Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in Western countries. Despite the progress achieved with the introduction of new cytotoxic agents, CRC recurrence rates for patients with resected stage II and/or stage III disease remain higher than 20%. Furthermore, for patients diagnosed with metastatic CRC, the median survival time remains below 2 years and cure is often an elusive goal. These data highlight the need for more-effective systemic therapies. The EGFR is frequently overexpressed in CRC and has been associated with the malignant phenotype. Numerous clinical trials are now investigating the role of EGFR-targeted agents in CRC and have produced some encouraging results. Panitumumab is a fully human IgG2 monoclonal antibody that in a randomized phase III trial was shown to increase efficacy when added to best supportive care in patients with chemotherapy-refractory metastatic CRC. In phase I–III trials, panitumumab was safe and well tolerated, with most of its adverse effects related to some form of skin toxic effect. Early studies assessing the safety and efficacy of panitumumab alongside chemotherapy have also yielded promising results, and this combination is now being investigated in the first-line and second-line settings in randomized clinical trials.
Key Points
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EGFR is frequently overexpressed in colorectal cancer (CRC) and is associated with the malignant phenotype
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EGFR is a promising treatment target in CRC
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Panitumumab is a high affinity, fully human IgG2 monoclonal antibody with proven clinical activity in metastatic CRC
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Panitumumab is active in metastatic CRC as a single agent or in combination with chemotherapy, regardless of the level of EGFR expression in the tumor
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In a phase III trial, panitumumab almost halved the risk of disease progression as compared with best supportive care alone after failure of standard chemotherapy
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Panitumumab is generally well tolerated by patients, with most of its adverse effects related to some form of skin reaction
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Predictive markers of response to EGFR-targeted therapy are currently under investigation
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References
Douillard JY et al. (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355: 1041–1047
de Gramont A et al. (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18: 2938–2947
Twelves C et al. (2002) Capecitabine as first-line treatment in colorectal cancer: pooled data from two large, phase III trials. Eur J Cancer 38 (Suppl 2): S15–S20
Twelves C et al. (2005) Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352: 2696–2704
de Gramont A et al. (2005) Oxaliplatin/5FU/LV in the adjuvant treatment of stage III colon cancer: efficacy results with a median follow-up of 4 years [abstract #3501]. J Clin Oncol 23: a16S
Wolmark N et al. (2005) A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: results of NSABP Protocol C-07 [abstract #3500]. J Clin Oncol 23: a16S
Landis SH et al. (1999) Cancer statistics, 1999. CA Cancer J Clin 49: 8–31
Tournigand C et al. (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22: 229–237
Colucci G et al. (2005) Gruppo Oncologico Dell'Italia Meridionale: phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23: 4866–4875
Hurwitz H et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335–2342
Saltz L et al. (2007) Bevacizumab (Bev) in combination with XELOX or FOLFOX4: updated efficacy results from XELOX-1/ NO16966, a randomized phase III trial in first-line metastatic colorectal cancer [abstract #4028]. J Clin Oncol 25: a18S
Porebska I et al. (2000) Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERBB2, ERBB3) in colorectal adenocarcinomas and adenomas. Tumour Biol 21: 105–115
Spano JP et al. (2005) Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives. Ann Oncol 16: 189–194
Carpenter G and Cohen S (1990) Epidermal growth factor. J Biol Chem 265: 7709–7712
Hemming AW et al. (1992) Prognostic markers of colorectal cancer: an evaluation of DNA content, epidermal growth factor receptor, and Ki-67. J Surg Oncol 51: 147–152
Mayer A et al. (1993) The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer 71: 2454–2460
Aaronson SA (1991) Growth factors and cancer. Science 254: 1146–1153
Ciardiello F and Tortora G (2001) A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 7: 2958–2970
Sako Y et al. (2000) Single-molecule imaging of EGFR signalling on the surface of living cells. Nat Cell Biol 2: 168–172
Spano JP et al. (2005) Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol 16: 102–108
McKay JA et al. (2002) Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumors and lymph node metastases. Eur J Cancer 38: 2258–2264
Yang XD et al. (1999) Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 59: 1236–1243
Yang XD et al. (2001) Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 38: 17–23
Foon KA et al. (2004) Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 58: 984–990
Lynch DH and Yang XD (2002) Therapeutic potential of ABX-EGF: a fully human anti-epidermal growth factor receptor monoclonal antibody for cancer treatment. Semin Oncol 29 (Suppl 4): S47–S50
Jia XC et al. (2000) Inhibition of vascular endothelial cell growth factor and interleukin-8 production in tumor and endothelial cell lines by a fully human monoclonal antibody to epidermal growth factor receptor [abstract #290]. Cancer Res
Yang XD et al. (2000) Inhibition of human cancer growth by ABX-EGF, a fully human anti-EGF receptor monoclonal antibody [abstract #530]. Cancer Res
Iannello A and Ahmad A (2005) Role of antibody-dependent cell-mediated cytotoxicity in the efficacy of therapeutic anti-cancer monoclonal antibodies. Cancer Metastasis Rev 24: 487–499
Figlin RA et al. (2002) ABX-EGF, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with advanced cancer: phase 1 clinical results [abstract #35]. Proc Am Soc Clin Oncol 21: 10a
Roskos L et al. (2002) Low pharmacokinetic variability facilitates optimal dosing of ABX-EGF in cancer patients [abstract #362]. Proc Am Soc Clin Oncol 21
Cunningham D et al. (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351: 337–345
Arends R et al. (2005) Flexible dosing schedules of panitumumab (ABX-EGF) in cancer patients [abstract #3089]. J Clin Oncol 23: a16S
Weiner LM et al. (2005) Updated results from a dose and schedule study of panitumumab (ABX-EGF) monotherapy, in patients with advanced solid malignancies [abstract #3059]. J Clin Oncol 23: a16S
Stephenson J et al. (2007) Administration of panitumumab (Pmab) as a 30-min or 60-min infusion: Safety and pharmacokinetics (PK) from a phase 1 study in patients (pts) with solid tumors [abstract #368]. Gastrointestinal Cancers Symposium: 2007, January 19–21: Orlando
Yamada Y et al. (2007) Safety and pharmacokinetics (PK) of panitumumab in Japanese patients (pts) with advanced solid malignancies [abstract #385]. Gastrointestinal Cancers Symposium: 2007, January 19–21: Orlando
Malik I et al. (2005) Safety and efficacy of panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC) [abstract #3520]. J Clin Oncol 23: a16S
Berlin J et al. (2006) Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing ≥ 10% epidermal growth factor receptor (EGFr) [abstract #3548]. J Clin Oncol 24: a18S
Hecht JR et al. (2007) Panitumumab activity in metastatic colorectal cancer (mCRC) patients (pts) with low or negative tumor epidermal growth factor receptor (EGFr) levels: an updated analysis [abstract #350]. Gastrointestinal Cancers Symposium: 2007, January 19–21: Orlando
Hecht J et al. (2006) Panitumumab in combination with 5-fluorouracil, leucovorin, and irinotecan (IFL) or FOLFIRI for first-line treatment of metastatic colorectal cancer (mCRC) [abstract # 237]. Gastrointestinal Cancers Symposium: 2007, January 19–21: Orlando
Saltz LB et al. (2005) Interim report of randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer [abstract #169b]. Gastrointestinal Cancers Symposium: 2007, January 19–21: Orlando
Schwartzberg L et al. (2007) Safety and pharmacokinetics (PK) of AMG 706 with panitumumab plus FOLFIRI or FOLFOX for the treatment of patients (pts) with metastatic colorectal cancer (mCRC) [abstract #4081]. J Clin Oncol 25: a18S
Hecht J et al. (2007) An interim analysis of efficacy and safety from a randomised controlled trial of panitumumab with chemotherapy plus bevacizumab (BEV) in metastatic colorectal cancer (MCRC) [abstract #O-0033]. Ann Oncol 18 (Suppl 7): aSvii21
Van Cutsem E et al. (2007) 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 25: 1658–1664
Peeters M et al. (2007) Efficacy and safety of panitumumab across five clinical studies in patients (pts) with metastatic colorectal cancer (mCRC) [abstract #336]. Gastrointestinal Cancers Symposium: 2007, January 19–21: Orlando
Hecht RJ et al. (2006) Safety and tolerability of panitumumab, a fully human monoclonal antibody (Mab), in patients with metastatic colorectal cancer (mCRC). Ann Oncol 17 (Suppl 9): 124
Giusti RM et al. (2007) FDA Drug Approval Summary: panitumumab (Vectibix™). Oncologist 12: 577–583
Segaert S and Van Cutsem E (2005) Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 16: 1425–1433
Hendlisz A et al. (2006) Treatment effect with panitumumab by skin toxicity: results from a phase 3 trial. Ann Oncol 17 (Suppl 9): 284
Humblet Y et al. (2007) Association of skin toxicity (ST) severity with clinical outcomes and health-related quality of life (HRQoL) with panitumumab (Pmab) [abstract #4038]. J Clin Oncol 25: a18S
Van Cutsem E et al. (2007) A phase III randomized controlled trial of panitumumab (Pmab) in patients (pts) with metastatic colorectal cancer (mCRC): Subset analyses in elderly pts and in pts with poor performance status [abstract #349]. Gastrointestinal Cancers Symposium: 2007, January 19–21: Orlando
Tejpar S et al. (2007) Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol 8: 387–394
Helbling D and Borner M (2007) Successful challenge with the fully human EGFR antibody panitumumab following an infusion reaction with the chimeric EGFR antibody cetuximab. Ann Oncol 18: 963–964
Langerak A et al. (2007) Institutional experiences with panitumumab monotherapy in metastatic colorectal cancer (mCRC) patients (pts) intolerant to cetuximab. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007. 14579
ERBITUX™ (Cetuximab) label details [http://www.fda.gov/cder/foi/label/2004/125084lbl.pdf]
Hotta K et al. (2005) Interstitial lung disease in Japanese patients with non-small cell lung cancer receiving gefitinib: an analysis of risk factors and treatment outcomes in Okayama Lung Cancer Study Group. Cancer J 11: 417–424
Amgen discontinues Vectibix(TM) treatment in PACCE trial evaluating Vectibix(TM) as part of triple combination regimen (2007). Press release 22/03/07 [http://www.ext.amgen.com/media/media_pr_detail.jsp?year=2007&releaseID =977186]
Saltz LB et al. (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22: 1201–1208
Saltz L (2005) Epidermal growth factor receptor-negative colorectal cancer: is there truly such an entity? Clin Colorectal Cancer 5 (Suppl 2): S98–S100
Chung KY et al. (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23: 1803–1810
Hebbar M et al. (2006) Lack of usefulness of epidermal growth factor receptor expression determination for cetuximab therapy in patients with colorectal cancer. Anticancer Drugs 17: 855–857
Lenz HJ et al. (2006) Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24: 4914–4921
Van Cutsem E et al. (2007) Cetuximab dose-escalation study in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): pharmacokinetic and efficacy data of a randomized study [abstract #237]. Gastrointestinal Cancers Symposium: 2007, January 19–21: Orlando
Cappuzzo F et al. (2005) Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97: 643–655
Takano T et al. (2005) Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 23: 6829–6837
Moroni M et al. (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6: 279–286
Lievre A et al. (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66: 3992–3995
Vallbohmer D et al. (2005) Molecular determinants of cetuximab efficacy. J Clin Oncol 23: 3536–3544
Vincenzi B et al. (2006) New issues on cetuximab mechanism of action in epidermal growth factor receptor-negative colorectal cancer: the role of vascular endothelial growth factor. J Clin Oncol 24: 1957
Eberhard DA et al. (2005) Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23: 5900–5909
Lynch TJ et al. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139
De Roock W et al. (2007) KRAS mutations preclude tumor shrinkage of colorectal cancers treated with cetuximab [abstract #4132]. Proc Am Soc Clin Oncol 25: a18s
Shia J et al. (2005) Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study. Mod Pathol 18: 1350–1356
Garufi C et al. (2006) Epidermal growth factor gene amplification is not frequent and cannot account for antitumor activity of cetuximab plus chemotherapy in advanced colorectal cancer patients. 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement) 3561
Sauer T et al. (2005) Demonstration of EGFR gene copy loss in colorectal carcinomas by fluorescence in situ hybridization (FISH): a surrogate marker for sensitivity to specific anti-EGFR therapy? Histopathology 47: 560–564
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Y Humblet declared he is a Consultant and has been on the Speakers bureau for Amgen. He also received grant and research support from Amgen. M Mano declared no competing interests.
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Mano, M., Humblet, Y. Drug Insight: panitumumab, a human EGFR-targeted monoclonal antibody with promising clinical activity in colorectal cancer. Nat Rev Clin Oncol 5, 415–425 (2008). https://doi.org/10.1038/ncponc1136
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DOI: https://doi.org/10.1038/ncponc1136
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