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Advances in Therapy

, Volume 35, Issue 10, pp 1497–1509 | Cite as

An Update of Efficacy and Safety of Cetuximab in Metastatic Colorectal Cancer: A Narrative Review

  • Giulia Fornasier
  • Sara Francescon
  • Paolo Baldo
Review

Abstract

Colorectal cancer is the second most common cancer, representing 13% of all diagnosed cancers. Cetuximab is a recombinant chimeric monoclonal IgG1 antibody and epidermal growth factor receptor (EGFR) inhibitor. Cetuximab is approved for the first-line treatment in combination with chemotherapy or as a single agent in patients who have failed or are intolerant to chemotherapy in patients with EGFR-expressing, RAS wild-type metastatic colorectal cancer. Cetuximab efficacy emerged from studies that were conducted to approve the drug. Cetuximab is well tolerated; its toxicities are caused by its mechanism of action and the most common adverse reaction is skin toxicity. The main purpose of this manuscript is to present an update on the evidence-based summary of efficacy and safety and on the cost-effectiveness of cetuximab. Furthermore, it suggests a management of adverse drug reactions to improve the tolerability of the drug.

Keywords

Adverse drug reactions BRAF Cetuximab EGFR Metastatic colorectal cancer 

Notes

Acknowledgements

Funding

No sources of funding were used in the preparation of this review. The article processing charges were funded by the author.

Editorial and Other Assistance

Literature search strategy was performed by Laura Ciolfi, a biomedical librarian of the Unit of Scientific and Patients’ Library at CRO Aviano IRCCS.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Giulia Fornasier, Sara Francescon and Paolo Baldo have nothing to disclose.

Compliance with Ethics Guidelines

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

Data Availability

The datasets during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. 1.
    Lenz H-J. Anti-EGFR mechanism of action: antitumor effect and underlying cause of adverse events. Oncol (Williston Park). 2006;20:5–13.Google Scholar
  2. 2.
    ERBITUX (cetuximab). https://www.erbitux.com/. Accessed 3 Apr 2018.
  3. 3.
    ClinicalTrials.gov. https://clinicaltrials.gov/. Accessed 3 Apr 2018.
  4. 4.
    Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012;13:33–42.CrossRefGoogle Scholar
  5. 5.
    Lenz H-J. Cetuximab in the management of colorectal cancer. Biol Targ Ther. 2007;1:77–91.Google Scholar
  6. 6.
    Vincenzi B, Schiavon G, Silletta M, Santini D, Tonini G. The biological properties of cetuximab. Crit Rev Oncol Hematol. 2008;68:93–106.CrossRefGoogle Scholar
  7. 7.
  8. 8.
    I numeri del cancro in Italia—2016, AIRTUM. http://www.registri-tumori.it/cms/it/node/4572. Accessed 3 Apr 2018.
  9. 9.
    Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017;3:524–48.CrossRefGoogle Scholar
  10. 10.
    De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753–62.CrossRefGoogle Scholar
  11. 11.
    Van Cutsem E, Köhne C-H, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.CrossRefGoogle Scholar
  12. 12.
    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;359:1757–65.CrossRefGoogle Scholar
  13. 13.
    Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015;26:13–21.CrossRefGoogle Scholar
  14. 14.
    Zhao B, Wang L, Qiu H, et al. Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget. 2016;8:3980–4000.PubMedCentralGoogle Scholar
  15. 15.
    Corcoran RB, André T, Atreya CE, et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer. Cancer Discov. 2018;8:428–43.CrossRefGoogle Scholar
  16. 16.
    ASCO Daily News. ASCO Annu. Meet. https://am.asco.org/daily-news. Accessed 17 May 2018.
  17. 17.
    Modest DP, Stintzing S, von Weikersthal LF, et al. Exploring the effect of primary tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic colorectal cancer: analysis of FIRE-3 (AIOKRK0306). Oncotarget. 2017;8:105749–60.CrossRefGoogle Scholar
  18. 18.
    Cao D-D, Xu H-L, Xu X-M, Ge W. The impact of primary tumor location on efficacy of cetuximab in metastatic colorectal cancer patients with different Kras status: a systematic review and meta-analysis. Oncotarget. 2017;8:53631–41.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017;3:194–201.CrossRefGoogle Scholar
  20. 20.
    Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials. Eur J Cancer. 1990;2017(70):87–98.Google Scholar
  21. 21.
    Missiaglia E, Jacobs B, D’Ario G, et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol. 2014;25:1995–2001.CrossRefGoogle Scholar
  22. 22.
    Van Cutsem E, Köhne C-H, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011–9.CrossRefGoogle Scholar
  23. 23.
    Van Cutsem E, Lenz H-J, Köhne C-H, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33:692–700.CrossRefGoogle Scholar
  24. 24.
    van Brummelen EMJ, de Boer A, Beijnen JH, Schellens JHM. BRAF mutations as predictive biomarker for response to anti-EGFR monoclonal antibodies. Oncologist. 2017;22:864–72.CrossRefGoogle Scholar
  25. 25.
    Piessevaux H, Buyse M, Schlichting M, et al. Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol. 2013;31:3764–75.CrossRefGoogle Scholar
  26. 26.
    Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065–75.CrossRefGoogle Scholar
  27. 27.
    Venook AP, Niedzwiecki D, Lenz H-J, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA. 2017;317:2392–401.CrossRefGoogle Scholar
  28. 28.
    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;30:1755–62.CrossRefGoogle Scholar
  29. 29.
    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;351:337–45.CrossRefGoogle Scholar
  30. 30.
    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;377:2103–14.CrossRefGoogle Scholar
  31. 31.
    Sotelo MJ, García-Paredes B, Aguado C, Sastre J, Díaz-Rubio E. Role of cetuximab in first-line treatment of metastatic colorectal cancer. World J Gastroenterol. 2014;20:4208–19.CrossRefGoogle Scholar
  32. 32.
    Chan DL, Pavlakis N, Shapiro J, et al. Does the chemotherapy backbone impact on the efficacy of targeted agents in metastatic colorectal cancer? A systematic review and meta-analysis of the literature. PLoS One. 2015;10:e0135599.CrossRefGoogle Scholar
  33. 33.
    Kotake M, Aoyama T, Munemoto Y, et al. Multicenter phase II study of infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin, plus biweekly cetuximab as first-line treatment in patients with metastatic colorectal cancer (CELINE trial). Oncol Lett. 2017;13:747–53.CrossRefGoogle Scholar
  34. 34.
    Bokemeyer C, Köhne C-H, Ciardiello F, et al. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur J Cancer. 1990;2015(51):1243–52.Google Scholar
  35. 35.
    Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–8.CrossRefGoogle Scholar
  36. 36.
    Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii1–9.CrossRefGoogle Scholar
  37. 37.
    Guren TK, Thomsen M, Kure EH, et al. Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study. Br J Cancer. 2017;116:1271–8.CrossRefGoogle Scholar
  38. 38.
    Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014;15:569–79.CrossRefGoogle Scholar
  39. 39.
    Moiseyenko VM, Moiseyenko FV, Yanus GA, et al. First-line cetuximab monotherapy in KRAS/NRAS/BRAF mutation-negative colorectal cancer patients. Clin Drug Investig. 2018;38:553–62.CrossRefGoogle Scholar
  40. 40.
    Ursem C, Atreya CE, Van Loon K. Emerging treatment options for BRAF-mutant colorectal cancer. Gastrointest Cancer Targ Ther. 2018;8:13–23.CrossRefGoogle Scholar
  41. 41.
    Lam M, Pant S, Yap TA. Combination drug development in BRAF mutant colorectal cancer. Oncoscience. 2018;5:51–3.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Van Cutsem E, Cuyle P-J, Huijberts S, et al. BEACON CRC study safety lead-in (SLI) in patients with BRAFV600E metastatic colorectal cancer (mCRC): efficacy and tumor markers. J Clin Oncol. 2018;36:627.CrossRefGoogle Scholar
  43. 43.
    Array BioPharma. Array BioPharma receives FDA Breakthrough Therapy Designation for Braftovi in combination with Mektovi and cetuximab for BRAF V600E-mutant metastatic colorectal cancer. http://www.arraybiopharma.com/. Accessed 24 Aug 2018.
  44. 44.
    EudraVigilance database. https://bi.ema.europa.eu/analyticsSOAP/saw.dll?PortalPages. Accessed 29 May 2018.
  45. 45.
    FDA Adverse Events Reporting System (FAERS) public dashboard—FDA adverse events reporting system (FAERS) public dashboard. https://fis.fda.gov/sense/app/777e9f4d-0cf8-448e-8068-f564c31baa25/sheet/45beeb74-30ab-46be-8267-5756582633b4/state/analysis. Accessed 28 May 2018.
  46. 46.
    Pinto C, Barone CA, Girolomoni G, et al. Management of skin toxicity associated with cetuximab treatment in combination with chemotherapy or radiotherapy. Oncologist. 2011;16:228–38.CrossRefGoogle Scholar
  47. 47.
    Potthoff K, Hofheinz R, Hassel JC, et al. Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion. Ann Oncol. 2011;22:524–35.CrossRefGoogle Scholar
  48. 48.
    Lacouture ME, Anadkat MJ, Bensadoun R-J, et al. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer. 2011;19:1079–95.CrossRefGoogle Scholar
  49. 49.
    Hofheinz R-D, Segaert S, Safont MJ, Demonty G, Prenen H. Management of adverse events during treatment of gastrointestinal cancers with epidermal growth factor inhibitors. Crit Rev Oncol Hematol. 2017;114:102–13.CrossRefGoogle Scholar
  50. 50.
    NHS. Guidelines for cetuximab induced rashes. NHS. February 2015. (http://www.kentmedwaycancerguide.nhs.uk/EasySiteWeb/GatewayLink.aspx?alId=419417).
  51. 51.
    Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K, ESMO Guidelines Committee. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2017;28:100–18.CrossRefGoogle Scholar
  52. 52.
    Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358:1109–17.CrossRefGoogle Scholar
  53. 53.
    Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J, ESMO Guidelines Committee. Management of oral and gastrointestinal mucosal injury: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2015;26(Suppl 5):v139–51.CrossRefGoogle Scholar
  54. 54.
    Shankaran V, Ortendahl JD, Purdum AG, et al. Cost-effectiveness of cetuximab as first-line treatment for metastatic colorectal cancer in the United States. Am J Clin Oncol. 2018;41:65–72.PubMedGoogle Scholar
  55. 55.
    Park T, Choi C, Choi Y, Suh D-C. Cost-effectiveness of cetuximab for colorectal cancer. Expert Rev Pharmacoecon Outcomes Res. 2016;16:667–77.CrossRefGoogle Scholar
  56. 56.
    Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413–8.CrossRefGoogle Scholar
  57. 57.
    Huxley N, Crathorne L, Varley-Campbell J, Tikhonova I, Snowsill T, Briscoe S, et al. The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation. Health Technol Assess. 2017;21:1–294.CrossRefGoogle Scholar
  58. 58.
    Carvalho AC, Leal F, Sasse AD. Cost-effectiveness of cetuximab and panitumumab for chemotherapy-refractory metastatic colorectal cancer. PLoS One. 2017;12:e0175409.CrossRefGoogle Scholar
  59. 59.
    Chan DLH, Segelov E, Wong RS, et al. Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer. Cochrane Database Syst Rev. 2017;6:CD007047.PubMedGoogle Scholar

Copyright information

© Springer Healthcare Ltd., part of Springer Nature 2018

Authors and Affiliations

  • Giulia Fornasier
    • 1
  • Sara Francescon
    • 1
  • Paolo Baldo
    • 1
  1. 1.Department of Pharmacy, Centro di Riferimento Oncologico (CRO) di Aviano-IRCCSNational Cancer InstituteAvianoItaly

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