Current Colorectal Cancer Reports

, Volume 9, Issue 4, pp 326–330 | Cite as

How Do We Make Choices in Salvage Therapy: Panitumumab, Cetuximab, or Regorafenib?

Translational Colorectal Oncology (Y Jiang, Section Editor)


Colorectal cancer is the fourth commonest cancer worldwide. The survival rate is suboptimal for patients with metastatic disease. The introduction of anti-epidermal growth factor receptor (EGFR) antibodies has remarkably improved clinical outcomes. Two monoclonal antibodies targeting EGFR and one multikinase inhibitor have been approved by the FDA and Health Canada for the treatment of metastatic colorectal cancer; however, only about 10 % of patients respond to this treatment. Having wild-type KRAS is necessary but not sufficient to derive benefit from EGFR inhibition. Interestingly, patients with certain mutations such as p.G13D represent a cetuximab-sensitive subtype of KRAS mutant metastatic colorectal cancer. A few biomarkers have been identified, but we still do not know the best way to administer drugs. In this article we review the clinical data and expert opinions and summarize the recommendations.


Colorectal cancer KRAS BRAF Cetuximab Panitumumab Regorafenib Anti-epidermal growth factor receptor therapy 


Compliance with Ethics Guidelines

Conflict of Interest

Elena Tsvetkova declares that she has no conflict of interest.

Timothy R. Asmis has received compensation for service as a consultant from Bristol-Myers Squibb and Amgen, is supported by grants from Bristol-Myers Squibb, Amgen, and Bayer, has received payment for lectures, including service on speakers bureaus, from Bristol-Myers Squibb, and currently holds stock in Amgen.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Public Health Agency of Canada. Canadian cancer statistics 2012. 2013.
  2. 2.
    National Cancer Institute. Surveillance Epidemiology and End Results. 2013.
  3. 3.
    Canadian Partnership Against Cancer. Colorectal cancer incidence and mortality. Cancer control snapshot 2; November 2010.
  4. 4.
    Chibaudel B, Tournigand C, Andre T, de Gramont A. Therapeutic strategy in unresectable metastatic colorectal cancer. Ther Adv Med Oncol. 2012;4(2):75–89.PubMedCrossRefGoogle Scholar
  5. 5.
    Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, et al. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS ONE. 2009;4(10):e7287.PubMedCrossRefGoogle Scholar
  6. 6.
    • Yen LC, Uen YH, Wu DC, Lu CY, Yu FJ, Wu IC, Lin SR, Wang JY. Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg. 2010;251(2):254–60. The authors introduced the concept that activating KRAS mutants is a particularly important independent predictive marker of response to treatment with cetuximab plus chemotherapy in patients with metastatic CRC, where combining activating KRAS mutants and EGFR could help to identify the subgroup of patients most likely to respond to this treatment.Google Scholar
  7. 7.
    Health Quality Ontario. KRAS testing for anti-EGFR therapy in advanced colorectal cancer. An evidence-based and economic analysis. Ont Health Technol Assess Ser. 2010;10(25):1–49.Google Scholar
  8. 8.
    Ruzzo A, Graziano F, Canestrari E, Magnani M. Molecular predictors of efficacy to anti-EGFR agents in colorectal cancer patients. Curr Cancer Drug Targets. 2010;10:68–79.PubMedCrossRefGoogle Scholar
  9. 9.
    •• Troiani T, Zappavigna S, Martinelli E, et al. Optimizing treatment of metastatic colorectal cancer patients with anti-EGFR antibodies: overcoming the mechanisms of cancer cells resistance. Expert Opin Biol Ther. 2013;13(2):241–55. The authors discussed a number of molecular alterations involved in the mechanism of resistance to treatment of metastatic CRC with EGFR antibodies and need for development of new strategies to overcome it.PubMedCrossRefGoogle Scholar
  10. 10.
    Sartore-Bianchi A, Bencardino K, Di Nicolantonio F, et al. Integrated molecular dissection of the epidermal growth factor receptor (EGFR) oncogenic pathway to predict response to EGFR-targeted monoclonal antibodies in metastatic colorectal cancer. Target Oncol. 2010;5:19–28.PubMedCrossRefGoogle Scholar
  11. 11.
    Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancers are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69(5):1851–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Siena S, Sartore-Bianchi A, Di Nicolantonio F, et al. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 2009;101(19):1308–24.PubMedCrossRefGoogle Scholar
  13. 13.
    • Martini M, Vecchione L, Siena S, et al. Targeted therapies: how personal should we go? Natl Rev Clin Oncol. 2011;9(2):87–97. The authors analyzed data that support the genetic, biological, and biochemical differences of individual mutations in a single cancer gene and their role as predictors of sensitivity to targeted therapy in metastatic CRC.CrossRefGoogle Scholar
  14. 14.
    Vecchione L, Saridaki Z, Tejpar S. Clinical implications and quality assurance of molecular testing for EGFR-targeting agents in colorectal cancer. Curr Color Cancer Rep. 2012;8:42–50.CrossRefGoogle Scholar
  15. 15.
    Cartwright TH. Treatment decisions after diagnosis of metastatic colorectal cancer. Clin Colorectal Cancer. 2012;11(3):155–66.PubMedCrossRefGoogle Scholar
  16. 16.
    Modest DP, Reinacher-Schick A, Stintzing S, Giessen C, et al. Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated metastatic colorectal cancer: a pooled analysis. Anticancer Drugs. 2012;23(6):666–73.PubMedCrossRefGoogle Scholar
  17. 17.
    National Institute for Health and Clinical Excellence. Cetuximab (monotherapy or combination therapy), bevacizumab (in combination with non-oxaliplatin chemotherapy), and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal 150and part review of technology appraisal guidelines 118). NICE technology appraisal guidelines 242. 2012.
  18. 18.
  19. 19.
  20. 20.
    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(4):337.PubMedCrossRefGoogle Scholar
  21. 21.
    Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–8. doi:10.1056/NEJMoa071834.PubMedCrossRefGoogle Scholar
  22. 22.
    Karapetis CS, Khambata-Ford S, Jonker D, et al. K-ras mutation and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65.PubMedCrossRefGoogle Scholar
  23. 23.
    Jean GW, Shah SR. Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer. Pharmacotherapy. 2008;28(6):742–54.PubMedCrossRefGoogle Scholar
  24. 24.
    Wilke H, Glynne-Jones R, Thaler J, et al. Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL study. J Clin Oncol. 2008;26(33):5335–43.PubMedCrossRefGoogle Scholar
  25. 25.
    Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(14):2311–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103–14.PubMedCrossRefGoogle Scholar
  27. 27.
    Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the Nordic-VII study. J Clin Oncol. 2012;30(15):1755–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Primrose JN, Falk S, Finch-Jones M, et al. A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in K-ras wild-type patients with operable metastases from colorectal cancer: the new EPOC study. J Clin Oncol. 2013;31(15 Suppl):3504.Google Scholar
  29. 29.
    • Hancen NL, Chandiramani DV, Morse MA, et al. Incidence and predictors of cetuximab hypersensitivity reactions in a North Carolina academic medical center. J Oncol Pharm Pract. 2011;17(2):125–30. The authors present a retrospective medical record review that confirms a high incidence of cetuximab hypersensitivity reactions in a North Carolina academic medical center and explores whether certain factors are potential predictors for cetuximab infusion reactions.CrossRefGoogle Scholar
  30. 30.
    Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1.3-galactose. N Engl J Med. 2008;358(11):1109–17.PubMedCrossRefGoogle Scholar
  31. 31.
    Van Cutsem E, Peeters M, Siena S, 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. 2007;25(13):1658–64.PubMedCrossRefGoogle Scholar
  32. 32.
    Hecht JR, Patnaik A, Berlin J, et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer. 2007;110(5):980–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Amado RG, Wolf M, Peeters M, et al. Wild type of KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–34. doi:10.1200/JCO.2007.14.7116.PubMedCrossRefGoogle Scholar
  34. 34.
    •• Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12. The authors present results of a multicenter international trial that compared regorafenib with best supportive care in the treatment of patients with metastatic CRC who have progressed after all standard therapies. It demonstrated a survival benefit in the regorafenib group and provided evidence for a continuing role of targeted therapy after disease progression.PubMedCrossRefGoogle Scholar
  35. 35.
  36. 36.
    Martinelli E, Troiani T, Morgillo F, et al. Emerging VGFR-receptor inhibitors for colorectal cancer. Expert Opin Emerg Drugs. 2013;18:25–37.PubMedCrossRefGoogle Scholar
  37. 37.
    Landherr L. Predictive and prognostic factors in the complex treatment of patients with colorectal cancer. Magy Oncol. 2010;54:383–94.Google Scholar
  38. 38.
    Helbling D, Borner M. Successful challenge with the fully human EGFR antibody panitumumab following an infusion reaction with a chimeric EGFR antibody cetuximab. Ann Oncol. 2007;18(5):963–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.The Ottawa Hospital Cancer CentreUniversity of OttawaOttawaCanada

Personalised recommendations