Abstract
Background
Since 2013, informative trials exploring the optimal use of available biologic agents in the first-line setting of metastatic colorectal cancer (mCRC) have been presented. These trials have opened a stimulating debate on the biological effect that first-line therapies may have on subsequent lines of treatment even long after the first-line progression.
Materials and methods
We reviewed available preclinical and clinical data on the effect of different sequences of the biological drugs approved for use in mCRC patients. The importance of molecular selection of patients based on RAS mutational status and toxicity and quality-of-life issues were also analyzed.
Results
Convincing evidence exists on the optimal therapeutic effect obtained by using anti-EGFR agents in first-line treatment before anti-VEGF agents. On the contrary, up-front anti-VEGF agents’ use seems to determine biological changes that increase the risk of acquired resistance to subsequent EGFR inhibitors. This hypothesis is confirmed by the scarce evidence of EGFR inhibitor activity in second-line treatment. Such a therapeutic optimum is subject to a fine molecular selection based on RAS mutational status.
Conclusion
There is accumulating evidence suggesting that, after precise and well-established molecular selection, anti-EGFR agents deliver their maximum efficacy in mCRC patients when given early in the treatment strategy. Their toxicity profile seems manageable under the supervision of experienced physicians. Large randomized trials prospectively confirming the impact of different sequencing strategies are eagerly awaited.
Similar content being viewed by others
References
Heinemann V, von Weikersthal LF, Decker T et al (2013) Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRASwildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). Proc Am Soc Clin Oncol 31:LBA3506
Schwartzberg LS, Rivera F, Karthaus M et al (2014) PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 32:2240–2247
Venook AP, Niedzwiecki D, Lenz HJ et al (2014) CALGB/SWOG 80405: phase III trial of irinotecan/5- FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). Proc Am Soc Clin Oncol 32(suppl):LBA3
Zeng M, Kikuchi H, Pino MS, Chung DC (2010) Hypoxia activates the K-ras proto-oncogene to stimulate angiogenesis and inhibit apoptosis in colon cancer cells. PLoS One 5(6):e10966
Stefanini MO, Wu FT (2010) Mac Gabhann F, Popel AS. Increase of plasma VEGF after intravenous administration of bevacizumab is predicted by a pharmacokinetic model. Cancer Res 70(23):9886–9894
Kopetz S, Hoff PM, Morris JS et al (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28(3):453–459
Derangère V, Fumet JD, Boidot R et al (2016) Does bevacizumab impact anti-EGFR therapy efficacy in metastatic colorectal cancer? Oncotarget. doi:10.18632/oncotarget.7008. [Epub ahead of print]
Mimeault M, Batra SK (2013) Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J Cell Mol Med 17(1):30–54
Zhou J, Wang J, Zeng Y et al (2015) Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer. Oncotarget. doi:10.18632/oncotarget.6293. [Epub ahead of print]
Siravegna G, Mussolin B, Buscarino M et al (2015) Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 21(7):795–801
Zhang X, Gaspard JP, Chung DC (2001) Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res 61(16):6050–6054
Bianco R, Rosa R, Damiano V et al (2008) Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. Clin Cancer Res 14(16):5069–5080
Ciardiello F, Bianco R, Caputo R et al (2004) Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res 10(2):784–793
Viloria-Petit A, Crombet T, Jothy S et al (2001) Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res 61(13):5090–6101
Heinemann V, von Weikersthal LF, Decker T et al (2014) 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. 15(10):1065–1075
Stintzing S, Modest DP, von Weikersthal LF et al (2014) Lba11:independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in fire-3 (aio krk-0306) in the final ras evaluable population. Ann Oncol. doi:10.1093/annonc/mdu438.9
Rivera F, Koukakis R, Karthaus M, Hecht et al (2015) PD-014. First-line treatment with modified FOLFOX6 (mFOLFOX6) + panitumumab or bevacizumab in patients with RAS/BRAF wild-type (WT) metastatic colorectal carcinoma (mCRC). Ann Oncol 26(suppl 4):101–107
Heinemann V, Stintzing S, Modest DP et al (2015) Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC). Eur J Cancer 51(14):1927–1936
Modest DP, Stintzing S, von Weikersthal LF et al (2015) Impact of subsequent therapies on outcome of the FIRE-3/AIO KRK0306 trial: first-line therapy with FOLFIRI plus Cetuximab or Bevacizumab in patients with KRAS wild-type tumors in metastatic colorectal cancer. J Clin Oncol 33(32):3718–3726
Venook A, Niedzwiecki D, Lenz HJ et al (2015) CALGB/SWOG 80405: phase III trial of irinotecan/5-fu/leucovorin (FOLFIRI) or oxaliplatin/5-fu/leucovorin (mFOLFOX6) with bevacizumab (bv) or cetuximab (cet) for patients (pts) with kras wild-type (wt) untreated metastatic adenocarcinoma of the colon. Ann Oncol 25(suppl 2):ii112–ii113
Khattak MA, Martin H, Davidson A, Phillips M (2015) Role of first-line anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy in advanced colorectal cancer: a meta-analysis of randomized clinical trials. Clin Colorectal Cancer 14(2):81–90
Pietrantonio F, Cremolini C, Petrelli F et al (2015) First-line anti-EGFR monoclonal antibodies in panRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol 96(1):156–166
Tamburini E, Rudnas B, Gianni L et al (2015) Anti-EGFR or Bevacizumab in first line treatment of RAS wild type metastatic colorectal neoplasm (RwtMCRC): meta-analysis of randomized clincal trials. Ann Oncol 26(suppl 6):vi36–vi52
Sobrero AF, Maurel J, Fehrenbacher L et al (2008) EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26(14):2311–2319
Langer C, Kopit J, Awad M et al (2008) Analysis of k-ras mutations in patients with metastatic colorectal cancer receiving cetuximab in combination with irinotecan: results from the epic trial. Ann Oncol 19(Supplement):8. doi:10.1093/annonc/mdn507.viii.133
Seymour MT, Brown SR, Middleton G et al (2013) Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 14(8):749–759
Peeters M, Price TJ, Cervantes A et al (2014) Final results from a randomized phase 3 study of FOLFIRI ± panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol 25(1):107–116
Peeters M, Oliner KS, Price TJ et al (2015) Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin Cancer Res 21(24):5469–5479
Giantonio BJ, Catalano PJ, Meropol NJ et al (2007) 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 25(12):1539–1544
Van Cutsem E, Tabernero J, Lakomy R et al (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30(28):3499–3506
Tabernero J, Van Cutsem E, Lakomý R et al (2014) Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 50(2):320–331
Bennouna J, Sastre J, Arnold D et al (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 14(1):29–37
Tabernero J, Yoshino T, Cohn AL et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 16(5):499–508
Cascinu S, Lonardi S, Rosati G et al (2015) A phase III multicenter trial comparing two different sequences of second/third line therapy (cetuximab/irinotecan followed by FOLFOX versus FOLFOX followed by cetuximab/irinotecan) in metastatic K-RAS wt colorectal cancer (mCC) patients, refractory to FOLFIRI/Bevacizumab). Eur J Cancer 51(suppl 3):S329
Hecht JR, Cohn A, Dakhil S et al (2015) SPIRITT: a randomized, multicenter, phase II study of panitumumab with FOLFIRI and bevacizumab with FOLFIRI as second-line treatment in patients with unresectable wild type KRAS metastatic colorectal cancer. Clin Colorectal Cancer. 14(2):72–80
Karapetis CS, Khambata-Ford S, Jonker DJ et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765
Hess GP, Wang PF, Quach D et al (2010) Systemic therapy for metastatic colorectal cancer: patterns of chemotherapy and biologic therapy use in US medical oncology practice. J Oncol Pract. 6(6):301–307
Abrams TA, Meyer G, Schrag D et al (2014) Chemotherapy usage patterns in a US-wide cohort of patients with metastatic colorectal cancer. J Natl Cancer Inst 106(2):djt371
Grothey A, Sargent D, Goldberg RM, Schmoll HJ (2004) Survival of patients with advanced colorectal cancer improves with the availability of fl uorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209–1214
Loupakis F, Cremolini C, Masi G et al (2014) Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 371(17):1609–1618
Cremolini C, Loupakis F, Antoniotti C et al (2015) FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 16(13):1306–1315
Cremolini C, Loupakis F, Antoniotti C et al (2015) Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol 26(6):1188–1194
Gruenberger T, Bridgewater J, Chau I et al (2015) Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol 26(4):702–708
Ranpura V, Hapani S, Wu S (2011) Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 305(5):487–494
Lacouture ME, Mitchell EP, Piperdi B et al (2010) Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 28(8):1351–1357
Kobayashi Y, Komatsu Y, Yuki S et al (2015) Randomized controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic colorectal cancer: hGCSG1001 study. J-STEPP. Future Oncol. 11(4):617–627
Melosky B, Anderson H, Burkes RL et al (2015) Pan canadian rash trial: a randomized phase III trial evaluating the impact of a prophylactic skin treatment regimen on epidermal growth factor receptor-tyrosine kinase inhibitor-induced skin toxicities in patients with metastatic lung cancer. J Clin Oncol. pii: JCO.2015.62.3918. [Epub ahead of print]
Van Cutsem E, Köhne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360(14):1408–1417
Láng I, Köhne CH, Folprecht G et al (2013) Quality of life analysis in patients with KRAS wild-type metastatic colorectal cancer treated first-line with cetuximab plus irinotecan, fluorouracil and leucovorin. Eur J Cancer 49(2):439–448
Rowland A, Dias MM, Wiese MD, Kichenadasse G, McKinnon RA, Karapetis CS, Sorich MJ (2015) Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer 112(12):1888–1894
Yoshino T, Uetake H, Tsuchihara K et al. (2016) PARADIGM study: A multicenter, randomized, phase III study of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer. J Clin Oncol 34, (suppl 4S; abstr TPS776)
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have declared no conflicts of interest.
Rights and permissions
About this article
Cite this article
Zaniboni, A., Formica, V. The Best. First. Anti-EGFR before anti-VEGF, in the first-line treatment of RAS wild-type metastatic colorectal cancer: from bench to bedside. Cancer Chemother Pharmacol 78, 233–244 (2016). https://doi.org/10.1007/s00280-016-3032-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-016-3032-8