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PubMed2004

Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.

BACKGROUND: The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan. METHODS: We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. RESULTS: The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone. CONCLUSIONS: Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.

Adenocarcinoma↗
PubMed2005

The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) overexpressed in approximately 80% of non-small cell lung cancers (NSCLC) is a target for novel therapeutics. Concurrent chemoradiation is the current standard of care for treatment of patients with locally advanced NSCLC. However, < 20% of patients remain disease-free at 5 years despite this aggressive treatment. Cetuximab is a humanized monoclonal antibody that recognizes the human EGFR, and in previous studies, inhibited the growth of EGFR-expressing human cancer cell lines. In this report, we investigated the cellular and molecular effects of cetuximab alone and in combination with radiation and/or chemotherapy in human NSCLC cell lines with varying levels of EGFR overexpression in vitro and in vivo. EXPERIMENTAL DESIGN: We evaluated the EGFR status of a panel of human NSCLC cancer cell lines by immunohistochemistry and flow cytometry. We then evaluated cetuximab effects on growth, cell cycle distribution, and downstream intracellular signaling molecules in this panel of NSCLC cancer cell lines. NSCLC cell lines were treated with cetuximab alone or in combination with radiation, chemotherapy, or chemoradiation to determine the cooperative effects of cetuximab both in vitro and in vivo in athymic nude mice bearing NSCLC xenografts. RESULTS: Cetuximab alone inhibited the in vitro growth of some but not all EGFR-expressing NSCLC cell lines in a dose-dependent manner. Flow cytometric analysis of cell cycle distribution after 24 hours of cetuximab treatment revealed a shift into the G(0)/G(1) phase of the cell cycle in cetuximab-sensitive EGFR-expressing cell lines and at concentrations that were growth-inhibitory. There were no cell cycle changes in the EGFR-negative cell lines. After 4 hours of exposure, cetuximab reduced epidermal growth factor (EGF)-induced phosphorylation of EGFR (pEGFR) and HER-2 (pHER2) in cetuximab-sensitive cell lines but not in cetuximab-resistant cell lines. Cetuximab reduced EGF-induced phosphorylation of extracellular signal-regulated kinase-1/2 (pERK) in all EGFR-expressing cell lines. In the absence of EGF, cetuximab alone increased the level of pEGFR and pHER2 above that seen in untreated control cells in both sensitive and resistant cell lines that were EGFR- and HER2-positive, but not in EGFR- or HER2-negative lines. Despite the cetuximab-induced increase in phosphorylation of EGFR and HER2, peak EGF-induced levels of pEGFR and pHER2 were reduced by cetuximab in the cetuximab-sensitive lines but not in the resistant lines. Cooperative (combination index values < 1.0) growth inhibitory effects were observed in vitro combination assays with cetuximab and radiation only in cetuximab-sensitive NSCLC cell lines. A lack of cooperation was seen in cetuximab-insensitive NSCLC cell lines. Similar findings were observed with in vitro combination studies of cetuximab plus cisplatin or paclitaxel. In nude mice bearing EGFR-expressing, cetuximab-sensitive, NSCLC cell line xenografts, cetuximab plus radiation induced a marked improvement in tumor growth inhibition over either agent alone. The growth inhibitory effects of cetuximab-radiation were similar to the growth inhibitory effects of concurrent chemoradiation. Triple combination therapy of cetuximab and chemoradiation yielded a nonsignificant advantage in tumor growth control over doublet combinations (cetuximab and radiation or chemoradiation) in vivo. CONCLUSIONS: Similar results in tumor growth inhibition observed in mice treated with cetuximab-radiation and cisplatin-radiation provide a rationale for the clinical investigation of cetuximab with concurrent radiation in selected patients with locally advanced NSCLC. Local tumor control and treatment toxicity should be evaluated between cetuximab-radiation and chemoradiation regimens. Proper patient selection will be critical to the success of such trials and further studies are needed to identify optimal patient selection criteria.

Animals↗
PubMed2005

Correlation of pharmacokinetics with the antitumor activity of Cetuximab in nude mice bearing the GEO human colon carcinoma xenograft.

PURPOSE: The epidermal growth factor receptor (EGFR), a protein tyrosine kinase expressed in many types of human cancers including colon and breast, has been strongly associated with tumor progression. Cetuximab, an IgG1 anti-EGFR chimeric mouse/human monoclonal antibody, has been proven to be effective in the treatment of advanced colon cancer. To date, there has not been a study to systematically evaluate the pharmacokinetics (PK) of Cetuximab in a preclinical model and to further explore any correlation of drug exposure between animal models and cancer patients. In the present study, we characterized the PK of Cetuximab in nude mice at efficacious dose levels and further compared the preclinical optimal dose and active plasma drug concentration with those determined in clinical studies. EXPERIMENTAL DESIGN: The antitumor activity of Cetuximab was evaluated using the GEO human colon carcinoma xenografts implanted subcutaneously in nude mice. The drug was administered ip every 3 days for five total injections (inj) (q3dx5) at dose levels ranging from 1 mg/inj to 0.04 mg/inj. The plasma PK of Cetuximab was determined at dose levels of 1.0, 0.25, and 0.04 mg/inj with a single bolus iv or ip administration in nude mice. The tumoral PK of Cetuximab was determined at dose levels of 0.25, and 0.04 mg/inj with a single bolus ip administration in nude mice bearing GEO tumor xenografts. The plasma and tumoral levels of Cetuximab were quantitated by an ELISA assay. RESULTS: Cetuximab demonstrated a dose-dependent antitumor activity at dose levels of 0.25, 0.1, and 0.04 mg/inj, with a statistically significant tumor growth delay (in reaching a tumor target size of 1 gm) of 18 days (P < 0.001), 12.3 days (P < 0.01), and 10 days (P < 0.01) for 0.25, 0.1, and 0.04 mg/inj, respectively. A separate study employing the same treatment schedule showed that Cetuximab was equally active at dose levels ranging from 0.25 mg/inj to 1 mg/inj. Therefore, dose levels of Cetuximab from 1 mg/inj to 0.04 mg/inj can be considered to be within the efficacious range, while dose levels of 0.25 mg/inj or higher appeared to be optimal for the antitumor activity of Cetuximab in the GEO tumor model. When Cetuximab was given iv to mice, the elimination half life (t(1/2)) was 39.6, 37.8, and 42.2 h for doses of 1.0, 0.25, and 0.04 mg/inj, respectively, suggesting a similar disposition kinetics of Cetuximab within this dose range. The volume of distribution (V(d)) ranged from 0.062 l/kg to 0.070 l/kg, suggesting that Cetuximab is primarily confined to the plasma compartment with limited peripheral tissue distribution. Clearance (CL) was similar and no apparent PK saturation was observed across the dose ranging from 0.04 mg/inj to 1.0 mg/inj. When mice were administered with a single bolus ip administration at doses of 1, 0.25, and 0.04 mg/inj, the maximum plasma concentration (C(max)) was 407.6, 66.4, and 16.5 microg/ml. The area under the curve of plasma drug concentration (AUC) was 19212.4, 3182.4, and 534.5 microg/ml h, for 1.0, 0.25, and 0.04 mg/inj, respectively. The average steady state plasma concentration (C(ss avg)) for the multiple dosing schedule was estimated to be 73.1 microg/ml at 0.25 mg/inj and was considered as an active plasma drug concentration. The maximum tumoral concentration of Cetuximab was 2.6 and 0.53 ng/mg-tumor while the tumoral drug exposure was 112.6 and 18.3 ng/mg h for 0.25 and 0.04 mg/inj, respectively. The EGFR was estimated to be nearly completely occupied by Cetuximab at the optimal dose of 0.25 mg/inj. CONCLUSION: In the present study, we compared the preclinical optimal dose and the corresponding active plasma concentration determined in mice with those being observed in cancer patients, i.e. 65-100 microg/ml. The preclinical optimal dose of 0.25 mg/inj was significantly lower than the current clinical dose. However, the active plasma concentration at 0.25 mg/inj is within the range of the active drug concentrations in cancer patients treated with Cetuximab under the current optimal dosing regimen. It appears that the active plasma drug concentration determined in preclinical model predicts better than the optimal preclinical dose for the clinical development of antibody drugs.

Animals↗
PubMed2005

Cetuximab: an epidermal growth factor receptor chemeric human-murine monoclonal antibody.

The epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptors. It is composed of extracellular domains, including a ligand-binding domain, a hydrophobic transmembrane region and a tyrosine kinase-containing cytoplasmic region. Stimulation of the EGFR by endogenous ligands, EGF or transforming growth factor-alpha (TGF-alpha), results in a conformational change in the receptor, permitting it to enter into dimers and other oligomers. Dimerization results in activation of intracellular tyrosine kinase, protein phosphorylation and stimulation of various cell signaling pathways that mediate gene transcription and cell cycle progression. The EGFR is expressed on normal human cells but higher levels of expression of the receptor have also been shown to be correlated with malignancy in a variety of cancers. In addition, expression of the EGFR by malignant cells is associated with poor prognosis and resistance to therapy. Cetuximab is a chimeric human-murine monoclonal antibody that binds competitively and with high affinity to the EGFR. Binding of the antibody to the EGFR prevents stimulation of the receptor by endogenous ligands and results in inhibition of cell proliferation, enhanced apoptosis, and reduced angiogenesis, invasiveness and metastasis. Binding of cetuximab to the receptor also results in internalization of the antibody-receptor complex which leads to an overall downregulation of EGFR expression. The EGFR is a prime target for new anticancer therapy, and other agents in development include small molecular tyrosine kinase inhibitors and antisense therapies. Preclinical studies have demonstrated that cetuximab reduces chemotherapy and radiotherapy resistance in human tumor cell lines in vitro and in nude mice bearing xenografts of human tumors. In clinical and preclinical studies cetuximab has been shown to induce response to treatment when used in combination with chemotherapy in patients previously refractory to chemotherapy. Based on these studies, cetuximab can be added to regimens using docetaxel, cisplatin, carboplatin, irinotecan, paclitaxel and fluorouracil and may add to treatment efficacy. Phase I dose-finding studies showed that saturation of cetuximab clearance occurred after administration of 400 mg/m2 as a loading dose followed by weekly infusions of 250 mg/m2. The most commonly reported adverse event associated with cetuximab treatment is an acneiform rash that occurs in 70-80% of patients treated with cetuximab. The rash is rarely dose- or treatment-limiting, and may diminish in intensity with continued exposure to cetuximab. Improvement may be seen after treatment with topical antibiotic preparations, topical steroids or topical retinoids. The rash resolves fully after discontinuation of cetuximab treatment. EGFR is widely expressed in skin and skin biopsies in areas involved with the characteristic cetuximab eruption demonstrate neutrophilic folliculitis. In fact, analysis of four phase II clinical trials of cetuximab in combination with chemotherapy in patients with colorectal cancer, squamous cell carcinoma of the head and neck, or pancreatic cancer showed that development of the acneiform rash was significantly correlated with response to treatment; grade 3 rash may be especially predictive of response. It is possible that development of acneiform rash may become an important clinical prognostic marker. Serious cetuximab-related toxicities include hypersensitivity, infusion reactions and interstitial lung disease. Results of a large phase II study have shown response when used in combination with irinotecan in 22.9% of patients with EGFR-expressing, irinotecan-refractory, colorectal cancer. Cetuximab has recently been approved for this indication in the United States, Switzerland, Iceland, Norway and the 25 member states of the European Union. Other phase II and III studies show significant response to treatment in variable proportions of patients with squamous cell carcinoma of the head and neck, non-small cell lung cancer and pancreatic cancer when cetuximab is used first or second line in combination with chemotherapy. Thus, cetuximab is emerging as a very promising new therapy to be used in conjunction with existing therapies for the treatment of a spectrum of solid tumors.

Animals↗
PubMed2005

Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer.

BACKGROUND: Cetuximab is a recombinant human/mouse chimeric epidermal growth factor receptor (EGFR) monoclonal antibody. It was approved by the US Food and Drug Administration in February 2004 to be used in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal cancer in patients who had failed to improve with irinotecan-based chemotherapy. Cetuximab was also approved for administration as a single agent in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are intolerant to irinotecan-based chemotherapy. OBJECTIVE: This article reviews the role of cetuximab, an EGFR monoclonal antibody, in the treatment of colorectal cancer. METHODS: A MEDLINE search was conducted of articles published from 1976 to the present using the terms cetuximab, C225, IMC-C225, colon cancer, colorectal cancer, monoclonal therapy, and target therapy. Abstracts presented at the American Society of Clinical Oncology annual meetings from 2000 to 2004 and the 2004 Gastrointestinal Cancers Symposium were reviewed and included as applicable. RESULTS: In a Phase III trial, cetuximab was administered to 329 patients with colorectal cancer who were irinotecan refractory and/or had failed to respond to oxaliplatin treatment. Partial response was achieved in 10.8% of patients who received cetuximab monotherapy and 22.9% of patients who received cetuximab plus irinotecan therapy (P = 0.007). The overall response rate in 2 Phase II trials using the conventional dosing regimen of cetuximab to treat EGFR-expressing, metastatic colorectal cancer that was refractory to irinotecan therapy ranged from 9% to 12%. The drug was well tolerated with proper administration precautions. The most common adverse events reported included acnelike rash and hypersensitivity reaction. The positive correlation of the incidence of skin reactions to response rates and median survival is one aspect that warrants further investigation in terms of its use as a response predictor. Unfortunately, the role of immunohistochemistry for EGFR expression continues to be a poor predictor of patients who may benefit from cetuximab. Clinical studies are ongoing of cetuximab in combination with radiation therapy and/or platinum in patients with squamous cell head and neck cancer, as well as cetuximab in combination with various antineoplastic agents in the treatment of non-small cell lung cancer and pancreatic cancer. CONCLUSIONS: Cetuximab has shown considerable activity-both as monotherapy and in combination with chemotherapy-in the treatment of metastatic colorectal cancer that is resistant to chemotherapy. The future of cetuximab lies in its use in combination with antineoplastic agents and/or radiation therapy in the treatment of colorectal cancer, head and neck cancer, non-small cell lung cancer, and pancreatic cancer. The lack of a predictive marker that would allow clinicians to select patients who are most likely to benefit from cetuximab therapy, especially taking into consideration the high costs of this medication, remains a challenge.

Antibodies, Monoclonal↗
PubMed2005

Anti-epidermal growth factor receptor monoclonal antibody cetuximab augments radiation effects in glioblastoma multiforme in vitro and in vivo.

OBJECTIVE: Previously, we demonstrated that the anti-epidermal growth factor receptor (EGFR) antibody cetuximab alone was effective against EGFR-amplified glioblastoma multiforme (GBM) cells in vivo and in vitro. The purpose of the present work was to study further the effectiveness of cetuximab as a monotherapy as well as combining it with radiation therapy or chemotherapy. METHODS: EGFR-amplified GBM cells were implanted either in the flanks of nude mice to determine the effectiveness of cetuximab on larger tumor burden or intracranially to assess the ability of cetuximab to cross the blood-brain barrier. Cells were also exposed to cetuximab in combination with radiation in vivo or chemotherapeutic agents in vitro. RESULTS: Increasing tumor burden in the flanks of mice decreased the amount of tumor growth inhibition. For the first two intracranial models using cetuximab for 5 weeks, the treated mice had a significant increase in median survival compared with controls. When cetuximab was given indefinitely, the results were encouraging, with an increase in median survival for the treated group not yet reached but at least 900%. Mice with flank GBM exposed to cetuximab and radiation had a larger increase in median survival than those with either treatment alone. Preliminary in vitro experiments using cetuximab and chemotherapeutic agents showed increased cytotoxicity. CONCLUSION: These results were encouraging, demonstrating the effectiveness of cetuximab against EGFR-amplified GBM. Surprisingly, cetuximab was effective when administered systemically in an intracranial model. Radiation augmented the effect of cetuximab on GBM in vitro and in vivo. In vitro analysis demonstrated additive effects for chemotherapeutic agents as well. These results confirm EGFR blockade with cetuximab as a potential treatment against human GBM.

Animals↗
PubMed2006

Cetuximab preclinical antitumor activity (monotherapy and combination based) is not predicted by relative total or activated epidermal growth factor receptor tumor expression levels.

Although Erbitux (cetuximab) has proven therapeutic benefit in the clinical setting, the molecular determinants predicting responsiveness to this agent are still not very well understood. Here, we assessed the relationship between basal total and activated (pY1068) epidermal growth factor receptor (EGFR) levels in a tumor and the responsiveness to cetuximab monotherapy or combination-based treatment using human xenograft models. Cetuximab treatment alone (0.25-1 mg/mouse/injection, q3d, i.p.) effectively delayed the growth of GEO and L2987 tumors by a minimum of 10 days corresponding to log cell kill values of >or=1.0. Borderline activity was seen in the A549 and WiDr xenografts. However, cetuximab failed to show any significant antitumor activity in the HT29, HCT116, LOVO, Colo205, LX-1, HCC70, and N87 models. All of the studied tumors had detectable yet variable levels of EGFR. For combination regimens, cetuximab (1 mg/mouse/injection, q3dx5, i.p.) and cisplatin (4.5 mg/kg/injection, q3dx5, i.v.) proved to be significantly more efficacious than individual monotherapies in the cisplatin-refractory yet cetuximab-responsive GEO tumor model (P < 0.001). However, no therapeutic enhancement was observed in the cisplatin and cetuximab weakly responsive A549 xenograft. Similarly, combinations of CPT-11 (48 mg/kg/injection, q3dx5, i.v.) with cetuximab (1 mg/mouse/injection, q3dx5, i.p.) failed to show any improvements over individual monotherapies in the cetuximab resistant/weakly responsive HT29, A549, and WiDr models. We conclude that preclinical activity associated with cetuximab monotherapy does not correlate directly with relative basal levels of total or activated (pY1068) EGFR in a tumor. Moreover, robust single-agent activity by cetuximab may be the best predictor for this agent to potentiate chemotherapy-mediated antitumor activities.

Animals↗
PubMed2007

Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma.

To evaluate the possibility of treatment with antiepidermal growth factor receptor (EGFR) mAb, Cetuximab against esophageal squamous cell carcinoma (SCC), we performed detail analysis of the antibody-dependent cellular cytotoxicity (ADCC) mediated by Cetuximab against esophageal SCC. Esophageal SCC cell lines with various levels of EGFR (n = 8) were evaluated for their Cetuximab-mediated ADCC by (51)Cr-release assay. As a result, Cetuximab was able to induce ADCC against EGFR-expressing esophageal SCC and the activities reflected the degree of EGFR expression on the esophageal SCC. The activities of Cetuximab-mediated ADCC by patients' PBMC were impaired in comparison with those by healthy donors' PBMC. Moreover, the inhibition of transforming growth factor (TGF)-beta could enhance Cetuximab-mediated ADCC against TGF-beta-producing SCC. In conclusion, Cetuximab was able to induce ADCC against EGFR-expressing esophageal SCC. Some modalities aiming at enhancing the Cetuximab-mediated ADCC may be necessary for successful Cetuximab treatment of patients with esophageal SCC.

Antibodies, Monoclonal↗
PubMed2005

Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations.

BACKGROUND: Many patients with non-small-cell lung cancer (NSCLC) who achieve radiographic responses to treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib have somatic mutations in the EGFR tyrosine kinase domain. However, little is known about the efficacy of cetuximab, an antibody against the EGFR extracellular domain, in EGFR mutant NSCLC. METHODS: NSCLC cell lines carrying wild-type EGFR (A549, H441, and H1666) or mutant EGFR (H3255, DFCILU-011, PC-9, and HCC827) were treated with various dilutions of gefitinib or cetuximab relative to maximal achievable serum concentration. Cell growth was analyzed by the MTS assay, with differences between dose-response curves analyzed nonparametrically. Apoptosis was analyzed by propidium iodide staining and immunoblotting for PARP. Phosphorylation of EGFR and the downstream signaling components ERK1/2 and Akt were analyzed by immunoblotting. Statistical tests were two-sided. RESULTS: Growth of NSCLC lines with wild-type EGFR was slightly (A549 and H441) or moderately (H1666) inhibited by gefitinib and cetuximab, and the effects of the two agents were similar. Both agents also induced no (H441) or moderate (H1666) apoptosis in NSCLC cells with wild-type EGFR. By contrast, gefitinib was statistically significantly more effective than cetuximab at inhibiting growth of EGFR mutant cells (H3255: P = .003, DFCILU-011: P = .011, and PC-9: P = .003), and gefitinib-treated EGFR mutant cells had higher levels of apoptosis than cetuximab-treated cells (mean fold increase in apoptosis by 1 microM of gefitinib and 10 microg/mL of cetuximab relative to control, H3255: 8.3 [95% confidence interval {CI} = 4.8 to 11.8] and 2.1 [95% CI = 2.0 to 2.2], respectively, P = .025; DFCILU-011: 5.7 [95% CI = 5.1 to 6.3] and. 0.9 [95% CI = 0.3 to 1.5], respectively, P < .001). Gefitinib treatment decreased EGFR, ERK1/2, and Akt phosphorylation in EGFR mutant cell lines whereas cetuximab had relatively little effect. Both gefitinib and cetuximab inhibited the growth of HCC827 cells, but gefitinib inhibited growth to a greater extent (P = .003). CONCLUSIONS: EGFR mutations in NSCLC cells are associated with sensitivity to gefitinib but not to cetuximab.

Adenocarcinoma↗
PubMed2006

Cetuximab and irinotecan interact synergistically to inhibit the growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice.

PURPOSE: Anaplastic thyroid carcinoma (ATC) remains one of the most lethal known human cancers. Targeted molecular therapy with cetuximab, a monoclonal antibody against epidermal growth factor receptor, offers new treatment potentials for patient with ATC. Cetuximab has also been reported to have synergistic effects when combined with irinotecan, a topoisomerase inhibitor. Therefore, we hypothesized that cetuximab and irinotecan would be effective in inhibiting the growth and progression of ATC in a murine orthotopic model. EXPERIMENTAL DESIGN: The in vitro antiproliferative effects of cetuximab and irinotecan on ATC cell line ARO were examined. We also studied the in vivo effects of cetuximab and irinotecan on the growth, invasion, and metastasis of orthotopic ATC tumors in nude mice. The in vivo antitumor efficacy of cetuximab/irinotecan combination was also compared with that of doxorubicin. RESULTS: Cetuximab alone did not show any antiproliferative or proapoptotic effect on this cell line. However, when combined with irinotecan, cetuximab potentiated the in vitro antiproliferative and proapoptotic effect of irinotecan. Cetuximab, irinotecan, and cetuximab/irinotecan combination resulted in 77%, 79%, and 93% in vivo inhibition of tumor growth, respectively. Incidences of lymph node metastasis, laryngeal invasion, and tumor microvessel density were also significantly decreased in these treatment groups. Furthermore, the cetuximab/irinotecan combination was significantly more effective than doxorubicin in inhibiting the growth of orthotopic ATC xenografts. CONCLUSIONS: Combination therapy with cetuximab/irinotecan inhibits the growth and progression of orthotopic ATC xenografts in nude mice. Given the lack of curative options for patients with ATC, combination therapy with cetuximab and irinotecan treatment warrants further study.

Animals↗
PubMed2006

Pharmacokinetics of cetuximab after administration of escalating single dosing and weekly fixed dosing in patients with solid tumors.

PURPOSE: Previous studies of cetuximab pharmacokinetics did not fully characterize its elimination phase. The purpose of this trial was to evaluate the pharmacokinetics of cetuximab given as a single dose followed by weekly fixed repeated dosing in patients with solid tumors. EXPERIMENTAL DESIGN: Patients were randomly assigned to treatment with a single 2-hour infusion of cetuximab at doses of 50, 100, 250, 400, or 500 mg/m2 followed 3 weeks later by weekly 1-hour infusions of cetuximab at a fixed dose of 250 mg/m2. Extended pharmacokinetic sampling was collected through 504 hours after the first drug administration. Trough samples were obtained before each fixed weekly dose. Single and multidose pharmacokinetic variables were correlated with clinical outcomes. RESULTS: Forty patients were enrolled. Pharmacokinetic analysis confirmed previous reports of nonlinear pharmacokinetics for cetuximab. Modeling studies predicted a 90% saturation of clearance at a dose of 260 mg/m2. Analyses of weekly trough concentrations indicated a slight accumulation of drug concentrations following repeated weekly dosing. Correlative studies indicated a significant association between cetuximab clearance and both body surface area (P=0.002) and weight (P=0.002). The occurrence of rash was significantly associated with disease stability (P<0.002) but not with cetuximab pharmacokinetic variables. CONCLUSIONS: Pharmacokinetic results support using body surface area or weight in calculating individual cetuximab doses. A weekly dose of 250 mg/m2 is predicted to nearly fully saturate cetuximab clearance and, by inference, epidermal growth factor receptors. The association between rash and disease stability supports further prospective studies of this relationship.

Adult↗
PubMed2005

Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry.

PURPOSE: To establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC). PATIENTS AND METHODS: Pharmacy computer records were reviewed to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first 3 months of cetuximab's commercial availability. Medical records of these patients were then reviewed to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. Pathology slides from these patients were reviewed by a reference pathologist to confirm EGFR negativity, and computed tomography scans during cetuximab-based therapy were reviewed by a reference radiologist. Response rates were reported using WHO criteria. RESULTS: Sixteen chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting were identified. Fourteen of these patients received cetuximab plus irinotecan, and two received cetuximab monotherapy. In the 16 patients, four major objective responses were seen (response rate, 25%; 95% CI, 4% to 46%). CONCLUSION: Colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by current IHC techniques does not seem to have predictive value, and selection or exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not seem warranted.

Aged↗
PubMed2005

The role of cetuximab in the treatment of squamous cell cancer of the head and neck.

The epidermal growth factor receptor (EGFR) is a member of the HER family of tyrosine kinase growth factor receptors. Binding to EGFR by its natural ligands, mainly epidermal growth factor (EGF) or transforming growth factor (TGF)-alpha, results in a conformational change in the receptor, which promotes homo- or heterodimerisation or oligomerisation with other EGFR molecules or other HER family members. Dimerisation results in the activation of intracellular tyrosine kinase, autophosphorylation and activation of signal transduction molecules, ultimately leading to cell cycle progression, reduced apoptotic capacity, angiogenesis and the metastatic phenotype. EGFR is expressed on normal human cells and also across a range of malignancies. Tumour EGFR expression correlates with poor prognosis and resistance to therapy. Cetuximab is a chimeric human:murine monoclonal antibody that binds competitively to the EGFR. Binding of the antibody to the EGFR prevents activation of the receptor by endogenous ligands; proliferation is reduced, apoptosis enhanced, and angiogenesis, invasiveness and metastasis reduced. Binding of cetuximab to the receptor also results in internalisation and degradation of the antibody-receptor complex, downregulating EGFR expression. EGFR has been recognised as an important therapeutic target in cancer. Other antibodies are also in development, and small molecular inhibitors of the tyrosine kinase domain are available. Cetuximab adds to the activity of radiotherapy in locoregional head and neck cancer, and when given with platinum-based chemotherapy is active in a proportion of patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck, as is cetuximab monotherapy. When cetuximab is added to cisplatin monotherapy in the first-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck, the objective response rate is significantly improved and the hazard ratio for progression is 0.78. The most commonly reported adverse event associated with cetuximab treatment is an acneiform rash that occurred in 70 - 80% of patients treated with cetuximab. Presence of the characteristic rash is significantly associated with response and/or survival. It is possible that development of acneiform rash may become an important clinical prognostic marker. Serious cetuximab-related toxicities include hypersensitivity reactions. Thus, cetuximab is biologically active across a range of clinical scenarios in squamous cell carcinoma of the head and neck. Ongoing studies will be important in establishing its role in the routine management of head and neck cancer.

Antibodies, Monoclonal↗
PubMed2006

The evolving role of cetuximab in non-small cell lung cancer.

Cetuximab is a monoclonal antibody directed against the ligand binding site in the extracellular domain of the epidermal growth factor receptor (EGFR). Cetuximab is currently approved for the treatment of patients with refractory colorectal cancer. In locally advanced head and neck carcinoma, cetuximab in combination with radiotherapy significantly improved survival compared with radiotherapy alone, and this treatment awaits Food and Drug Administration approval. In previously treated non-small cell lung cancer, single-agent cetuximab produced an objective response in 3 of 66 eligible patients and a median survival of 8.1 months. Treatment was well tolerated, with skin rash as the principal toxicity. The vast majority of patients (60 of 66) expressed EGFR by immunohistochemistry but no correlation existed between response and EGFR mutations. Two single-arm phase II trials testing cetuximab in combination with a platinum-based doublet in previously untreated patients showed responses in the range of 26% to 29%, with median survival times of 10 to 11 months. A European phase II randomized trial tested cisplatin/vinorelbine with or without cetuximab as first-line therapy in 86 patients with advanced non-small-cell lung cancer. Overall efficacy was slightly superior in the cetuximab arm and a phase III trial is currently ongoing to definitively determine the role of cetuximab in this setting.

Antibodies, Monoclonal↗
PubMed2006

Cetuximab-induced hypomagnesemia in patients with colorectal cancer.

BACKGROUND: Cetuximab treatment has been associated with severe hypomagnesemia, but the predisposing factors and management of this toxicity have been poorly characterized. PATIENTS AND METHODS: The charts of 114 patients with colorectal cancer treated with cetuximab were reviewed. Forty-eight evaluable patients had normal magnesium levels before initiation of cetuximab and >or=1 repeat magnesium level during cetuximab treatment. The incidence, grade, and management of hypomagnesemia were described in the evaluable population. RESULTS: Among the evaluable population, 13 patients developed grade 3/4 hypomagnesemia (27%). The incidence of grade 3/4 hypomagnesemia was 6%, 23%, and 47% in patients receiving < 3 months, 3-6 months, and > 6 months of cetuximab therapy, respectively. Grade 3/4 hypomagnesemia was refractory to oral supplementation and required daily to 3-times-weekly intravenous magnesium sulfate supplementation at 6-10 g per dose. Recovery or amelioration in hypomagnesemia occurred approximately 4 weeks after cetuximab discontinuation. CONCLUSION: Severe hypomagnesemia is a frequent side effect of cetuximab therapy. Treatment of hypomagnesemia requires frequent intravenous magnesium supplementation and can be associated with significant patient inconvenience and an increased risk of venous access-related complications. Intermittent cetuximab schedules need to be investigated in order to reduce the frequency and severity of hypomagnesemia.

Adolescent↗