Phase II Trial of Cetuximab in Patients With Refractory Colorectal Cancer That Expresses the Epidermal Growth Factor Receptor

Saltz, Leonard B.; Meropol, Neal J.; Loehrer, Patrick J.; Needle, Michael N.; Kopit, Justin; Mayer, Robert J.

doi:10.1200/jco.2004.10.182

Cited by 1,621 publications

(1,109 citation statements)

References 19 publications

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“…Among the different molecules against EGFR that have been developed, IMC-C225, directed against the extracellular domain of the receptor, inhibits EGFR ligand-binding and autocrine activation and should be promising in patients overexpressing EGFR. However, in refractory colorectal cancer, EGFR immunohistochemical overexpression, with a rate of 1% tumoral positive cells for a positive score, did not predict response to this therapy (Saltz et al, 2004). Such a scoring system may not then be entirely relevant, and the therapeutic implications due to technical procedures (especially in the assessment of EGFR status before treatment) clearly emphasise the need for consensus publications.…”

Section: Epidermal Growth Factor Receptor In Sccomentioning

confidence: 99%

“…It can be targeted by specific monoclonal antibodies, for example, IMC-C225 (Mendelsohn and Baselga, 2000), which is directed against the extracellular domain of the receptor. Phase-II and phase-III trials with this molecule have been performed in patients with progressive disease, in addition to chemotherapy, in refractory colorectal (Saltz et al, 2004), or head and neck (Trigo et al, 2004) cancers. As for HER-2, it is mostly overexpressed through gene amplification and can be targeted by a monoclonal antibody, trastuzumab, which has proved to be quite promising in metastatic breast cancer patients (Slamon et al, 2001).…”

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confidence: 99%

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Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer

et al. 2005

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Squamous cell carcinoma of the oesophagus (SCCO) is still a pathology of bad prognosis. Specific therapies are now developed against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, c-kit receptor (CD117), vascular endothelial growth factor (VEGF) and p53 protein. This study was aimed at assessing their expression in a large series of SCCO, as well as their potential therapeutic interest in this pathology. Immunohistochemical expression of these factors was assessed retrospectively in 107 cases of SCCO with primary surgery, as well as their relationships to recurrence, metastasis and overall survival on a long-term follow-up. Human epidermal growth factor receptor 2 and CD117 were expressed in less than 3% of the cases. Epidermal growth factor receptor and p53 were overexpressed in 68.2 and 66.4% of the cases, and VEGF in 38.3%. Epidermal growth factor receptor overexpression was significantly related to vascular invasion (P ¼ 0.023). Its diffuse positivity was significantly related in multivariate analysis to higher local recurrence (P ¼ 0.006) and lower overall survival (P ¼ 0.003), in a subgroup of patients of poor outcome who had received postoperative adjuvant treatment. These results highlight the great potential prognostic and therapeutic interest of evaluating EGFR diffuse positivity in locally advanced SCCO.

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Section: Epidermal Growth Factor Receptor In Sccomentioning

confidence: 99%

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confidence: 99%

Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer

et al. 2005

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“…Pertuzumab has a favorable toxicity profile and demonstrated clinical activity in a Phase I clinical trial in patients with advanced solid cancers (Agus et al, 2005b). Skin rash of grade 2 and greater (NCI-CTC) is dose dependent and occurs in 20 -50% of patients treated with EGFRdirected therapies such as gefitinib (Fukuoka et al, 2003), erlotinib (Soulieres et al, 2004) and cetuximab (Saltz et al, 2004). However, only about 1% of the patients in phase I and II studies with pertuzumab developed skin rash greater than grade 1 which did not demonstrate the rash characteristics typical for EGFR inhibitor therapy (Agus et al, 2005a, b); (S Kelsey, Genentech, personal communication).…”

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Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Laux

Jain

Singh³

et al. 2005

Br J Cancer

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Skin toxicity, a common drug-related adverse event observed in cancer patients treated with epidermal growth factor receptor (EGFR)-directed therapies is rarely seen with therapies targeting HER2. This study reports the significance of the EGFR and HER2 dimerization status in skin with regard to these dermatologic side effects. We demonstrate the differential effect of HER-directed therapies on the ligand driven activation status of EGFR, HER2 and MAPK in normal human epidermal keratinocytes. EGFR-directed therapies, such as gefitinib and cetuximab, inhibited ligand-induced activation of EGFR and MAPK in human keratinocytes. Pertuzumab, an antibody interfering with functional HER2 heterodimerization, failed to block ligand-induced HER signaling in primary keratinocytes. Using a novel proximity-based dimerization assay (eTagt) we show that EGFR homodimers are the predominant HER dimer pair in normal primary kertinocytes and in normal skin tissue from 16 patients with solid malignancies. The presence of [p]EGFR and [p]MAPK, but the absence of [p]HER2, demonstrates productive signaling via EGFR but not HER2 in human skin. These data illustrate the importance of the EGFR dimerization partner in human skin and suggests that inhibition of EGFR homodimer signaling rather than EGFR/HER2 heterodimer signaling maybe the key molecular event determining dermatologic toxicity discrepancies observed between EGFR-targeted versus HER2-targeted therapies.

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“…Toxic effects of cetuximab consist of infusion reactions and constitutional symptoms, as well as an acne-like skin rash that occurred in up to 75% of patients and was of grade 3 severity in 16% of patients. Development of this rash after treatment with cetuximab is a predictor of increased survival: the more intense the rash is, the greater the benefit is [47].…”

Section: Cetuximab (Erbitux ® )mentioning

confidence: 99%

Monoclonal antibodies as therapeutic agents in oncology and antibody gene therapy

et al. 2007

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Antibodies as therapeutic agents are mostly used in oncology, as illustrated by their applications in lymphoma, breast cancer or colorectal cancer. This review provides a brief historical sketch of the development of monoclonal antibodies for cancer treatment and summarizes the most significant clinical data for the best-established reagents to date. It also discusses strategies to improve the anti-tumor efficacy of antibody therapy, including antibody gene therapy and exploitation of bone marrow derived primary mesenchymal stem cells as the antibody gene transporter.

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Phase II Trial of Cetuximab in Patients With Refractory Colorectal Cancer That Expresses the Epidermal Growth Factor Receptor

Cited by 1,621 publications

References 19 publications

Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer

Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Monoclonal antibodies as therapeutic agents in oncology and antibody gene therapy

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