Panitumumab, a Fully Human Anti-EGFR Monoclonal Antibody, Augments Radiation Response in Xenograft Models of Upper Aerodigestive Tract Cancers
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Two anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) have been approved in Canada for the treatment of metastatic colorectal cancer (mCRC) - cetuximab, a mouse-human chimeric MoAb, and panitumumab, a fully human MoAb. This paper reviews the efficacy of the anti-EGFR monoclonal antibodies cetuximab and panitumumab - both as monotherapy and in combination with cytotoxic chemotherapy - in the treatment of mCRC. Both cetuximab and panitumumab have demonstrated clinical efficacy in monotherapy in patients with mCRC, an advantage that has recently been found to be limited largely to those with wild-type KRAS tumors. Advantages of using these agents in monotherapy include reduced cost and toxicity. While the addition of cetuximab to irinotecan has shown superior progression-free survival and response compared with cetuximab monotherapy, there is currently no evidence for a benefit of panitumumab in combination with irinotecan.
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The activation of the epidermal growth factor receptor (EGFR) pathway correlates with a worse prognosis in many solid tumours. Hence, EGFR inhibitors have been developed as a treatment for cancer. The EGFR inhibitor cetuximab has been successfully combined with radical radiotherapy in head and neck cancer. In metastatic colorectal cancer, cetuximab and panitumumab have activity as single agents, and increased response rates are achieved when added to standard chemotherapy schedules. This approach of using EGFR inhibitors has also been extrapolated to the preoperative treatment of locally advanced rectal cancer. Counterintuitively, the combination of chemotherapy, EGFR inhibitors and anti-VEGF antibodies seem to show lower response rates, suggesting antagonism. In rectal cancer, disappointingly low pathological complete response (pCR) rates have often been observed in chemoradiation regimens using EGFR inhibitors. In this study, we aimed to examine the rationale for the integration of EGFR inhibitors into chemoradiation schedules for rectal cancer. We have reviewed the clinical evidence and potential mechanisms for an interaction when EGFR inhibitors are added to fluoropyrimidine-based preoperative chemoradiation, the majority of which have used cetuximab. The primary outcome measure used was pCR. The overall pooled pCR for cetuximab-based chemoradiation was 10.71% (38/356). The rate of G3/G4 gastrointestinal toxicity, in terms of diarrhoea, varied from 5 to 30%, with an overall pooled rate of 13.8% (49/353). A better understanding of the mechanisms involved in combining chemotherapy and radiotherapy might allow more effective future scheduling of biological and chemical agents in combination with radiation.
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The treatment of metastatic colorectal cancer (mCRC) includes drugs targeting the epidermal growth factor receptor (EGFR). Mutation in codon 12 or 13 in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, downstream of the EGFR, evokes constitutive activation of the RAS/RAF/MAPK signaling pathway and correlates with resistance to anti-EGFR monoclonal antibody (mAb) therapies. However, a retrospective study reported that a proportion of patients with the KRAS G13D mutation may respond to cetuximab. A similar analysis for panitumumab was not as conclusive. We sought to determine the sensitivity of CRC cell lines to cetuximab or panitumumab treatment and to investigate the correlation of the KRAS mutational status of the CRC cell lines to the responsiveness to cetuximab or panitumumab.To determine the responsiveness of CRC cell lines to cetuximab or panitumumab, cell lines were treated with an optimized concentration of each mAb, and proliferation assays were conducted.After treatment with cetuximab or panitumumab, at the optimum concentration of 8 μg/well, the KRAS G13D mutant cell lines HCT-116, LoVo, and T84 showed intermediate sensitivity to both treatments, between the resistant KRAS G12V mutant cell line SW480 and the sensitive KRAS wild-type cell line LIM1215. One of the G13D cell lines was significantly more sensitive to panitumumab than to cetuximab (P = .02).The specific KRAS mutation determines the responsiveness to anti-EGFR monoclonal antibody treatment, corresponding to reported clinical observations.
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Panitumumab and cetuximab are monoclonal antibodies known to be effective in metastatic colorectal cancer (mCRC). Although the survival benefits when combined with chemotherapy have been determined, there are no studies comparing the two agents with chemotherapy in the second-line treatment. In this study, we aimed to compare the efficacy of cetuximab vs panitumumab in patients who previously received chemotherapy. Who progressed after first-line treatment for K-ras wild type mCRC were analyzed. The efficacy of cetuximab vs panitumumab on overall survival (OS) and progression-free survival (PFS) when combined with FOLFIRI regimen was compared retrospectively. Median PFS was 6.9 months in the cetuximab group and 4.7 months in the panitumumab group. Median OS cetuximab and panitumumab groups were 18.4 and 12.2 months, respectively. In the second-line treatment of K-ras wild type mCRC, both PFS and OS were found to be longer in patients receiving cetuximab than in patients receiving panitumumab, but no statistically significant difference was found.
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The human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, panitumumab, represents a significant advance in the treatment of colorectal cancer. The strategy to target this receptor is based on sound cancer biology demonstrating its essential role in colorectal carcinogenesis. Panitumumab, unlike its predecessor, cetuximab, is fully human and thus reduces the incidence of hypersensitivity reactions. But, in several clinical trials, unexpected toxicities have become more apparent, raising concerns of how readily panitumumab can succeed cetuximab. This paper reviews the development of this agent and the pivotal clinical trials that help our understanding of its optimal use in colorectal cancer treatment.
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Overexpression and/or amplification of the epidermal growth factor receptor (EGFR) is present in 35–45% of primary glioblastoma multiforme tumors and has been correlated with a poor prognosis. In this study, we investigated the effect of cetuximab and intracellular signaling pathways downstream of EGFR, important for cell survival and proliferation. We show insufficient EGFR downregulation and competition with endogenous EGFR ligands upon cetuximab treatment. Dose–response experiments showed inhibition of EGFR phosphorylation without affecting two of the prominent downstream signaling pathways. Our results indicate that amplification and/or overexpression of EGFR is an unsatisfactory predictor for response to cetuximab.
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in which they reported that panitumumab and cetuximab pro-vide similar overall survival and toxicity profi les as would be expected in heavily pretreated patients with colorectal cancer. Their results also showed that the incidence of grade 3 or 4 hypomagnesaemia was greater in patients receiving panitumumab than in those receiving cetuximab, although the incidence of severe skin toxicities was similar in the two groups. A meta-analysis of randomised studies that included panitumumab and cetuximab in the treatment of several cancer types showed that risk of the hypo-magnesaemia to be even higher for panitumumab than for cetuximab.
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Monoclonal antibodies to the epidermal growth factor receptor (EGFR) are among the promising novel targeted therapies being explored in colorectal cancer. Two such agents that inhibit EGFR signaling by interfering with ligand-binding are cetuximab (Erbitux) and panitumumab (Vectibix). This review will address the use of cetuximab and panitumumab in chemotherapy-refractory colorectal cancer as well as in front-line therapy for the disease, consider predictors of response and resistance, and outline comparisons between these agents.
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