The CRYSTAL trial provided strong support for the front-line use of cetuximab with FOLFIRI, although recent disappointing results in the COIN and Nordic VII trials have suggested that perhaps there is greater benefit in combining EGFR antibodies with irinotecan than with oxaliplatin. The combination of cetuximab with oxaliplatin-based therapy remains an area of uncertainty, with negative results in the phase III COIN and Nordic VII trials contrasting with very high response rates seen with FOLFOX-cetuximab in the phase II OPUS and CELIM trials.
With the increasing data showing benefit for panitumumab in phase III trials (both in first- and second-line treatment settings), selection of either agent is reasonable. In certain areas where there is a high rate of hypersensitivity reactions to cetuximab, panitumumab may be a preferred agent. There remains no evidence to support the use of panitumumab after cetuximab failure or vice versa.
The CAIRO-2 and PACCE ¬trials failed to validate the hope that a combination of targeted therapies would be additive or synergistic, and this overly toxic strategy has been eliminated from ongoing trials. The use of cetuximab in the neoadjuvant setting continues to be an active area of investigation, given the high response rates that have been reported in KRAS wild-type patients. Finally, a direct comparison of cetuximab versus bevacizumab with chemotherapy in the first-line setting remains a critical question to be addressed by ongoing studies, including CALGB 80405.
References
1. Arteaga CL. Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia. Semin Oncol 2002;29(5 suppl 14):3–9.
2. Lockhart AC, Berlin JD. The epidermal growth factor receptor as a target for colorectal cancer therapy. Semin Oncol 2005;32:52–60.
3. Messa C, Russo F, Caruso MG, Di Leo A. EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol 1998;37:285–289.
4. Porebska I, Hartozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 2000;21:105–115.
5. Khorana AA, Ryan CK, Cox C, Eberly S, Sahasrabudhe DM. Vascular endothelial growth factor, CD68, and epidermal growth factor expression and survival in patients with stage II and stage III colon carcinoma: a role for the host response in prognosis. Cancer 2003;97:960–968.
6. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001;37(suppl 4):S9–S15.
7. Huang SM, Harari PM. Epidermal growth factor receptor inhibition in cancer therapy: biology, rationale and preliminary clinical results. Invest New Drugs 1999;17:259–269.
8. Mendelsohn J. Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy. Clin Cancer Res 1997;3:2703–2707.
9. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin ¬(FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539–1544.
10. Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxali¬platin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013–2019.
11. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005;23:1803–1810.
12. Hecht JR, Mitchell E, Neubauer MA, et al. Lack of correlation between epidermal growth factor receptor status and response to panitumumab monotherapy in metastatic colorectal cancer. Clin Cancer Res 2010;16:2205–2213.
13. Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010;11:38–47.
14. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. 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.
15. 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.
16. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040–2048.
17. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757–1765.
18. Sobrero AF, Maurel J, Fehrenbacher L. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:2311–2319.