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Cancer Therapy: Clinical |
Authors' Affiliations: 1 The Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri; 2 Tennessee Oncology, The Sarah Cannon Cancer Center, Nashville, Tennessee; 3 H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; 4 Tripath Imaging, Inc., Raleigh, North Carolina; and 5 Bristol-Myers Squibb Pharmaceuticals Research Institute, Princeton, New Jersey
Requests for reprints: Christopher R. Garrett, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612-9497. Phone: 813-745-8329; Fax: 813-745-7229; E-mail: garrett{at}moffitt.usf.edu.
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Abstract |
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Experimental Design: Following a skin and tumor biopsy, patients with advanced epithelial malignancies were randomized to receive a single dose of cetuximab at 50, 100, 250, 400, or 500 mg/m2 i.v. Repeat skin (days 2, 8, 15, and 22) and tumor (day 8) biopsies were obtained. Immunohistochemical expression of epidermal growth factor receptor (EGFR) and its pathway members was done on biopsies. Blood samples were obtained over 22 days for pharmacokinetic analyses. After day 22, all patients received weekly 250 mg/m2 cetuximab until disease progression or unacceptable toxicity.
Results: Thirty-nine patients enrolled. Rash was noted in 26 (67%) patients. Three patients (two with colon cancer and one with laryngeal cancer) achieved a partial response and 13 patients had stable disease. Pharmacokinetic data revealed mean maximum observed cetuximab concentrations and mean area under the concentration-time curve from time zero to infinity increased in a dose-dependent manner up to 400 mg/m2 cetuximab. Mean clearance was similar at cetuximab doses 
100 mg/m2, supporting saturation of EGFR binding at 250 mg/m2. Pharmacodynamic evaluation revealed that patients with partial response/stable disease had a higher-grade rash and higher cetuximab trough levels than those with progressive disease (P = 0.032 and 0.002, respectively). Administration of single doses (250-500 mg/m2) of cetuximab resulted in a dose-dependent decrease in EGFR protein expression levels in skin over time, supporting a minimal dose of cetuximab at 250 mg/m2 for a pharmacodynamic effect.
Conclusion: This study provides a pharmacokinetic and pharmacodynamic rationale for the dosing of cetuximab.
leads to receptor dimerization, kinase activation, and autophosphorylation, which triggers many signaling reactions. Such stimulation can perturb the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase, and AKT pathways triggering biological responses, including cell proliferation, angiogenesis, metastases, and inhibition of apoptosis (2). Although the EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle, overexpression of EGFR is detected in many epithelial malignancies, and studies have linked expression and/or overexpression of EGFR with early disease progression, poor survival, and resistance to chemotherapy (2). Therefore, inhibition of the EGFR signal transduction pathway is a potential target for anticancer therapy.
Cetuximab (C225, Erbitux) is a chimerized monoclonal antibody of the IgG1 subclass, which blocks binding of receptor ligands, such as epidermal growth factor and transforming growth factor-, to the EGFR, thereby inhibiting ligand-induced activation of this receptor on both normal and tumor cells. Cetuximab exposure to epithelial cells in vitro results in decreased levels of VEGF and matrix metalloproteinases, inhibition of DNA repair, and a reduction in cell proliferation and differentiation. In preclinical models, cetuximab was active as a single agent but also in combination with chemotherapy prompting its study in humans (2). In early clinical studies, single-agent activity of cetuximab was shown in several carcinomas, including colorectal, head and neck, lung, and pancreatic (3–12). Monotherapy was found to be safe with the most common side effect being acneiform skin rash and less common side effects being fatigue, nausea and vomiting, diarrhea, mucositis, and hypersensitivity reactions (HSR; refs. 13, 14). Clinical studies with cetuximab revealed that combination therapy with chemotherapy or radiotherapy is active in head and neck and colorectal carcinomas leading to its approval in these diseases (10, 12, 15–17).
Despite the activity of cetuximab as a single agent or in combination with chemotherapy or radiotherapy in several malignancies, the published pharmacokinetic data describing the behavior of this agent in man are limited (13, 14, 16). Studies revealed that cetuximab administered as monotherapy or in combination with concomitant chemotherapy or radiotherapy exhibited nonlinear pharmacokinetics (13, 14). Based on preclinical studies, the optimal biological dose was defined as the dose that the EGFR was completely saturated such that maximal inhibition of tumor growth would be achieved. Early cetuximab investigators suggested that complete saturation of the EGFR binding might be associated with a plateau of the systemic clearance of antibody. This was achieved within cetuximab doses of 200 and 400 mg/m2 weekly (13, 17). At these doses, the clearance of cetuximab was similar and its half-life was estimated to be 7 days (13).
The present study was designed to do a detailed characterization of the pharmacokinetics of single administration of cetuximab over a 10-fold dose range (50-500 mg/m2) and to explore the pharmacodynamic effects of cetuximab on expression of EGFR and related downstream signaling pathways in normal skin and tumor tissue of patients with advanced malignancies.
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Patients and Methods |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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18 years of age with a life expectancy 4 months, Eastern Cooperative Oncology Group performance of 0 to 2, hemoglobin 9 g/dL, absolute granulocyte count 1,500 µL, a platelet count 100,000 µL, serum creatinine 
1.5 x upper limit of normal, aspartate aminotransferase and alanine aminotransferase 2.5 x upper limit of normal, and total bilirubin 1.5 x upper limit of normal. Prior cytotoxic or radiation therapy had to be completed at least 4 weeks before enrollment. Women of childbearing potential were required to use an acceptable nonhormonal method of contraception. Written informed consent was obtained from all patients before they were entered on to the study. This protocol was approved by the Institutional Review Boards at the participating institutions.
Treatment plan
This phase 1 pharmacokinetic/pharmacodynamic study had two phases of treatment: an open-label, randomized, single-dose phase followed by a weekly, fixed-dose, safety, and immunogenicity extension phase (Fig. 1
). Patients were randomly assigned to receive one of the five initial doses of cetuximab ranging from 50, 100, 250, 400, and 500 mg/m2 for the purpose of single-dose pharmacokinetic/pharmacodynamic evaluations. Within 24 h of starting the first infusion, patients had baseline skin and tumor biopsy specimens taken. Before each cetuximab infusion, patients received an antihistamine as a preventive measure against HSRs. Cetuximab was administered as a 2-h infusion on day 1 followed by a 21-day washout period to allow for characterization of pharmacokinetic and pharmacodynamic end points over time. On day 22, each patient received continuous weekly administrations of cetuximab at a fixed maintenance dose of 250 mg/m2, administered as a 1-h infusion. Serum samples for trough cetuximab concentration determinations were obtained for up to 10 weeks of fixed maintenance dosing (250 mg/m2). Treatment continued until disease progression or unacceptable toxicity.
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Antitumor response was evaluated by physical examination and/or imaging prestudy and every 6 weeks until documented progressive disease (PD) or study withdrawal. Responses were defined by the WHO criteria (18).
Pharmacokinetic, immunogenicity, and pharmacodynamic assessments
Pharmacokinetics. Blood samples were taken for determination of serum cetuximab concentrations on days 1 and 22 before dosing and at 1, 2 (2 min before the end of the cetuximab infusion), 2.5, 3, 4, 6, 8, 24, 48, 96, 168, 264, 336, 432, and 504 h after dosing. A blood sample was also drawn before dosing on day 22, 36, 43, etc., for a maximum of 10 samples or until the patient completed study whichever occurred first. Cetuximab concentration was determined in serum by a validated ELISA. The ELISA method used a recombinant human EGFR (extracellular domain) adsorbed onto a microtiter plate to capture cetuximab in 0.1% serum. The captured cetuximab was detected using a peroxidase-conjugated AffiniPure rabbit anti-human IgG, Fc
fragment. The assay has a calibration range of 0.475 to 14.25 µg/mL (475-14,250 ng/mL in 100% human serum), and the lower limit of quantification was determined to be 475 ng/mL. Deviations of the predicted concentrations from the nominal values for the quality control samples were within 3.7%. The inter-run and intra-run variability estimates were within 5.4% and 4.6% coefficient of variation (CV), respectively. Noncompartmental variables were calculated on cetuximab concentration-time profiles obtained following the first course of treatment using Kinetica version 2.2 (InnaPhase Corp., Philadelphia, PA).
Human anti-chimeric antibody studies. A validated double-antigen radiometric assay was done for the determination of human anti-chimeric antibodies. Cetuximab was immobilized onto polystyrene beads, which were then incubated with serum samples. [125I]cetuximab was added to the samples and the radioactivity derived from the bound [125I]cetuximab was used to calculate the results. Serum samples were obtained before the first, second, and fourth dose of cetuximab and then every 6 weeks (before the weekly infusion). A positive response was defined as a pretreatment baseline sample and at least one postinfusion sample, which was twice the baseline value in addition to being greater than the upper limit values observed in unexposed human serum (>10 ng/mL [125I]cetuximab binding).
Pharmacodynamics. Normal skin biopsies from regions that contained hair follicles were obtained in the form of a 4-mm diameter punch biopsy (8 mm depth) from either the upper thorax, the upper extremities, or the chest area before treatment with cetuximab and on days 2, 8, 15, and 22 (before the first fixed maintenance dose). Within individual patients, the anatomic location and size of the skin biopsies were consistent throughout the study. Although a percentage of skin biopsy samples were devoid of adnexal structure, if an intact epidermis was present, it was used for analysis.
Tumor samples were obtained by needle biopsy, excisional biopsy, or excision resection before the start of treatment with cetuximab and on day 8. All samples were processed by formalin fixation at each site. Sample adequacy was determined by the presence of tumor and no criteria for percentage of tumor were specified. The expression and saturation of EGFR and expression of a series of related downstream proteins [activated (phosphorylated) MAPK (p-MAPK), p27kip1, and Ki-67] was done by Genzyme Genetics (formerly IMPATH Predictive Oncology, Inc., Los Angeles, CA) in paraffin-embedded tissue using the appropriate antibodies. These antibodies included the following: EGFR (DAKO EGFr PharmDX kit, DAKO, Carpinteria, CA), phosphorylated EGFR (p-EGFR; Biosource, Invitrogen Corp., Carlsbad, CA), p-MAPK (Sigma-Aldrich Corp., St. Louis, MO), p27kip1 (NeoMarkers, LabVision Corp., Fremont, CA), and Ki-67 (DAKO). Following antibody staining, specimens were analyzed by Tripath Technology, Inc. (Raleigh, NC) for quantitative image analyses.
Pharmacodynamic activity as assessed by immunohistochemistry was quantitated by two independent methods. Standard histologic analysis was done by a pathologist in a blinded fashion. The intensity of staining was measured on a 0 to 3+ scale. Further quantitation was done by automated image analysis. To determine the amount of marker in the targeted subcellular compartment (nuclear, cytoplasmic, or membrane staining), chromogen separation of nuclear counter stain (hematoxylin) and marker positive stain (3,3'-diaminobenzidine) were done based on the respective extinction coefficients of each dye in the color channels of the 3CCD camera of the Imaging Platform (Tripath Imaging, Inc., Raleigh, NC). Following the delineation of the region of interest in the tumor area and the subcellular segmentation of the selected fields of view, the amount of specific nucleus, cytoplasmic, and membrane staining was calculated and integrated for each cell in the chromogen separated 3,3'-diaminobenzidine only image through the nucleus, cytoplasmic, and membrane masks, respectively. These measures at the cell level have been compiled at the case level to ease data mining, data analysis, and interpretation.
To guaranty the accuracy and reproducibility of the imaging system in its ability to measure the amount of specific stain in the selected region of interest, the imager (from microscope optical path to digitized captured image) was carefully calibrated and controlled. The microscope was operated in Köhler illumination mode for image acquisition allowing the use of the additive property of the Lambert-Beer law to do chromogen separation. The camera was checked for linearity and the images were corrected for shading and normalized according to the black and white references. These different calibration steps allowed measurement of the absorbance of the targeted marker within the region of interest with a CV not exceeding a few percentage intrasystem and intersystem, regardless of the position of the region of interest within the captured field of view. The accuracy of the system was further validated using filters of known spectral absorption characteristics. This imaging system has received 510 (k) clearances from the Food and Drug Administration for quantitative evaluation of estrogen receptor, progesterone receptor, Her2 (clone cb11), Ki-67, and p53 antibody staining.
Statistical analyses
Descriptive analyses on patient characteristics, toxicities, and responses have been done. Summary statistics were tabulated for the single-dose pharmacokinetic variables by dose. Mean, SDs, and CVs were calculated for the pharmacokinetic variables. Kendell's 
correlation coefficients were used to explore the relationship between rash with cetuximab trough levels, duration of drug administered, and EGFR staining intensity. Fisher's exact test was used to evaluate the association between rash and response. Mixed models have been fitted to characterize the relationship between cetuximab trough levels and degree of EGFR staining intensity with response after adjusting for the potential influence of the initial dose. Instead of comparing the measures (trough levels or staining intensity) at a single time point, mixed model approach compared the profiles of measures among response groups while accounting for possible correlations among repeated measurements within the same individual. In the analyses of trough levels and response, patients with PD were more likely to have a shorter length of stay in the study than patients with partial response (PR)/stable disease (SD), thus introducing a bias in comparing the average trough levels between response groups. Therefore, last-observation-carryover-forward method, which assumed that the trough levels remained the same for those individuals who withdraw from the study, was used to account for such a problem. A P value of 0.05 was taken to indicate significance and all the analyses were base on two-sided tests.
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Results |
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Assessments
Pharmacokinetics. Pharmacokinetic data were available for 34 of the 39 patients. Pharmacokinetic data for four patients who discontinued during the single-dose phase due to HSRs and for one patient whose serum samples were not available for analyses were not included. A summary of the cetuximab pharmacokinetic variables are presented in Figs. 2
and 3
and Table 3
. Following infusion of a single dose of cetuximab at either 50 mg/m2 (n = 7), 100 mg/m2 (n = 7), 250 mg/m2 (n = 7), 400 mg/m2 (n = 6), or 500 mg/m2 (n = 7), cetuximab serum concentrations reached a maximum at 
3 h and then declined slowly (Fig. 2). Serum concentrations of cetuximab reached baseline levels within 504 h for the majority of patients. The last measurable concentration in the 50 and 100 mg/m2 group was at approximately 96 and 168 h, respectively. Individual serum concentrations of cetuximab were quantifiable up to 504 h in the other dose groups (Fig. 2, inset).
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) increased in a generally dose-proportional manner up to 400 mg/m2 (Table 3). Mean Cmax values of 228.9 and 245.6 µg/mL and AUC0- values of 24,620 and 24,740 µg·h/mL were indistinguishable for the 400 and 500 mg/m2 dose groups, respectively. The extrapolation of AUC beyond the last quantifiable concentration did not exceed 30% for any subject. Dose-normalized individual and mean Cmax and AUC0- as a function of cetuximab dose are shown in Fig. 3A and B. Dose-normalized cetuximab exposure increased with increasing dose, an indication that at doses of cetuximab up to 400 mg/m2, exposure is greater than proportional to dose.
Mean terminal half-life (T1/2) ranged from 26.3 ± 7.4 to 94.7 ± 23.9 h across the 50 to 500 mg/m2 doses. The lower T1/2 estimates at the 50 and 100 mg/m2 doses may be due to serum concentrations of cetuximab that fall below the limit of quantification before the terminal elimination phase but are more likely due to dose-related differences in clearance. Clearance as a function of dose is shown in Fig. 3C. The mean total body clearance based on body surface area for cetuximab was similar following doses of 100 mg/m2 (range, 34.4-19.3 L/h/m2) but greater in the 50 mg/m2 dose group (65.9 L/h/m2). Dose-related differences in clearance may be due to the lack of quantifiable concentrations beyond 96 h in most of the patients receiving 50 mg/m2. Mean estimates of the volume of distribution at steady state based on body surface area ranged from 2.4, 2.2, 2.2, 2.7, and 3.1 L/m2 across the dose range (50, 100, 250, 400, and 500 mg/m2 cetuximab) and were consistent with minimal distribution of cetuximab into the extravascular space.
Human anti-chimeric antibody response. Thirty patients had baseline and posttherapy samples for determination of human anti-chimeric antibodies directed against cetuximab. Consistent with another published report (19), only one patient with colon cancer on therapy for 31 weeks exhibited a low level anti-cetuximab immune response (baseline, 6 ng/mL; two posttherapy levels, 15 and 16 ng/mL before the second and fourth doses, respectively). Four subsequent samples, each taken 6 weeks apart, returned to baseline levels.
Pharmacodynamic assessments. Pharmacodynamic data were available from 39 patients. Each patient underwent a total of seven biopsies, including five skin biopsies on days 0, 2, 8, 15, and 22 and two tumor biopsies on days 0 and 8. EGFR protein in the cytoplasm showed a dose- and time-dependent response secondary to cetuximab infusion in skin biopsies as determined by image analyses (Fig. 4 ). Marker down-regulation had a threshold effect at 250 mg/m2 and was observed across the 250 to 500 mg/m2 dose range, with a maximum effect seen on day 8 in the 400 mg/m2 dose group (Fig. 4, inset). However, a slight increase in EGFR expression was seen across the 50 to 100 mg/m2 dose range. No nuclear EGFR staining was observed.
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p27kip1 expression up-regulation was observed in skin biopsies after administration of single dose of cetuximab. However, this trend was independent of dose and exposure. The effect of cetuximab on p27kip1 in tumor biopsy samples was variable and inconclusive. Ki-67 expression seemed unaffected by single of dose cetuximab administration in both skin and tumor biopsy samples and across both dose and exposure analyses. Despite the use of several antibodies, the quality of MAPK staining by immunohistochemistry was determined to be inconsistent in both skin and tumor samples. A time-dependent down-regulation of p-MAPK was observed, although no relation to cetuximab dose or exposure was observed. Tumor expression of p-MAPK was variable.
Efficacy
Of the 39 patients entered on to this study, 6 patients discontinued during the single-dose phase and did not enter the long-term, fixed-dose phase due to either grade 3 or 4 HSR (n = 4) or disease progression (n = 2). A total of 33 patients entered the fixed-dose phase. Three patients achieved an overall response to therapy of PR and 13 patients achieved a response of SD. The overall response was PD in 17 patients. In the three patients who had a PR, two had colon cancer and one had cancer of the larynx (median, 12.1 weeks; range, 11.4-24.0 weeks). In the 13 patients whose response was SD (median, 18.0 weeks; range: 9.0-47.3 weeks), tumor types were colon cancer (n = 5), breast cancer (n = 2), and one patient each with cholangiocarcinoma, melanoma, and cancer of the head and neck, liver, ovary, and pancreas.
Several significant observations were made with respect to the correlation of response with rash, cetuximab trough levels, and EGFR staining intensity in skin. Those patients with a PR/SD tended to have a higher overall grade of rash than those with PD (56% grade 2/3 rash in PR/SD versus 29% in PD; P = 0.032), although the association between the grade of first occurrence of rash as documented by medical assessment and response was marginally significant (P = 0.053). Not unexpectedly, patients with a longer duration on study tended to have a rash with a higher overall grade, with a correlation coefficient of 0.311 (P = 0.022). Interestingly, these patients had higher grade at first rash, with correlation coefficient 0.381 (P = 0.007). There was no association between rash, cetuximab trough levels, and EGFR staining intensity in skin. Evaluation of cetuximab trough levels and response revealed, on average, patients with PR/SD response tended to have a higher trough level than those with PD (P = 0.002). In Fig. 5 , average trough concentrations of cetuximab were based on last-observation-carryover-forward, which assumes that the trough level remained the same for those individuals that withdrew from study due to PD. The difference in EGFR staining intensity in skin was not significant between response groups (PR/SD versus PD). However, the change in EGFR staining intensity in skin over time was significant for cetuximab dose levels 250 mg/m2 (P = 0.042) and 400 mg/m2 (P = 0.006).
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Discussion |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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Noncompartmental analysis of concentration-time data following a single 2-h i.v. infusion of various concentrations of cetuximab (50, 100, 250, 400, and 500 mg/m2) provided evidence of generally dose-proportional pharmacokinetics. Following infusion of a single dose of cetuximab, cetuximab serum concentrations reached a maximum at 3 h and then declined slowly over the next 22 days at dose levels above 100 mg/m2. Mean Cmax and AUC0- values increased in a dose-related manner up to 400 mg/m2 cetuximab. Estimates of systemic clearance of cetuximab were indicative of possible nonlinear elimination at doses 250 mg/m2 cetuximab. If systemic clearance of cetuximab depends on the binding of antibody to EGFR and saturation of EGFR binding is accompanied by saturation of clearance as previously proposed (13, 14), then the pharmacokinetics in this study support the dosing of cetuximab at 250 mg/m2. The decrease in estimated clearance values over the dose range was reflected in the dose-dependent estimates of T1/2. Mean T1/2 values ranged from 26.3 h (50 mg/m2) to 97.5 h (400 mg/m2) and support once a week dosing. The average trough level of patients with both PRs and SD was 60,742 ng/mL (400 nmol/L) compared with those patients with PD (33,208 ng/mL), suggesting that trough levels are important in response.
The most dramatic pharmacodynamic effects of cetuximab were noted in the skin toxicity noted by patients and on EGFR expression in skin samples. Consistent with other cetuximab studies, patients with PR and SD had a statistically significant higher overall grade of rash than those with PD (10, 15, 16, 20–23). In our study, the association between the grade of first occurrence of rash and response was marginally significant. In addition, those patients that remained longest on study because of a response to therapy had a higher grade at the first appearance of a rash. EGFR protein expression in skin biopsies decreased in a dose- and time-dependent fashion secondary to cetuximab infusion. The difference in EGFR staining intensity in skin was not significant between response groups (PR/SD versus PD), although it was significant in a larger study of patients with head and neck cancers (15). Interestingly, the change in EGFR staining intensity in skin over time was significant for cetuximab dose levels 250 and 400 mg/m2. Maximal inhibition of EGFR expression was observed on day 8 in skin biopsies from patients in the 400 mg/m2 dose group. In contrast, p-EGFR expression minimally increased in skin biopsy samples across the 50 to 500 mg/m2 dose range. We believe that several reasons account for these results. First, p-EGFR assays are inherently difficult assays to optimize due to the labile nature of phosphorylated proteins. Specimen handling is critical and particularly challenging across a multi-institutional study. Second, because p-EGFR changes are often best appreciated in hair follicles, ensuring consistent number of hair follicles within and across patients was not always done. Although recommendations on appropriate sampling were outlined in the study protocol, not all specimens contained adnexal structures. Consequently, not all specimens were "equivalent" with respect to quality. Third, establishing a robust baseline for p-EGFR staining would require multiple pretreatment skin biopsies, thus allowing for a greater accuracy in assessing pharmacodynamic effects. However, practical limitation of the study did not allow for this type of sampling. Use of Western blotting rather than immunohistochemistry may have offered a more standardized approach, but we felt the histologic context was important to maintain.
MAPK and p-MAPK are markers of EGFR downstream signaling and are components of a complex network of signal transduction pathways, all of which potentially interact to regulate the cell cycle. EGFR signaling through MAPK may exert an effect on cell cycle through Ki-67 (a nuclear proliferation-associated antigen present in proliferating cells) and p27kip1 (a cyclin-dependent kinase inhibitor). A measurable and dose-dependent effect of cetuximab on MAPK, p-MAPK, Ki-67, and p27kip1 expression may be expected after consistent inhibition of the EGFR following repeated-dose administration of cetuximab. However, considering the numerous other activators of these signal transduction proteins and their respective pathways, the inconsistent pharmacodynamic effect of single-dose administration of cetuximab on the expression of p-MAPK, Ki-67, and p27kip1 in skin samples as seen in this study may be expected.
Inconsistent findings in tumor biopsy samples were most likely due to several factors, including significant intrapatient and interpatient tumor sample heterogeneity, limited numbers of evaluable tumor samples (often small samples obtained by fine-needle aspiration or needle biopsy), and a lack of EGFR-positive status as assessed by immunohistochemistry in some tumor samples. Strict comparisons of marker expression between days 0 and 8 in tumor samples from a patient, as well as comparisons of responses within and across patient cohorts, were not possible. This is in contrast to Shin et al. (17), in which patients with head and neck cancers treated with cetuximab and cisplatin had easily accessible tumors available for larger biopsies.
An additional pharmacodynamic objective of this study was to evaluate the capacity of cetuximab to saturate the EGFR. The variable balance of EGFR degradation and production within a skin biopsy sample, along with the limitations of study design and analytic capability, left this question unanswered. Within skin, the constitutive expression of receptor and ligand may result in an unsaturable level of EGFR. In view of the fact that many EGFR-positive tumors express EGFR at much lower levels compared with skin, EGFR saturation by cetuximab in tumor may be achievable and important to its antineoplastic activity, although we could not confirm this in our study.
In summary, we examined single-dose pharmacokinetics of cetuximab across a 10-fold dose range and identified a dose effect relationship of cetuximab with EGFR in normal skin biopsies. Pharmacokinetic analyses support once a week dosing at 250 mg/m2, although higher weekly dosing was not explored. We had hoped to definitively show that pharmacodynamic changes in EGFR and its downstream pathway members in the tumors would correlate with the pharmacokinetic data. Perhaps, it is not surprising that we did not, given the small patient numbers with various malignancies, variability in tumor biopsies, choice of biomarkers, and use of immunohistochemistry as our only testing modality for these biomarkers. Given the clinical activity of cetuximab as a single agent and in combination with chemotherapy in selected patients with solid tumor malignancies, further studies now must identify the biological markers and their tests that are predictive of response to this agent.
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Acknowledgments |
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Received 6/23/06; revised 11/ 7/06; accepted 11/22/06.
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, individuals; 
, mean. B, dose-normalized area under the serum-concentration time curve (AUC0-
), where the lines represent the average trough levels based on last-observation-carryover-forward–adjusted data.