Journal of Clinical Oncology, Vol 24, No 30 (October 20), 2006: pp. 4914-4921
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.06.7595
Multicenter Phase II and Translational Study of Cetuximab in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin, and Fluoropyrimidines
Heinz-Josef Lenz,
Eric Van Cutsem,
Shirin Khambata-Ford,
Robert J. Mayer,
Philip Gold,
Philip Stella,
Barry Mirtsching,
Allen L. Cohn,
Andrew W. Pippas,
Nozar Azarnia,
Zenta Tsuchihashi,
David J. Mauro,
Eric K. Rowinsky
From the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA; University Hospital Gasthuisberg, Leuven, Belgium; Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ; Dana-Farber/Partners CancerCare, Boston, MA; Swedish Cancer Institute, Seattle, WA; St Joseph Mercy Hospital, Ann Arbor, MI; Center for Oncology Research and Treatment, Dallas, TX; Rocky Mountain Cancer Center, Denver, CO; Lakeland Regional Cancer Center, Lakeland, FL; and ImClone Systems Incorporated, New York, NY
Address reprint requests to Eric K. Rowinsky, MD, ImClone Systems, 33 ImClone Dr, Branchburg, NJ 08876; e-mail: eric.rowinsky{at}imclone.com
PURPOSE: This multicenter study evaluated the antitumor activity of cetuximab, an immunoglobulin G1 antibody directed at the epidermal growth factor receptor (EGFR), in metastatic colorectal carcinoma (CRC) refractory to irinotecan, oxaliplatin, and a fluoropyrimidine. It also evaluated the safety, pharmacokinetics, immunokinetics, and biologic determinants of activity.
PATIENTS AND METHODS: Patients with metastatic CRC, whose tumors demonstrated EGFR immunostaining and were refractory to irinotecan, oxaliplatin, and fluoropyrimidines, were treated with cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly. An independent review committee (IRC) reviewed responses. Blood was collected for cetuximab pharmacokinetics and to detect antibodies to cetuximab. EGFR gene sequencing of the tyrosine kinase domain and gene copy number assessments were performed.
RESULTS: The response rates in 346 patients, as determined by the investigators and IRC, were 12.4% (95% CI, 9.1 to 16.4) and 11.6% (95% CI, 8.4 to 16.4). The median progression-free survival (PFS) and survival times were 1.4 months (95% CI, 1.4 to 2.1) and 6.6 months (95% CI, 5.6 to 7.6), respectively. An acneiform rash occurred in 82.9% of patients; grade 3 rash was observed in 4.9%. Response and survival related strongly to the severity of the rash. In contrast, clinical benefit did not relate to EGFR immunostaining. EGFR tyrosine kinase domain mutations were not identified, and EGFR gene copy number did not relate to response or PFS, but to survival (P = .03).
CONCLUSION: Cetuximab is active and well tolerated in metastatic CRC refractory to irinotecan, oxaliplatin, and fluoropyrimidines. The severity of rash was related to efficacy. Neither EGFR kinase domain mutations nor EGFR gene amplification appear to be essential for response to cetuximab in this setting.
Supported by ImClone Systems, New York, NY, and Merck, Darmstadt, Germany.
The investigators and centers participating in this multicenter, multinational study are listed in online only Appendix 1.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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|
 
M. A. Pantaleo, M. Nannini, A. Maleddu, S. Fanti, C. Nanni, S. Boschi, F. Lodi, G. Nicoletti, L. Landuzzi, P. L. Lollini, et al.
Experimental results and related clinical implications of PET detection of epidermal growth factor receptor (EGFr) in cancer
Ann. Onc.,
October 7, 2008;
(2008)
mdn625v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Tahara, K. Shirao, N. Boku, K. Yamaguchi, Y. Komatsu, Y. Inaba, T. Arai, N. Mizunuma, T. Satoh, H. Takiuchi, et al.
Multicenter Phase II Study of Cetuximab Plus Irinotecan in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin and Fluoropyrimidines
Jpn. J. Clin. Oncol.,
October 4, 2008;
(2008)
hyn102v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Personeni, S. Fieuws, H. Piessevaux, G. De Hertogh, J. De Schutter, B. Biesmans, W. De Roock, A. Capoen, M. Debiec-Rychter, J.-L. Van Laethem, et al.
Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study
Clin. Cancer Res.,
September 15, 2008;
14(18):
5869 - 5876.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Arnold, T. Hohler, C. Dittrich, F. Lordick, T. Seufferlein, J. Riemann, E. Woll, T. Herrmann, A. Zubel, and H.-J. Schmoll
Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: a phase Ib/II study of the AIO GI Group
Ann. Onc.,
August 1, 2008;
19(8):
1442 - 1449.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Shimura, H. Kataoka, N. Ogasawara, E. Kubota, M. Sasaki, S. Tanida, and T. Joh
Suppression of proHB-EGF Carboxy-Terminal Fragment Nuclear Translocation: A New Molecular Target Therapy for Gastric Cancer
Clin. Cancer Res.,
June 15, 2008;
14(12):
3956 - 3965.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. F. Sobrero, J. Maurel, L. Fehrenbacher, W. Scheithauer, Y. A. Abubakr, M. P. Lutz, M. E. Vega-Villegas, C. Eng, E. U. Steinhauer, J. Prausova, et al.
EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer
J. Clin. Oncol.,
May 10, 2008;
26(14):
2311 - 2319.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. K. Oldham and R. O. Dillman
Monoclonal Antibodies in Cancer Therapy: 25 Years of Progress
J. Clin. Oncol.,
April 10, 2008;
26(11):
1774 - 1777.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Cappuzzo, G. Finocchiaro, E. Rossi, P.A. Janne, C. Carnaghi, C. Calandri, K. Bencardino, C. Ligorio, F. Ciardiello, T. Pressiani, et al.
EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients
Ann. Onc.,
April 1, 2008;
19(4):
717 - 723.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Italiano, C. Massard, R. Bahleda, A.-L. Vataire, E. Deutsch, N. Magne, J.-P. Pignon, G. Vassal, J.-P. Armand, and J.-C. Soria
Treatment outcome and survival in participants of phase I oncology trials carried out from 2003 to 2006 at Institut Gustave Roussy
Ann. Onc.,
April 1, 2008;
19(4):
787 - 792.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pessino, S. Artale, S. Sciallero, A. Guglielmi, G. Fornarini, I.C. Andreotti, S. Mammoliti, D. Comandini, F. Caprioni, E. Bennicelli, et al.
First-line single-agent cetuximab in patients with advanced colorectal cancer
Ann. Onc.,
April 1, 2008;
19(4):
711 - 716.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Graziano, A. Ruzzo, F. Loupakis, E. Canestrari, D. Santini, V. Catalano, R. Bisonni, U. Torresi, I. Floriani, G. Schiavon, et al.
Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer
J. Clin. Oncol.,
March 20, 2008;
26(9):
1427 - 1434.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Ciardiello and G. Tortora
EGFR Antagonists in Cancer Treatment
N. Engl. J. Med.,
March 13, 2008;
358(11):
1160 - 1174.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Yang, D. Fu, Q. Ni, F. Fraggetta, G. Pelosi, F. Roila, M. C. Garassino, C. Mantica, E. van der Spek, G. S. Sonke, et al.
Cetuximab for Colorectal Cancer
N. Engl. J. Med.,
March 13, 2008;
358(11):
1195 - 1197.
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. De Roock, H. Piessevaux, J. De Schutter, M. Janssens, G. De Hertogh, N. Personeni, B. Biesmans, J.-L. Van Laethem, M. Peeters, Y. Humblet, et al.
KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab
Ann. Onc.,
March 1, 2008;
19(3):
508 - 515.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Giusti, K. Shastri, A. M. Pilaro, C. Fuchs, R. Cordoba-Rodriguez, K. Koti, M. Rothmann, A. Y. Men, H. Zhao, M. Hughes, et al.
U.S. Food and Drug Administration Approval: Panitumumab for Epidermal Growth Factor Receptor-Expressing Metastatic Colorectal Carcinoma with Progression Following Fluoropyrimidine-, Oxaliplatin-, and Irinotecan-Containing Chemotherapy Regimens
Clin. Cancer Res.,
March 1, 2008;
14(5):
1296 - 1302.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Italiano, P. Follana, F.-X. Caroli, J.-L. Badetti, D. Benchimol, G. Garnier, J. Gugenheim, J. Haudebourg, F. Keslair, G. Lesbats, et al.
Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors for Which FISH Analysis Does Not Detect an Increase in EGFR Gene Copy Number
Ann. Surg. Oncol.,
February 1, 2008;
15(2):
649 - 654.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Lievre, J.-B. Bachet, V. Boige, A. Cayre, D. Le Corre, E. Buc, M. Ychou, O. Bouche, B. Landi, C. Louvet, et al.
KRAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab
J. Clin. Oncol.,
January 20, 2008;
26(3):
374 - 379.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Van Cutsem, S. Siena, Y. Humblet, J.-L. Canon, J. Maurel, E. Bajetta, B. Neyns, D. Kotasek, A. Santoro, W. Scheithauer, et al.
An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy
Ann. Onc.,
January 1, 2008;
19(1):
92 - 98.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Butts, D. Bodkin, E. L. Middleman, C. W. Englund, D. Ellison, Y. Alam, H. Kreisman, P. Graze, J. Maher, H. J. Ross, et al.
Randomized Phase II Study of Gemcitabine Plus Cisplatin or Carboplatin, With or Without Cetuximab, As First-Line Therapy for Patients With Advanced or Metastatic Non-Small-Cell Lung Cancer
J. Clin. Oncol.,
December 20, 2007;
25(36):
5777 - 5784.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Scartozzi, I. Bearzi, C. Pierantoni, A. Mandolesi, F. Loupakis, A. Zaniboni, V. Catalano, A. Quadri, F. Zorzi, R. Berardi, et al.
Nuclear Factor-kB Tumor Expression Predicts Response and Survival in Irinotecan-Refractory Metastatic Colorectal Cancer Treated With Cetuximab-Irinotecan Therapy
J. Clin. Oncol.,
September 1, 2007;
25(25):
3930 - 3935.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Strome, E. A. Sausville, and D. Mann
A Mechanistic Perspective of Monoclonal Antibodies in Cancer Therapy Beyond Target-Related Effects
Oncologist,
September 1, 2007;
12(9):
1084 - 1095.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Zhang, M. Gordon, A. M. Schultheis, D. Y. Yang, F. Nagashima, M. Azuma, H.-M. Chang, E. Borucka, G. Lurje, A. E. Sherrod, et al.
FCGR2A and FCGR3A Polymorphisms Associated With Clinical Outcome of Epidermal Growth Factor Receptor Expressing Metastatic Colorectal Cancer Patients Treated With Single-Agent Cetuximab
J. Clin. Oncol.,
August 20, 2007;
25(24):
3712 - 3718.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. A. Messersmith and M. Hidalgo
Panitumumab, a Monoclonal Anti Epidermal Growth Factor Receptor Antibody in Colorectal Cancer: Another One or the One?
Clin. Cancer Res.,
August 15, 2007;
13(16):
4664 - 4666.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Khambata-Ford, C. R. Garrett, N. J. Meropol, M. Basik, C. T. Harbison, S. Wu, T. W. Wong, X. Huang, C. H. Takimoto, A. K. Godwin, et al.
Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab
J. Clin. Oncol.,
August 1, 2007;
25(22):
3230 - 3237.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Sartore-Bianchi, M. Moroni, S. Veronese, C. Carnaghi, E. Bajetta, G. Luppi, A. Sobrero, C. Barone, S. Cascinu, G. Colucci, et al.
Epidermal Growth Factor Receptor Gene Copy Number and Clinical Outcome of Metastatic Colorectal Cancer Treated With Panitumumab
J. Clin. Oncol.,
August 1, 2007;
25(22):
3238 - 3245.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. B. Vermorken, J. Trigo, R. Hitt, P. Koralewski, E. Diaz-Rubio, F. Rolland, R. Knecht, N. Amellal, A. Schueler, and J. Baselga
Open-Label, Uncontrolled, Multicenter Phase II Study to Evaluate the Efficacy and Toxicity of Cetuximab As a Single Agent in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Who Failed to Respond to Platinum-Based Therapy
J. Clin. Oncol.,
June 1, 2007;
25(16):
2171 - 2177.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Van Cutsem, C. Verslype, and P. A. Grusenmeyer
Lessons Learned in the Management of Advanced Pancreatic Cancer
J. Clin. Oncol.,
May 20, 2007;
25(15):
1949 - 1952.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Van Cutsem, M. Peeters, S. Siena, Y. Humblet, A. Hendlisz, B. Neyns, J.-L. Canon, J.-L. Van Laethem, J. Maurel, G. Richardson, et al.
Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer
J. Clin. Oncol.,
May 1, 2007;
25(13):
1658 - 1664.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Dragovich and C. Fenoglio-Preiser
In Reply
J. Clin. Oncol.,
March 1, 2007;
25(7):
911 - 911.
[Full Text]
[PDF]
|
|
|
|
