Annals of Oncology Advance Access originally published online on March 13, 2006
Annals of Oncology 2006 17(6):1007-1013; doi:10.1093/annonc/mdl042
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© 2006 European Society for Medical Oncology
A phase I study of the humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody EMD 72000 (matuzumab) in combination with paclitaxel in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC)
1 Department of Hematology/Oncology, University of Tuebingen, 72076 Tuebingen, Germany; 2 Division of Medical Oncology, British Columbia Cancer Agency - Vancouver Cancer Center, Vancouver, Canada; 3 Merck KGaA, Darmstadt; 4 Department of Oncology, Hematology, Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Germany
* Correspondence to: Dr C. Bokemeyer, Department of Oncology/Hematology, Bone Marrow Transplantation, University Medical Center Hamburg Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Tel: +49-40-42803-2960; Fax: +49-40-42803-8054; E-mail: c.bokemeyer{at}uke.uni-hamburg.de
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Abstract |
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Background: Epidermal growth factor receptor (EGFR) is overexpressed in 80%–90% of non-small-cell lung cancer (NSCLC). Matuzumab, a humanized immunoglobulin G1 (IgG1) anti-EGFR monoclonal antibody, blocks activation of EGFR. Paclitaxel and EGFR inhibitors have additive antitumour effects in vitro. This phase I study assessed the tolerability, pharmacokinetics and efficacy of the combination of matuzumab and paclitaxel in patients with advanced NSCLC.
Materials and methods: Eighteen chemotherapy-naïve (n = 9) or pretreated (n = 9) patients with stage IIIB or IV EGFR-positive NSCLC received weekly doses of matuzumab (100, 200, 400 or 800 mg) followed by paclitaxel 175 mg/m2 every 3 weeks. Toxicity was evaluated weekly and pharmacokinetics were measured during cycles 1 and 2.
Results: The maximum planned matuzumab dose of 800 mg was achieved without reaching the maximum tolerated dose. Grade 4 neutropenia occurred in one of three patients at 800 mg but resolved within 1 week; five additional patients treated with 800 mg had no dose-limiting toxicity (DLT). Grade 1/2 acneiform skin rash in 14 patients was the most frequent matuzumab-related side-effect. There were no higher-grade adverse events. Grade 2 toxicities included pruritus (n = 2), bronchospasm (n = 1), fissures (n = 1), abdominal pain (n = 1) and hot flushes (n = 1). Paclitaxel was discontinued in four patients due to allergic reactions. Coadministration of paclitaxel did not alter matuzumab pharmacokinetics. Responses occurred in four of 18 patients and included one complete response.
Conclusions: Matuzumab doses up to 800 mg weekly with paclitaxel 175 mg/m2 every 3 weeks are well tolerated, with no apparent drug interactions and with evidence of antitumor activity.
Key words: EMD 72000, matuzumab, lung cancer, paclitaxel, phase I
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introduction |
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Patients with inoperable advanced or metastatic non-small-cell lung cancer (NSCLC) possess a poor prognosis, with 5-year survival rates being less than 5% following combination chemotherapy [1
]. The development of new treatment strategies for these patients remains an important objective of clinical research. The new treatments, which include molecularly targeted therapy directed at the epidermal growth factor receptors (EGFRs), have been tested in several cancer types, including advanced NSCLC. The EGFR pathway appears to contribute to a number of processes important to cancer development and progression, including cell proliferation, apoptosis, angiogenesis and metastatic spread [2, 3]. The presence of the EGFR is typical for several epithelial malignancies, and in approximately 80%–90% of patients with NSCLC an overexpression of EGFR can be found within the tumors [4]. Receptor tyrosine kinases not only serve as therapeutic targets but may also offer prognostic information for the clinical course of the subject and may be involved in the development of chemotherapy resistance [2, 5]. For example, results of in vitro experiments suggest a relationship between the overexpression of EGFR and HER2-neu and a resistance to cisplatin and paclitaxel [6, 7]. In addition, amplification and overexpression of either HER2-neu or EGFR are correlated with an unfavorable outcome in patients with metastatic breast, ovarian, esophageal and lung cancers [8–10]. Inhibition of the EGFR pathway has enhanced the antitumor activity of paclitaxel in EGFR-positive cell lines [11, 12].
Different strategies have been developed to target the EGFR. Receptor activation can be blocked by monoclonal antibodies such as cetuximab, which binds to the extracellular domain of EGFR. In contrast, small-molecule tyrosine kinase inhibitors, such as gefitinib or erlotinib, selectively and competitively inhibit receptor tyrosine kinase activity by blocking the adenosine triphosphate binding site within the tyrosine kinase domain [13–15]. Four studies of small molecule tyrosine kinase inhibitors combined with chemotherapy performed in an unselected NSCLC patient population have been reported negative. No randomized study using monoclonal antibodies has yet been reported. Antibodies appear to differ from small molecules with regards to pharmacokinetic and pharmacodynamic characteristics, but also in their mechanism of action [16, 17]. Whether the now known EGFR mutations, which appear to predict for the majority of responses to small molecule TK inhibitors, play a similar critical role for the efficacy of EGFR monoclonal antibodies is unknown [18, 19]. More research on EGFR monoclonal antibodies in NSCLC is therefore warranted.
Matuzumab is a novel humanized monoclonal antibody of the immunoglobulin G1 (IgG1) subclass that binds selectively to the EGFR and inhibits ligand-mediated activation. In contrast to the chimeric antibody cetuximab, the humanized antibody matuzumab has a prolonged half-life of 6–8 days. Matuzumab as a humanized antibody does not induce auto-antibodies, which is a known problem with chimeric or murine antibodies [20]. Substantial antitumor activity of matuzumab has been observed in non-clinical xenograft models [21, 22]. Besides blocking ligand-binding and subsequently inhibiting signal transduction, matuzumab has shown in these models the ability to attract immunocompetent cells by antibody-dependent cellular cytotoxicity (ADCC), which might contribute to its antitumor activity [23]. Paclitaxel, administered as single-agent therapy or in combination regimens, is one of the most active drugs for the treatment of advanced NSCLC [24–26]. In preclinical xenograft and cell line models, the combination of paclitaxel plus EGFR inhibitors has shown enhanced efficacy compared with either drug given as a single agent (data on file) and matuzumab has demonstrated activity in paclitaxel resistant xenograft models [21]. Additive effects have also been demonstrated for the combination of gemcitabine with matuzumab in pancreatic cancer nude mouse models [22].
Therefore, in this phase I study we investigated the maximum tolerated dose (MTD), safety and tolerability, as well as the pharmacokinetic profile of matuzumab plus paclitaxel, in patients with both chemotherapy-naïve and pretreated advanced NSCLC. In addition, preliminary data on antitumor activity were collected.
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Inclusion criteria were as follows: age
18 years, histologically confirmed NSCLC stage IIIB or IV, measurable disease either by computed tomography (CT) or magnetic resonance imaging (MRI), immunohistochemical evidence of EGFR expression in tumor tissue (as defined in the next section), predicted life expectancy >3 months, Karnofsky performance status 60%, no chemotherapy or radiotherapy within 4 weeks before the first infusion of matuzumab and paclitaxel, adequate baseline organ functions [creatinine level <1.5 x upper limit of normal (ULN); bilirubin level <2 x ULN, alanine aminotransferase/aspartate aminotransferase (ALT/AST) <5 x ULN], adequate bone marrow function (white blood count >3000/µl; platelet count >100 000/µl; hemoglobin level >9 mg/dl), no severe uncontrolled comorbidities, and signed informed consent. The study was approved by the Ethics Committees of the University of Tuebingen and was carried out according to the Declaration of Helsinki and good clinical practice guidelines. The subject's informed consent was obtained prior to any study-related activities.
EGFR expression
For the analysis of EGFR expression, tumor material was obtained from the initial tumor resection or biopsy that had yielded the primary diagnosis. EGFR expression was determined in representative paraffin-embedded tumor blocks using the binding of a specific monoclonal anti-EGFR antibody (Clone E30; Merck KGaA, Darmstadt, Germany). Slides were pretreated using 0.07% Pronase E (Sigma Nr. P5147; Sigma Chemical Co, St Louis, MO) for 13 min. The primary antibody was diluted 1:25 in Tris-buffered saline (pH 7.62) and incubated overnight at 4°C. Visualization was performed using the ChemMateEnVision Detection Kit (AP, Mouse, code No. K5005; DakoCytomation, Hamburg, Germany) and with neufuchsin (Merck KGaA) as the chromogen. Tumors were considered positive if any membrane staining was observed in at least 10% or more of tumor cells. EGFR expression was defined by immunohistochemistry as follows: score 1+, faint or barely perceptible partial staining of the membrane; score 2+, weak to moderate complete membrane staining or strong partial staining of the membrane; and score 3+, strong complete membrane staining in at least 10% of tumor cells. Only patients with EGFR-positive tumors were enrolled in the study. All immunohistochemical investigations were centrally performed and reviewed. Only the reference pathologist (Prof Stoerkel, Wuppertal, Germany) was allowed to determine whether EGFR positivity fulfilled the inclusion criteria for this study.
pretreatment evaluation and follow-up
Pretreatment evaluation consisted of a medical history, physical examination, complete blood count (CBC), serum chemistry, urine analysis, electrocardiogram (ECG), echocardiogram, and chest X-ray study. All sites of measurable disease were documented by CT scans. During study treatment, subject monitoring included the assessment of clinical toxicities, CBC, serum chemistry and physical examination before each weekly matuzumab administration. The target lesion(s) were measured by CT scans every 6 weeks. Responses had to be confirmed at 4-week intervals. A chest X-ray study or CT scan and ECG were repeated at the end of treatment. During the follow-up period, patients were evaluated every 2 months until disease progression was documented.
treatment and dose-escalation plan
The study was subdivided into two parts. The first 6-week period was designated as phase A, to determine the MTD and pharmacokinetic parameters. In phase B, from week 7 onwards, matuzumab plus paclitaxel treatment was continued until disease progression or occurrence of unacceptable toxicity. Paclitaxel was given at a dose of 175 mg/m2 over 3 h on day 1 of a 3-week cycle. Premedication for paclitaxel included dexamethason 20 mg i.v., diphenhydramine 50 mg and ranitidine 300 mg i.v. Matuzumab was administered as a 1-h i.v. infusion once weekly without premedication in 250 ml of 0.9% (wt/vol) normal saline solution. On day 1 of the 3-week cycle, matuzumab was given prior to paclitaxel, with a 1-h time interval from the end of infusion to the start of paclitaxel administration. Matuzumab was supplied by Merck KGaA, Germany, as a lyophilisate of 200 mg/vial. The starting dose was 100 mg (absolute dose) of matuzumab per week (dose level 1) with no loading dose. Doses were escalated to dose levels 2–4 using 200, 400 and 800 mg (absolute doses) per week. No intrasubject dose escalation was allowed. At each dose level, three patients were initially enrolled. If none of the patients experienced a dose-limiting toxicity (DLT) during the first 6 weeks of treatment, the next cohort of three patients was treated at the subsequent dose level. If one of three patients experienced DLT at a given dose level, an additional three patients were enrolled at the same dose level. If two or more patients at one dose level experienced any DLT, three additional patients were enrolled at the next lower dose level. The MTD was defined as the dose level at which no more than one of six patients had experienced a DLT. Treatment was given on an outpatient basis.
evaluation of toxicities and response
Toxicities were evaluated weekly and graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 2.0). Assessment of DLT was limited to the first two treatment cycles (phase A). A DLT was defined as follows: non-hematologic toxicities exceeding grade 2 (with the exception of alopecia, nausea, vomiting and skin reactions); NCI-CTC grade 4 nausea, vomiting, or skin reactions; neutropenia grade 4 or grade 3 associated with complications (e.g. neutropenic fever); thrombocytopenia NCI-CTC grade 4; and toxicity-related discontinuation of treatment for more than 1 week during the first two treatment cycles. Tumor response was assessed by CT or MRI of the target lesion(s) and non-target lesion(s) every 6 weeks and defined according to RECIST [27]. All radiologic assessment was performed by two study-assigned radiologists at the Department of Radiology at Tuebingen University.
pharmacokinetics
For pharmacokinetic analysis of matuzumab, blood samples of 5 ml were drawn before and 1, 2, 5, 48 and 96 h after the start of the first infusion in cycles 1 and 2. Samples were allowed to clot and then centrifuged. Serum was collected and stored at –20°C. Serum concentrations of matuzumab were determined using a validated sandwich enzyme-linked immunosorbent assay with a lower limit of quantification of 0.5 µg/ml. The pharmacokinetic parameters of matuzumab in cycles 1 and 2 were calculated independently according to non-compartmental methods using the pharmacokinetic software program KineticaTM, version 4.0 (InnaPhase Corp, Philadelphia, PA). The following parameters were determined: maximum serum concentration (Cmax), time to reach Cmax (tmax), elimination half-life (t1/2), area under the serum concentration-versus-time curve from zero to the last detectable serum concentration (AUC0–t), area under the serum concentration-versus-time curve until infinity (AUC0–
), volume of distribution during terminal phase (Vz), total-body clearance of drug from serum (CL) and mean residence time (MRT). Cmax and tmax were taken directly from the plasma concentration curve. 
z (where z is the elimination rate constant) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve; t1/2 was calculated by using 0.693/z. AUC0–t was determined using the log linear trapezoidal rule, and AUC0– was derived from the following formula: AUC0–t + Ct/z, where Ct is the last measurable concentration. For calculation of Vz, CL and MRT, the following equations were used: dose/(AUC0– · z) for Vz; dose/AUC0– for CL and (AUMC0–/AUC0–) – T/2 for MRT, where AUMC is the area under the moment curve, and T/2 is half of the infusion time. Concentrations below the lower limit of quantification (i.e. below the last quantifiable data point) were denoted as zero for the purpose of calculating the AUC. Pharmacokinetic results were presented descriptively only; no statistical tests were performed with pharmacokinetic parameters. Paclitaxel concentrations were not determined.
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From July 2001 to August 2003, 33 patients were registered for this study at the University of Tuebingen Medical Center, Tuebingen, Germany and tumor tissue was investigated for EGFR expression. Immunohistochemical analysis of EGFR expression on tumor tissue was positive in all patients (100%) with adequate tumor material available for testing. Of these 33 patients, 18 (13 male and five female) received matuzumab plus paclitaxel at four different dose levels (Table 1); 15 patients were not enrolled and did not receive matuzumab. Reasons for not enrolling in the study included the following: eight patients withdrew their informed consent or received another treatment between signing the informed consent and receiving the results of EGFR testing; the histological diagnosis was reassessed in one patient; chemotherapy was administered within 4 weeks prior to the start of the study in one patient; two patients were diagnosed with brain metastases; one patient had an uncontrolled infection with deteriorating performance status; one patient had inadequate liver function; and one patient had an insufficient amount of tumor tissue available for EGFR testing. The demographics of the treated patients are listed in Table 2.
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Median age was 63 (29–76) years. Of the 18 patients, 14 had a histological diagnosis of adenocarcinoma and four had a diagnosis of squamous cell carcinoma of the lung. Nine patients (50%) had been pretreated with a median of one chemotherapy regimen (range 0–3 regimens) and six patients (33%) had previously received radiation therapy to either the primary tumor region or sites of symptomatic metastases. Prior single agent chemotherapy included vinorelbine (two patients), gemcitabine (three patients), trofosfamide (one patient) and oral etoposide (one patient). Prior combination chemotherapy included carboplatin/paclitaxel (two patients), cisplatin/gemcitabine (one patient), carboplatin/vinorelbine (three patients) and carboplatin/etoposide (one patient).
The maximum planned dose of 800 mg given once weekly was achieved without reaching the MTD. At the first three dose levels, 10 patients were treated without a DLT. At the fourth dose level, 800 mg once weekly, a DLT of grade 4 neutropenia occurred in one of the three patients and resolved within 1 week without complication. Five additional patients were enrolled at dose level 4 to assess further the safety of the combination of paclitaxel with matuzumab at a dose of 800 mg once weekly. No further DLTs were observed among these patients.
A total of 103 cycles of matuzumab were administered with a median of three (range 1–23) cycles per patient. Maximum treatment duration was 74+ weeks in one patient and 58+ weeks in a second patient. During the infusions three patients developed grade 3/4 dyspnea, which was considered an allergic reaction to paclitaxel. Paclitaxel was discontinued due to allergic reactions in four patients. These patients continued on matuzumab single-agent therapy. The most frequent matuzumab-related side effect was grade 1/2 acneiform skin rash in 14 patients. One patient developed grade 2 bronchospasm related to matuzumab. This patient continued on study and with glucocorticoid premedication received additional doses of matuzumab without recurrence of the event. Other grade 2 matuzumab-related events (there were no other grade 3/4 adverse events) included pruritus (n = 2), fissures (n = 1), abdominal pain (n = 1), and hot flushes (n = 1) (Table 3).
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pharmacokinetic analysis
Eighteen patients were assessable for pharmacokinetic analyses, and the results are listed in Table 4. Peak serum concentrations were generally achieved within 1–4 h after the start of the infusion. Mean values for Cmax for weekly doses between 100 and 800 mg ranged from 33.5 to 248.6 µg/ml and from 35.0 to 422.3 µg/ml in cycles 1 and 2, respectively. The range of mean AUC0–
was 2131–32 299 µg/ml · h and 2974–75 042 µg/ml · h in cycles 1 and 2, respectively. The increase of Cmax and AUC0– was dose proportional in week 1 within the tested dose range (Table 4). The terminal elimination t1/2 was not constant for the four dose groups in both cycles. Mean t1/2 increased from 38.7 h at 100 mg to 137.6 h at 800 mg in cycle 1. Values for t1/2 were slightly higher in cycle 2 than in cycle 1 (see Table 4).
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The sampling period (168 h) was short in relation to the observed t1/2, and accordingly, the extrapolated part of the AUC0–
exceeded the 20% margin in all dose groups in cycle 2 and the two highest dose groups in cycle 1. The mean values for Vz were small and dose independent (see Table 4). Drug accumulation was more pronounced at higher doses.
antitumor activity
Although tumor response was not a primary end point of this study, all patients received at least two cycles of the combination of paclitaxel plus weekly matuzumab and were therefore evaluable for antitumor activity. Of 18 patients, three achieved a partial response and one a complete response (overall response rate 22%; 95% CI 2.6% to 41.8%) All but one of these patients were untreated prior to study entry. The patient with the complete response had been diagnosed with a metastatic squamous cell carcinoma of the left upper lobe. After two cycles, his chest CT scan showed no evidence of disease (Figure 1). This patient has had an ongoing complete remission and has received matuzumab as a single agent for 8 months following 7 months of receiving matuzumab together with paclitaxel. One of the patients achieving a partial remission had been pretreated with two different chemotherapy regimens. All responding patients were smokers. An additional six patients (33.3%; 95% CI 11.1% to 55.6%) showed a stabilization of their formerly progressive disease, including one patient with a minor response. Duration of disease stabilization in these patients lasted from 2.5 to 6 months. Two of the responding patients received matuzumab for more than 12 months.
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This phase I study demonstrated that the humanized monoclonal anti-EGFR antibody matuzumab administered intravenously at doses up to 800 mg weekly is generally well tolerated when combined with paclitaxel given at the standard dose of 175 mg/m2 every 3 weeks. The MTD of matuzumab in combination with paclitaxel was not reached in this study, with only one DLT occurring at the 800-mg dose level. Since paclitaxel at 175 mg/m2 every 3 weeks is known to be associated with a 25%–30% risk of inducing an NCI-CTC grade 4 neutropenia, it is likely that the observed DLT of grade 4 neutropenia was paclitaxel related. This is supported by the outcome of a study with matuzumab monotherapy in which the MTD was found to be 1600 mg weekly [20
]. The same study demonstrated no differences in the pharmacodynamic effects for doses between 800 mg and 1600 mg of matuzumab, indicating that 800 mg, as used as the highest dose level in our study, is a biologically active dose with a significant abrogation of downstream signaling [20].
As in other studies investigating monoclonal anti-EGFR antibodies, the most commonly reported adverse event for the combination tested here was a mild acneiform rash, which occurred in almost all patients. This type of skin toxicity has been described as the most common side-effect of both monoclonal anti-EGFR antibodies and low molecular-weight tyrosine kinase inhibitors targeting EGFR [28]. Diarrhea was mild and only rarely observed in our study. A higher rate of severe diarrhea has been reported following treatment with low molecular-weight EGFR tyrosine kinase inhibitors, such as gefitinib [29].
The rate of allergic reactions to paclitaxel appeared slightly elevated compared with data in the literature, but it is unclear whether this was related to a drug interaction between paclitaxel and matuzumab or a chance occurrence. Drug interactions involving paclitaxel are common because paclitaxel is metabolized via cytochrome P450 isoenzymes [30]. However, there is no evidence that matuzumab affects cellular cytochromes, and it would therefore not be expected to alter the metabolism of drugs metabolized by cytochrome P450 isoenzymes. If pharmacokinetic data from this study are compared with results of single-agent matuzumab studies, the pharmacokinetic profile of matuzumab does not appear to be altered in the presence of paclitaxel, suggesting that the matuzumab dose does not need to be adjusted when these drugs are coadministered. Similar data were reported for the combination of trastuzumab (a monoclonal HER2-neu antibody) and paclitaxel, and no new or unexpected toxicities were observed [31].
The pharmacokinetic analyses showed that the increase of AUC and Cmax was dose-proportional for matuzumab over the range of 100–800 mg weekly, indicating linear pharmacokinetics in this dose range. In contrast, the terminal elimination t1/2 was not constant and increased with dose, but it seemed to level between 400 and 800 mg. Varying t1/2 values at lower dose ranges is a typical characteristic for anti-EGFR monoclonal antibodies. Results of several recently performed studies with matuzumab monotherapy reveal that t1/2 increases at lower doses (50–400 mg weekly doses) but finally levels off at doses above 400 mg [20]. So far, there is no explanation for these contradictory results for AUC (indicating linear pharmacokinetics) and t1/2 (indicating non-linear pharmacokinetics). The extrapolated part of the total AUC increased with dose, which is evidence of an insufficient sampling interval. Extended sampling may lead to somewhat different AUC values which do not increase in proportion with dose. Results of this trial correlate well with results of previous studies. AUC0–t after the first infusion calculated for doses of 400 and 800-mg matuzumab monotherapy were 10 414 and 21 471 µg · h/ml [20]. In addition, t1/2 values obtained from this study and matuzumab monotherapy studies do not differ substantially. There is no indication that matuzumab pharmacokinetics were altered by co-administration of paclitaxel, with evidence of accumulation at doses above 400 mg weekly.
Chemotherapy treatment for NSCLC patients provides only a modest survival benefit. The response rate of 22% plus 33% disease stabilization achieved with the combination of matuzumab plus paclitaxel is an encouraging result in this study, particularly since half of the patients had been pretreated with chemotherapy. One of our patients achieved a durable complete remission, which is seen only rarely after cytotoxic chemotherapy. He continued receiving matuzumab therapy for 15 months without any signs of cumulative toxicity. From cycle 7 onwards, he received matuzumab alone to avoid cumulative paclitaxel toxicity and has not yet had disease progression.
Evidence of antitumor activity was also reported in another phase I study using escalating doses of matuzumab as a single agent [20]. In that phase I study, no clear dose–response relationship was observed for antitumor activity (i.e. results similar to those seen in our study). Vanhoefer et al. [20] demonstrated similar pharmacodynamic effects in skin biopsies for matuzumab at doses between 800 and 1600 mg, suggesting that the maximal inhibition of EGFR in skin may be achieved at doses below the level of 2000 mg, which resulted in DLT in two of three patients. In contrast to cytotoxic therapy, in which the MTD is close to the dose of choice, increasing data based on pharmacodynamic, pharmacokinetic and clinical data suggest that for matuzumab, antitumor activity may be seen at doses below the MTD. Preliminary pharmacodynamic and pharmacokinetic data from a phase I study investigating matuzumab as a single agent in advanced cancer with administration of 1200 mg matuzumab weekly, every 2 weeks and every 3 weeks suggest that 1200 mg given every 3 weeks is feasible and a potential target effective dose (TED) [32]. This new dosing schedule for matuzumab is currently being explored in NSCLC patients in combination with paclitaxel.
In conclusion, the combination of matuzumab and paclitaxel is associated with acceptable toxicity and should be explored further in patients with NSCLC.
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Supported in part by a research grant from Merck KGaA Darmstadt.
These data were in part presented at the 39th Annual Meeting of the American Society of Clinical Oncology in Chicago, 2003.
Received for publication October 19, 2005. Revision received February 6, 2006. Accepted for publication February 6, 2006.
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References |
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|---|
1. Anonymous. Chemotherapy for non-small cell lung cancer:Non-small cell lung cancer Collaborative Group. Cochrane Database of Systematic Reviews 2000; VD002139.
2. Ciardiello F, Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 2001; 7: 2958–2970.
3. Ciardiello F. An update of new targets for cancer treatment: receptor-mediated signals. Ann Oncol 2002; 13: 29–38.
4. Rusch V, Baselga J, Cordo-Gardo J et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993; 53 (Suppl 10): 2379–2385.
5. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003; 21: 2787–2799.
6. Chen Z, Ke LD, Yuan XH, Adler-Storthz K. Correlation of cisplatin sensitivity with differential alteration of EGFR expression in head and neck cancer cells. Anticancer Res 2000; 20: 899–902.[Web of Science][Medline]
7. Montgomery R, Guzman J, O'Rourke D, Stahl W. Expression of oncogenic epidermal growth factor receptor family kinases induces paclitaxel resistance and alters beta-tubulin isotype expression. J Biol Chem 2000; 275: 17358–17363.
8. Cooke T, Reeves J, Lanigan A et al. HER2 as a prognostic and predictive marker for breast cancer. Ann Oncol 2001; 12 (Suppl 1): S23–S28.
9. Scambia G, Benedetti Panici P, Ferrandina G et al. Prognostic significance of receptors for epidermal growth factor, estrogen, and progesterone in ovarian cancer. Ann NY Acad Sci 1996; 784: 202–208.[Medline]
10. Dassonville O, Formento JL, Francoual M et al. Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 1993; 11: 1873–1878.
11. Sirotnak FM, Zakowski MF, Miller VA et al. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000; 6: 4885–4892.
12. Fan Z, Masui H, Altas I, Mendelsohn J. Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1993; 53: 4322–4328.
13. Yang XD, Jia XC, Corvalan JR et al. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 2001; 38: 17–23.[Web of Science][Medline]
14. Baselga J, Albanell J. Epithelial growth factor receptor interacting agents. Hematol Oncol Clin North America 2002; 16: 1041–1063.[CrossRef][Web of Science][Medline]
15. Baselga J. Targeting the epidermal growth factor receptor with tyrosine kinase inhibitors: small molecules, big hopes. J Clin Oncol 2002; 20: 2217–2219.
16. Matar P, Rojo F, Cassia R et al. Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): superiority over single-agent receptor targeting. Clin Cancer Res 2004; 10: 6487–6501.
17. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005; 23: 2445–2459.
18. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New Engl J Med 2004; 350: 2129–2139.
19. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004; 305: 1163–1167.
20. Vanhoefer U, Tewes M, Rojo F et al. Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J Clin Oncol 2004; 22: 175–184.
21. Burger A, Heiss NS, Kreysch H-G et al. The humanized monoclonal anti-EGFR antibody EMD 72000 potently inhibits the growth of EGFR-expressing human tumor xenografts insensitive to chemotherapeutic drugs. Am Ass Cancer Res 2003; 44: 1139 (Abstr 5719).
22. Amendt C, Mantell O, Peters M et al. In vivo activity of humanized monoclonal anti-EGFR antibody EMD72000 in combination with gemcitabine on growth of primary pancreatic tumors and metastases in an orthotopic nude mouse model. Proc Am Ass Cancer Res 2003; 44: 1234 (Abstr 6180).
23. Gillies S, Lan Y, Wesolowski J et al. The role of ADVV effector function in the anti-tumor efficacy of anti-EGFR antibodies in a mouse xenograft model. Clin Cancer Res 2003; 9: 127 (Abstr B224).
24. Belani CP, Barstis J, Perry MC et al. Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation. J Clin Oncol 2003; 21: 2933–2939.
25. Bonomi P. Review of paclitaxel/carboplatin in advanced non-small cell lung cancer. Semin Oncol 1999; 26: 55–59.[Medline]
26. Gatzemeier U, von Pawel J, Gottfried M et al. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 2000; 18: 3390–3399.
27. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216.
28. Needle MN. Safety experience with IMC-C225, an anti-epidermal growth factor receptor antibody. Semin Oncol 2002; 29: 55–60.[Web of Science][Medline]
29. Herbst S, Giaccone G, Schiller J et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 2004; 22: 785–794.
30. Cresteil T, Monsarrat B, Alvinerie P et al. Taxol metabolism by human liver microsomes: identification of cytochrome P450 isozymes involved in its biotransformation. Cancer Res 1994; 54: 386–392.
31. Leyland-Jones B, Gelmon K, Ayoub JP et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol 2003; 21: 3965–3971.
32. Salazar R, Tabernero J, Rojo F et al. Dose-dependent inhibition of the EGFR and signalling pathways with the anti-EGFR monoclonal antibody (MAb) EMD 72000 administered every three weeks (q3w). A phase I pharmacokinetic/pharmacodynamic (PK/PD) study to define the optimal biological dose (OBD). Proc Am Soc Clin Oncol 2004; 23: 127 (Abstr 2002).
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  B. Pfost, C. Seidl, M. Autenrieth, D. Saur, F. Bruchertseifer, A. Morgenstern, M. Schwaiger, and R. Senekowitsch-Schmidtke Intravesical {alpha}-Radioimmunotherapy with 213Bi-Anti-EGFR-mAb Defeats Human Bladder Carcinoma in Xenografted Nude Mice J. Nucl. Med., October 1, 2009; 50(10): 1700 - 1708. [Abstract] [Full Text] [PDF]
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 L. Horn and A. Sandler Epidermal Growth Factor Receptor Inhibitors and Antiangiogenic Agents for the Treatment of Non-Small Cell Lung Cancer Clin. Cancer Res., August 15, 2009; 15(16): 5040 - 5048. [Abstract] [Full Text] [PDF]
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 C. Gridelli, P. Maione, M. L. Ferrara, and A. Rossi Cetuximab and Other Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in the Treatment of Non-Small Cell Lung Cancer Oncologist, June 1, 2009; 14(6): 601 - 611. [Abstract] [Full Text] [PDF]
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 M. M. Schittenhelm, C. Kollmannsberger, K. Oechsle, A. Harlow, J. Morich, F. Honecker, R. Kurek, S. Storkel, L. Kanz, C. L. Corless, et al. Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer Mol. Cancer Ther., March 1, 2009; 8(3): 481 - 489. [Abstract] [Full Text] [PDF]
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A. Kleespies, I. Ischenko, M. E. Eichhorn, H. Seeliger, C. Amendt, O. Mantell, K.-W. Jauch, and C. J. Bruns Matuzumab Short-Term Therapy in Experimental Pancreatic Cancer: Prolonged Antitumor Activity in Combination with Gemcitabine Clin. Cancer Res., September 1, 2008; 14(17): 5426 - 5436. [Abstract] [Full Text] [PDF]
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 B. Vahid and P. E. Marik Pulmonary Complications of Novel Antineoplastic Agents for Solid Tumors* Chest, February 1, 2008; 133(2): 528 - 538. [Abstract] [Full Text] [PDF]
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 K. Seitz and H. Zhou Pharmacokinetic Drug-Drug Interaction Potentials for Therapeutic Monoclonal Antibodies: Reality Check J. Clin. Pharmacol., September 1, 2007; 47(9): 1104 - 1118. [Abstract] [Full Text] [PDF]
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M. A. Socinski Antibodies to the Epidermal Growth Factor Receptor in Non Small Cell Lung Cancer: Current Status of Matuzumab and Panitumumab Clin. Cancer Res., August 1, 2007; 13(15): 4597s - 4601s. [Abstract] [Full Text] [PDF]
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