Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
First Published Online January 31, 2009
The Oncologist, Vol. 14, No. 2, 119-124, February 2009; doi:10.1634/theoncologist.2008-0124
© 2009 AlphaMed Press

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow All Versions of this Article:
theoncologist.2008-0124v1
14/2/119    most recent
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Guarino, M. J.
Right arrow Articles by Ettinger, D. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guarino, M. J.
Right arrow Articles by Ettinger, D. S.

Clinical Pharmacology

Dual Inhibition of the Epidermal Growth Factor Receptor Pathway with Cetuximab and Erlotinib: A Phase I Study in Patients with Advanced Solid Malignancies

Michael J. Guarinoa, Charles J. Schneidera, Martha A. Hosforda, Julie R. Brahmerb, Charles M. Rudinb, Friedrich Graf Finckensteinc, Robyn E. Philip-Nortond, Haolan Lue, Martin R. Webere, David S. Ettingerb

aHelen F. Graham Cancer Center, Christiana Care, Newark, Delaware, USA; bThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA; cBristol-Myers Squibb Company, Princeton, New Jersey, USA; dOSI Oncology, Melville, New York, USA; eBristol-Myers Squibb Company, Wallingford, Connecticut, USA

Key Words. Cetuximab • Erlotinib • Phase I • Solid malignancies

Correspondence: Michael J. Guarino, M.D., Medical Oncology Hematology Consultants, PA, Helen F. Graham Cancer Center, 4701 Ogletown-Stanton Road, Suite 2200, Newark, Delaware 19713, USA. Telephone: 302-366-1200; Fax: 302-366-1700; e-mail: mguarino{at}cbg.org

Received May 29, 2008; accepted for publication December 1, 2008; first published online in THE ONCOLOGIST Express on January 31, 2009.

Disclosures: Michael J. Guarino: None; Charles J. Schneider: None; Martha A. Hosford: None; Julie R. Brahmer: Consultant/advisory role: Abbott, Cephalon, Genentech, Eli Lilly, AstraZeneca; Charles M. Rudin: Consultant/advisory role: CTI

Pharmaceuticals, Amgen; Research funding/contracted research: Pharmion; Friedrich Graf Finckenstein: Employment/leadership position: Bristol-Myers Squibb; Ownership interest: Bristol-Myers Squibb; Robyn E. Philip-Norton: Employment/leadership position: OSI Pharmaceuticals; Haolan Lu: Employment/leadership position: Bristol-Myers Squibb; Martin R. Weber: Employment/leadership position: Bristol-Myers Squibb; Ownership interest: Bristol-Myers Squibb; David S. Ettinger: Consultant/advisory role: AstraZeneca, Bristol-Myers Squibb; Eli Lilly, GlaxoSmithKline, Merck, MGI Pharma, Pfizer, Sanofi-Aventis; Research funding/contracted research: Bayer, Genentech, Pharmion.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Author Contributions
 References
 
Purpose. To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies.

Patients and Methods. Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m2 i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity.

Results. Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1–31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1–25.1 weeks).

Conclusion. Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m2 i.v. weekly for cetuximab and 150 mg daily orally for erlotinib.


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Author Contributions
 References
 
The epidermal growth factor receptor (EGFR) is overexpressed in a variety of solid tumors; increased EGFR expression has been associated with poorer clinical outcomes in some of these malignancies [1–3]. The anti-EGFR chimeric monoclonal IgG1 cetuximab (Erbitux®; ImClone Systems Incorporated, New York, and Bristol-Myers Squibb Company, Princeton, NJ) is approved by the U.S. Food and Drug Administration for use in combination with irinotecan for the treatment of metastatic colorectal cancer and for use with radiotherapy for treatment of locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) [4, 5]. Single-agent cetuximab is also approved for metastatic colorectal cancer in patients intolerant to irinotecan and in SCCHN patients after failure of prior platinum-based therapy [6–9]. Clinical trials show that cetuximab may also have promising activity when used with chemotherapy in first-line treatment of non-small cell lung cancer (NSCLC) [10–15]. Erlotinib (Tarceva®; Genentech, Inc, South San Francisco, CA and OSI Pharmaceuticals Inc., Melville, NY) is a tyrosine kinase inhibitor (TKI) that improves the survival time of patients with advanced NSCLC who progress after one or two prior chemotherapy regimens [16]. Erlotinib is approved for use in advanced NSCLC after failure of previous chemotherapy, and in combination with gemcitabine in first-line treatment of advanced pancreatic cancer [16, 17].

The combination of an anti-EGFR monoclonal antibody and a TKI may enhance the inhibition of downstream signaling and lead to better treatment responses and outcomes [18–20]. This phase I study was designed to assess the feasibility and safety of administering an optimal dose of cetuximab in combination with a standard 150-mg/day dose of erlotinib in patients with advanced malignancies who had previously failed standard chemotherapy regimens.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Author Contributions
 References
 
Eligibility Criteria
Patients were treated at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Baltimore, MD) and the Helen F. Graham Cancer Center (Newark, DE). Patients aged ≥18 years with advanced solid malignancies who had failed standard chemotherapies and had Eastern Cooperative Oncology Group performance status score of 0–1, at least one bidimensionally measurable lesion, and a life expectancy ≥3 months were eligible. Prior chemotherapy, major surgery, or radiation therapy were acceptable (≥4 weeks, ≥3 months if radiation therapy to chest area). Patients with inadequate hematologic, hepatic, or renal function, symptomatic or uncontrolled central nervous system metastases, uncontrolled heart disease, or pulmonary fibrosis, and those who had received prior anti-EGFR therapy were excluded.

All patients provided written informed consent before any study procedures were performed. The study was approved by the investigational review board at both participating sites, and was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with good clinical practice and national regulatory guidelines.

Trial Design
This was an open-label, dose-escalation, phase I trial with an accelerated titration design. Cetuximab was administered once weekly, without an initial 400-mg/m2 dose, in sequential cohorts at dose levels of 100, 200, and 250 mg/m2, via 60-minute i.v. infusion after diphenhydramine premedication. After the first cetuximab dose, patients started erlotinib at a fixed dose of 150 mg/day orally. Each treatment cycle was 4 weeks regardless of omitted doses; doses could be omitted, but no delayed cycles were allowed. Treatment was continued until disease progression or unacceptable toxicity. Dose modifications of cetuximab or erlotinib were allowed in the event of severe toxicity.

One patient per cohort was to be treated until a dose-limiting toxicity (DLT) was observed during the first treatment cycle; that cohort was to be expanded to a total of six patients before further dose escalation was considered. If two instances of grade 2 toxicity were observed in the first cycle, the cohort was to be expanded to three patients before further escalation. The maximum-tolerated dose (MTD) was defined as the highest dose at which less than one third of the patients experienced a DLT during the first cycle. The recommended phase II dose (RPIID) was to be defined by the MTD or the highest dose level (250 mg/m2) if an MTD was not reached. Up to 15 additional patients were to be enrolled at this RPIID to confirm its safety. Intrasubject dose escalation to a new level shown to be safe was allowed provided the patient did not experience a DLT after at least 4 weeks on the lower dose level.

DLT was defined by any of the following events occurring during the first cycle only: any grade 4 toxicity other than infusion reaction; any grade 3 skin toxicity that required treatment interruption for >14 days; grade 3 or 4 diarrhea, vomiting, or nausea that could not be controlled with medical intervention or prophylaxis; any other grade ≥3 nonhematologic toxicity except for asthenia or infusion reaction; delayed recovery from toxicity (other than skin toxicity) resulting in withholding of retreatment >4 weeks; grade 4 neutropenia for at least five consecutive days or grade 3 or 4 neutropenia with sepsis or fever; or thrombocytopenia ≤25,000 cells/mm3 or bleeding requiring a platelet transfusion.

Assessments
High-resolution computed tomographic (CT) scans of the chest and of other tumor-bearing regions were performed within 4 weeks of the first dose of study treatment. All other baseline evaluations were performed within 14 days of the first dose.

The primary endpoint was identification of the RPIID for cetuximab in combination with erlotinib. Secondary endpoints included safety—defined by the MTD and incidence of adverse events (AEs) and abnormal laboratory parameters—and objective tumor response. AEs were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and coded to the Medical Dictionary for Regulatory Activities version 10.

Patients were evaluated for response according to modified World Health Organization criteria. CT analyses of tumor-bearing regions and other tumor response assessments were performed every 8 weeks, or more frequently if indicated. Responses to treatment required confirmation at least 4 weeks later. Criteria for stable disease (SD) had to be met ≥35 days after the first dose. The duration of SD was defined by the time between the first dosing date and the documented progression date in patients with SD as the best tumor response. Tumor measurements made by the investigator were reviewed by the study sponsor to determine the best tumor response and date of progression.

Evaluations for demographic and baseline characteristics, as well as safety, efficacy, and dosing, were carried out on the total group of treated patients, using descriptive statistics.


   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Author Contributions
 References
 
Patient Disposition and Demographics
From August 2005 to December 2006, 25 patients in total were screened and 22 patients were treated. One patient each was treated at the first two dose levels, and 20 patients were treated at the third dose level with cetuximab weekly at 250 mg/m2 i.v. plus 150 mg erlotinib orally. All patients had been treated previously with chemotherapy in the adjuvant or metastatic setting, most of them (77.3%) with two or more prior regimens. Most patients (64%) had NSCLC (supplemental online data, supplemental Table S1).

Treatment Exposure
One patient was enrolled in each of the first two cohorts. Those patients received cetuximab for 8 weeks and erlotinib for 7.9 and 7.3 weeks, respectively, without dose modification or omission. In the third dose-level cohort, 20 patients were enrolled in total; cetuximab and erlotinib were each administered for a median duration of 5.5 weeks (range, 1.0–31.0 weeks and 1.0–30.1 weeks, respectively). In total, 135 infusions of cetuximab (250 mg/m2) were administered, and 28 planned infusions were omitted for toxicity or other reasons. Four cetuximab infusions were administered at a reduced dose: two because of skin toxicity, one as a result of delayed recovery from asthenia, and one because of an unknown reason. In total, 980 doses of erlotinib were administered, and 142 planned doses were omitted. The erlotinib dose was reduced in one patient for 11 days.

The most common drug-toxicity reasons for study treatment discontinuation were: five patients with acneform rash (four with grade 1 or 2 and one with grade 3), one patient with grade 3 diarrhea, one patient with grade 2 hypomagnesemia and hypocalcemia, and one patient with mild eye and skin pain.

Safety
No DLT was reported at the first two dose levels. One DLT (grade 3 rash) was reported in the third dose-level cohort. The cohort was expanded to six patients without another DLT, and subsequently to a total of 20 patients to collect additional safety data at this dose level. The MTD was not reached at the third dose level, and consequently, 250 mg/m2 of cetuximab and 150 mg of erlotinib were determined to be the RPIIDs.

Overall, the safety profile of the combination was consistent with the individual safety profiles of each drug (Tables 1 and 2). The most common AEs were acneform rash and diarrhea. No grade 4 acneform rash was reported. Two patients (9.1%) had grade 3 acneform rash, whereas the rash was mild to moderate (grade 1 or 2) in the other 20 patients. Severe infusion reactions were not reported; three patients (13.6%) had grade 1 infusion reactions. Grade 3 or 4 hypomagnesemia was reported in two patients (12%).


View this table:
[in this window]
[in a new window]

  		Table 1. Adverse events of special interest (n = 22)

 


View this table:
[in this window]
[in a new window]

  		Table 2. Drug-related adverse events (n = 22)

 
Hematologic abnormalities were mostly mild to moderate, with grade 3 leukopenia reported in one patient (4.8%), grade 2 neutropenia in one patient (4.8%), and 16 patients (76.2%) experiencing anemia (none of them severe). No grade 3 or 4 values in liver or renal function tests were reported.

Efficacy
Eighteen patients were evaluable for response. No objective responses were observed. Seven patients (38.9%)—four with NSCLC and one each with colorectal cancer, cervical cancer, and an epithelial neoplasm with neuroendocrine features—had SD lasting for a median of 16.6 weeks (range, 6.1–25.1 weeks). All SD was seen in the highest dose-level cohort.


   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Author Contributions
 References
 
This study demonstrates that the combination of cetuximab and erlotinib is feasible and tolerable in patients with advanced malignancies who had previously failed standard chemotherapies. The safety profile of the combination was consistent with each of the individual drugs, with no unexpected toxicities seen during the study. The doses recommended for phase II evaluation were 250 mg/m2 weekly for cetuximab and 150 mg daily erlotinib.

An accelerated-titration dose escalation design was used for cetuximab. Given that the safety profile of each individual drug is well characterized, this design enabled us to escalate doses rapidly, starting from a 100-mg/m2 dose of cetuximab that would allow detecting and monitoring potentially prohibitive or unexpected safety signals, minimizing the number of patients treated with a dose below the approved cetuximab standard (250 mg/m2). The intermediate level (200 mg/m2) was included to merely avoid a dose gap larger than twofold, because, with one single patient enrolled, potential interpatient variability could override any relevant exposure difference between this and the highest dose allowed (250 mg/m2).

Although the initial dose of cetuximab has been used in other phase I studies of cetuximab plus TKI combinations [21, 22], the 400-mg/m2 initial cetuximab dose was not included in this trial, an omission designed to curtail potential overlapping toxicities. This approach was considered acceptable based on previous pharmacokinetic studies showing that weekly administration of cetuximab at 250 mg/m2 [2] without the initial higher dose still resulted in serum levels providing >50% target occupancy, and therefore would not compromise activity [23].

This study did not include a pharmacokinetic analysis for the potential interaction between the two drugs. This approach was based on the expected lack of drug interactions between an antibody and an oral small molecule and the fact that the individual pharmacokinetic profiles of cetuximab and erlotinib were well characterized, as both agents were already commercially available when the study was conducted.

Rash affected every patient and was the most frequent reason for toxicity-related treatment discontinuation; it may therefore emerge as a relevant safety concern with this combination. Even with the caveats implicit in any comparison across trials, a 100% incidence with concurrent use appears greater than the 76%–80% rates reported in studies of single-agent erlotinib or cetuximab; interestingly, however, there was no apparent increase in the rate of severe events [4, 6]. Whether a potential exacerbation of this toxicity may have a meaningful impact on the clinical use of this regimen will not be clear until larger trials are conducted.

Other studies have recommended more conservative dosing schemas, lowering the erlotinib dose to 50 mg in combination with the full dose of cetuximab [22]. In this trial, the tolerability of the highest dose in the 20 patients from the expansion cohort would validate cetuximab at a dose of 250 mg/m2 weekly plus erlotinib at 150 mg daily as the recommended doses for future investigation. Although objective responses were not seen, seven of 18 evaluable patients had SD lasting for a median of nearly 4 months. In conclusion, this regimen warrants further evaluation in malignancies where either cetuximab or erlotinib is known to be active, including colorectal cancer, NSCLC, and SCCHN, with some studies already initiated.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Author Contributions
References
 
Conception/design: Robyn E. Philip-Norton, David S. Ettinger

Provision of study materials: Michael J. Guarino, Charles J. Schneider, Martha A. Hosford, Julie R. Brahmer, Charles M. Rudin, Robyn E. Philip-Norton, David S. Ettinger

Collection/assembly of data: Michael J. Guarino, Charles J. Schneider, Martha A. Hosford, Julie R. Brahmer, Friedrich Graf Finckenstein, Martin R. Weber

Data analysis: Michael J. Guarino, Julie R. Brahmer, Friedrich Graf Finckenstein, Haolan Lu, Martin R. Weber, David S. Ettinger

Manuscript writing: Michael J. Guarino, Julie R. Brahmer, Friedrich Graf Finckenstein, Martin R. Weber

Final approval of manuscript: Michael J. Guarino, Charles J. Schneider, Martha A. Hosford, Julie R. Brahmer, Charles M. Rudin, Friedrich Graf Finckenstein, Robyn E. Philip-Norton, Haolan Lu, Martin R. Weber, David S. Ettinger

The authors take full responsibility for the content of our paper but thank Barry Weichman, Ph.D., Julia Saiz, Ph.D., and the Clinical Insights Inc. editorial team supported by Bristol-Myers Squibb for their assistance in researching for references, creating the first draft in collaboration with the authors, preparing figures and tables, and formatting the manuscript for submission. No author has received reimbursement for his/her contributions.


   ACKNOWLEDGMENTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Author Contributions
 References
 
This study was supported in full by Bristol-Myers Squibb and ImClone Systems Incorporated, and partially by OSI Pharmaceuticals Incorporated.

This study was presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, San Francisco, CA, October 22–26, 2007.

Editorial assistance for the development of this manuscript was provided by Clinical Insights, Inc., with the financial support of Bristol-Myers Squibb and ImClone Systems, Inc.


   REFERENCES
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Author Contributions
 References
 

  1. Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2001;2:127–137.[CrossRef][Medline]
  2. Mendelsohn J, Baselga J. Status of the epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003;21:2787–2799.[Abstract/Free Full Text]
  3. Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: A new paradigm for cancer therapy. Cancer 2002;94:1593–1611.[CrossRef][Medline]
  4. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–345.[Abstract/Free Full Text]
  5. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–578.[Abstract/Free Full Text]
  6. Jonker DJ, O'Callaghan CJ, Karapetis CS et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040–2048.[Abstract/Free Full Text]
  7. Saltz LB, Meropol NJ, Loehrer PJ Sr et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201–1208.[Abstract/Free Full Text]
  8. Baselga J, Trigo JM, Bourhis J et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2005;23:5568–5577.[Abstract/Free Full Text]
  9. Herbst RS, Arquette M, Shin DM et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 2005;23:5578–5587.[Abstract/Free Full Text]
  10. Thienelt CD, Bunn PA Jr, Hanna N et al. Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer. J Clin Oncol 2005;23:8786–8793.[Abstract/Free Full Text]
  11. Rosell R, Robinet G, Szczesna A et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol 2008;19:362–369.[Abstract/Free Full Text]
  12. Herbst RS, Chansky K, Kelly K et al. A phase II randomized selection trial evaluating concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in patients with advanced non-small cell lung cancer (NSCLC): Final report of SWOG 0342. Proc Am Soc Clin Oncol 2007;25(suppl 18):7545.
  13. Butts CA, Bodkin D, Middleman EL et al. Randomized phase II study of gemcitabine plus cisplatin, with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J Clin Oncol 2007;25:5777–5784.[Abstract/Free Full Text]
  14. Lynch T, Patel T, Dreisbach L et al. A randomized multicenter phase III study of cetuximab (Erbitux®) in combination with taxane/carboplatin versus taxane/carboplatin alone as first-line treatment for patients with advanced/metastatic non-small cell lung cancer (NSCLC). J Thorac Oncol 2007;2(suppl 4):S340–S341.
  15. Pirker R, Szczesna A, Von Pawell J et al. FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2008;27:3.
  16. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132.[Abstract/Free Full Text]
  17. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960–1966.[Abstract/Free Full Text]
  18. Jimeno A, Rubio-Viqueira B, Amador ML et al. Epidermal growth factor receptor dynamics influences response to epidermal growth factor receptor targeted agents. Cancer Res 2005;65:3003–3010.[Abstract/Free Full Text]
  19. Huang S, Armstrong EA, Benavente S et al. Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): Combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res 2004;64:5355–5362.[Abstract/Free Full Text]
  20. 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.[Abstract/Free Full Text]
  21. Baselga J, Schöffski, Rojo F et al. A phase I pharmacokinetic (PK) and molecular pharmacodynamic (PD) study of the combination of two anti-EGFR therapies, the monoclonal antibody (MAb) cetuximab (C) and the tyrosine kinase inhibitor (TKI) gefitinib (G), in patients (pts) with advanced colorectal cancer (CRC), head and neck (HNC) and non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2006;24(suppl 18):3006.
  22. Preston GG, Calvo E, Papadopoulos K et al. Multi-targeted inhibition of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways: A phase I study of cetuximab (C), erlotinib (E), and bevacizumab (B) in patients with solid tumors. Proc Am Soc Clin Oncol 2006;24(suppl 18):3005.
  23. Tan AR, Moore DF, Hidalgo M et al. Pharmacokinetics of cetuximab after administration of escalating single dosing and weekly fixed dosing in patients with solid tumors. Clin Cancer Res 2006;12:6517–6522.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow All Versions of this Article:
theoncologist.2008-0124v1
14/2/119    most recent
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Guarino, M. J.
Right arrow Articles by Ettinger, D. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guarino, M. J.
Right arrow Articles by Ettinger, D. S.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS