [2] [3] [4] [5] [6] [7] [8] [9] – – first-and second-line treatment with doublet regimens or even in first-line treatment with triplet regimens. The third-line therapy can be anticipated in a multiline therapeutic strategy (Table 1). "
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    ABSTRACT: Colorectal cancer is the third most common cancer, with recent advances in the management of unresectable metastatic lesions. The aim of this review is to discuss the remaining options for heavily pretreated patients with unresectable metastatic colorectal cancer. Beyond second-line treatment, two epidermal growth factor receptor (EGFR) inhibitors, cetuximab and panitumumab, have a demonstrated clinical interest in patients with KRAS wild-type tumours. However, few data exist in patients pretreated with an anti-EFGR and who are being rechallenged with anti-EGFR drugs. Reintroduction of chemotherapy should be considered. In September 2012, regorafenib, a multi-kinase inhibitor was approved by the US Federal Drug Administration for patients refractory to other standard treatments. In the case of metastases limited to the liver, transarterial chemoembolization, hepatic artery infusion and radioembolization could also be discussed in selected patients. With the multiplication of therapeutic options in first-line, second-line treatment, and beyond, the concept of subsequent lines of chemotherapy should be replaced by a multiline strategy, dependent on the patient and on tumour biology. A better understanding of the tumour biology and predictive factors for the response to these therapies is needed, and further strategic trials are urgently warranted.
    Digestive and Liver Disease 08/2013; 46(2). DOI:10.1016/j.dld.2013.07.002 · 2.89 Impact Factor
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