The EGFR is composed of four extracellular domains, a hydrophobic transmembrane region, a juxta-membrane domain, an intracellular protein tyrosine kinase domain. It is monomeric in inert state, but binding of a ligand results in conformational change which promotes homo- and hetero-dimerization and activates signal transduction.
High EGFR expression is also associated with resistance to radiation. In contrast to cytoplasmic signaling induced by EGF, radiation prompts nuclear EGFR translocation. This process is associated with a nuclear influx of proteins Ku70/80 and phosphatase 1, a surge in nuclear DNA-PK activity, and formation of DNA end-binding protein complexes containing DNA-PK, which performs a major role in repairing radiation-induced DNA double strand-breaks through a non-homologous end-joining mechanism. (6)
The concept that inhibiting EGFR might have antitumor activity was presented in 1980s. Mendelsohn et al. provided the first pre-clinical demonstration of an antiproliferative effect of monoclonal antibodies directed against EGF-binding site. Since then, numerous EGFR inhibitors are studied. (7)
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Cetuximab is a recombinant, human/mouse chimeric IgG1 monoclonal antibody that attaches to epidermal growth factor receptor (EGFR, HER1, ErbB-1) on its extracellular domain .It competitively inhibits epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha (TGF-α) from binding to EGFR.
Attachment of cetuximab to the epidermal growth factor receptor halts phosphorylation and activation of receptor-associated kinases, leading to cell growth inhibition. It prevents EGFR from adopting the conformation needed for dimerization, also barrs EGFR from inducing autocrine ligand production, it downregulates the expression of matrix metalloproteinases and vascular endothelial growth factor production, thereby promotes endothelial cell apoptosis and vasculature collapse (8) .It also induces an antibody-dependent cellular toxicity(9) .
Cetuximab also increases radiosensitivity as EGFR blockade abolishes nuclear EGFR import, diminishes radiation-induced activation of DNA-PK, inhibits DNA repair, and enhances cellular radiation sensitivity .(6)
NICE has approved Cetuximab along with radiotherapy as a treatment choice for patients with locally advanced squamous cell cancer of the head and neck .Only those patients can have cetuximab who exhibit 90% or more Karnofsky performance-status score and for them all other types of platinum-based chemoradiotherapy treatment are contraindicated.
NICE has recommended Cetuximab based on evidence from Bonner Trial .Bonner Trial was a Randomized Control Trial which compared cetuximab with radiotherapy versus radiotherapy alone in patients with stage III or IV non-metastatic SCCHN. Only those patients were included in the trial that exhibit at least 60% Karnofsky performance-status score, were medically suitable for definitive radiotherapy, and have normal hepatic, renal and hematopoietic functions. The primary endpoint was the duration in which locoregional disease was controlled. The secondary outcomes were overall survival, progression-free survival, response rate and safety.
The trial demonstrated that the 211 patients in the cetuximab plus radiotherapy arm had a prolonged median duration of locoregional control than the 213 patients in the radiotherapy-alone arm (24.4 against 14.9 months, P = 0.005, hazard ratio 0.68, 95% confidence interval is 0.52 to 0.89) and greater median overall survival (49.0 months against 29.3 months, P = 0.03, hazard ratio 0.74, 95% confidence interval is 0.57 to 0.97). (10)
The longest survival ever documented in patients with recurrent / metastatic cancer of head and neck has been reported from EXTREME Trial. In EXTREME Trial Cetuximab was added to first-line platinum-based chemotherapy with fluorouracil. The Trial recruited 442 patients .One third of patients had cancer in the oral cavity , nearly half of them had metastatic disease, and most of patients had already received treatment in form of radiotherapy (77% - 80%) and chemotherapy (36% - 41%).Cetuximab considerably prolonged the median overall survival (7.4 versus 10.1 months -in chemotherapy-alone arm against the arm that received chemotherapy and cetuximab together ) .Hazard ratio for death was 0.80; 95% confidence interval was 0.64 to 0.99; and P = 0.04). The median progression-free survival improved from 3.3 to 5.6 months (hazard ratio for progression was 0.54 and P<0.001) also response rate was increased from 20% to 36% (P<0.001) due to the addition of cetuximab.
The most common grade 3 or 4 toxicities in the chemotherapy-alone versus cetuximab arms were neutropenia (23% and 22% respectively), anemia (19% and 13%), and thrombocytopenia (11% in both arms). Sepsis was documented in 9 patients in the cetuximab arm and in only one patient in the chemotherapy-alone arm (P = 0.02). Among 219 patients who received cetuximab, 9% of patients exhibited grade 3 skin reactions and 3% of them experienced grade 3 or 4 infusion-related reactions. There were no deaths reported due to cetuximab. (11)
The 5-year survival data from BONNER Trial is also available now, which has demonstrated that for patients with locally advanced Squamous cell cancer of head and neck, cetuximab along with radiotherapy reasonably improves overall survival at 5 years as compared to radiotherapy alone. In BONNER Trial Patients were randomly selected. 211 patients received radiotherapy with cetuximab and 213 received radiotherapy without cetuximab, and all patients were followed for survival. The median overall survival for patients who received cetuximab with radiotherapy was 49·0 months (95% confidence interval 32·8 to 69·5) versus 29·3 months (95% confidence interval 20·6 to 41·4) in the radiotherapy-alone arm .The hazard ratio was 0·73, and 95% confidence interval was 0·56 to 0·95; P = 0·018). In the cetuximab-plus-radiotherapy arm the 5-year overall survival was 45·6% versus 36·4% in the radiotherapy-alone arm. Interestingly for the patients who received cetuximab, the overall survival was considerably improved if they exhibited an acne form rash of at least grade 2 severity as compared to patients with no rash or grade 1 rash (hazard ratio 0·49, 95% confidence interval 0·34 to 0·72; P =0·002). (12)
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Cetuximab is licensed in USA and Europe for use in combination with platinum-based chemotherapy, for treating patients with recurrent / metastatic Squamous cell cancer of head and neck based on EXTREME Trial. On the other hand in 2009 the SMC in Scotland and NICE in England decided not to recommend cetuximab for this group of patients under NHS.
NICE should reconsider its decision regarding Cetuximab based on EXTREME Trial as it has shown that cetuximab is the first systemic therapy in 25 years to exhibit a survival advantage over platinum-based chemotherapy in head and neck cancer. Cetuximab is generally well-tolerated drug, and it did not increase the side effects which are associated with platinum based therapy. 5 year survival data from the BONNER Trial also goes in favor of cetuximab.
Pao et al has shown that patients who initially respond to epidermal growth factor receptor inhibitors may become unresponsive afterwards (13) .Recent research has demonstrated that prolonged exposure to cetuximab leads to deregulation of epidermal growth factor receptor processing which in turn cause activation of HER2, HER3, cMET, MAPK and Akt. This resistance accumulated against cetuximab may be a result of activation of Receptor Tyrosine Kinases, like HER2 and HER3, which share overlapping signaling circuits. (14) .Based on these findings we should explore novel combinations of molecularly targeted therapies inhibiting both epidermal growth factor receptor and other HER family member receptors to overcome acquired resistance and complement the effectiveness of EGFR-targeted therapy