Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J Clin. 2014. doi:10.3322/caac.21208
Hynes NE, Lane HA. ErbB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–54.PubMedCrossRefGoogle Scholar
Fry DW, Kraker AJ, McMichael A, et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science. 1994;265:1093–5.PubMedCrossRefGoogle Scholar
Ward WHJ, Cook PN, Slater AM, et al. Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem Pharmacol. 1994;48:659–66.PubMedCrossRefGoogle Scholar
Rodríguez J, Viúdez A, Ponz-Sarvisé M, et al. Improving disease control in advanced colorectal cancer: panitumumab and cetuximab. Crit Rev Oncol Hematol. 2010;74:193–202.PubMedCrossRefGoogle Scholar
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.PubMedCrossRefGoogle Scholar
Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.PubMedCrossRefGoogle Scholar
Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.PubMedCrossRefGoogle Scholar
Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–8.PubMedCrossRefGoogle Scholar
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;25:1658–64.PubMedCrossRefGoogle Scholar
Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28:4697–705. The authors emphasize the importance of KRAS testing for patients with mCRC
Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706–13.PubMedCrossRefGoogle Scholar
Bardelli A, Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010;28:1254–61.PubMedCrossRefGoogle Scholar
Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11–22.PubMedCrossRefGoogle Scholar
Bamford S, Dawson E, Forbes S, et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer. 2004;91:355–8.PubMedCentralPubMedGoogle Scholar
Yarden Y. The EGFR family and its ligands in human cancer signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37:S3–8.PubMedCrossRefGoogle Scholar
Ciardiello F, Tortora G. EGFR antagonist in cancer treatment. N Engl J Med. 2008;358:1160–74.PubMedCrossRefGoogle Scholar
Baselga J, Pfister D, Cooper MR, et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol. 2000;18:904–14.PubMedGoogle Scholar
Robert F, Ezekiel MP, Spencer SA, et al. Phase I study of anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol. 2001;19:3234–43.PubMedGoogle Scholar
Foon KA, Yang XD, Weiner LM, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys. 2004;58:984–90.PubMedCrossRefGoogle Scholar
Normanno N, Bianco C, De Luca A, et al. Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocrinol Relat Cancer. 2003;10:1–21.CrossRefGoogle Scholar
Saltz L, Meropol NJ, Loehrer PJ, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that express the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201–8.PubMedCrossRefGoogle Scholar
Lenz HJ, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol. 2006;24:4914–21.PubMedCrossRefGoogle Scholar
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;26:2311–9.PubMedCrossRefGoogle Scholar
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.PubMedCentralPubMedCrossRefGoogle Scholar
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. In this trial the authors showed that cetuximab did not add significant benefit to the FLOX regimen for first-line treatment of mCRC
Morgillo F, Cantile F, Fasano M, et al. Resistance mechanisms of tumour cells to EGFR inhibitors. Clin Transl Oncol. 2009;11:270–5.PubMedCrossRefGoogle Scholar
Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66:3992–5.PubMedCrossRefGoogle Scholar
Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67:2643–8.PubMedCrossRefGoogle Scholar
Van Cutsem E Lang I, Folprecht G, et al. Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mCRC): The influence of KRAS and BRAF biomarkers on outcome: Updated data from the CRYSTAL trial. Presented at the 2010 Gastrointestinal Cancers Symposium, Jan 22-24, Orlando, FL. Abstract 281.
Kohne C, Rogier P, Stroh C. Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): A meta-analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. Presented at the 2010 Gastrointestinal Cancers Symposium, Jan 22-24, Orlando, FL. Abstract 406.
Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34. In this trial the authors emphasize the importance of better selection of patients who might benefit from anti-EGFR moAbs by considering other RAS mutations
Stintzing S, Jung A, Rossius L, et al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. ESMO 2013, Amsterdam, The Netherlands: abstract LBA 17. This trial emphasizes the importance of RAS analysis and is the first randomised multicenter study to directly compare two biological agents that are active in mCRC.
Ciardiello F, Normanno N, Maiello E, et al. Molecular profiling of the CAPRI GOIM trial in KRAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pts): Cetuximab + FOLFIRI followed by FOLFOX4 ± cetuximab. ESMO 2013. Amsterdam, The Netherlands: abstract LBA 31. The authors report high intra and inter-tumor heterogeneity, indicating that several mutations can coexist in the same cancer cell, and, by considering RAS mutations, identify a subgroup of patients most likely to benefit from FOLFIRI plus cetuximab in first-line treatment.
Yang XD, Jia XC, Corvalan JR, et al. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol. 2001;38:1723.CrossRefGoogle Scholar
Peeters M, Price T, Hotko Y, et al. Randomized phase III study (20050181) of panitumumab with FOLFIRI compared to FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer (mCRC). Eur J Cancer. 2009;7:9.Google Scholar
European Medicines Agency: Committee for Medicinal Products for Human Use. May 2008 plenary meeting monthly report. http://www.emea.europa.eu/pdfs/human/press/pr/27923508en.pdf
Genome Web Daily News. FDA adds KRAS testing info to Vectibix, Erbitux Labels (Press Release, Genome Web News). http://www.genomeweb.com/dxpgx/fda-adds-kras-testing-info-vectibix-erbituxlabels
Friedman LM, Rinon A, Schechter B, et al. Synergistic down regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc Natl Acad Sci U S A. 2005;102:1915–20.PubMedCentralPubMedCrossRefGoogle Scholar
Kamat V, Donaldson JM, Kari C, et al. Enhanced EGFR inhibition and distinct epitope recognition By EGFR antagonistic MABS C225 and 425. Cancer Biol Ther. 2008;7:726–33.PubMedCrossRefGoogle Scholar
Pedersen MW, Jacobsen HJ, Koefoed K, et al. Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy. Cancer Res. 2010;70:588–97.PubMedCrossRefGoogle Scholar
Skartved NJ, Jacobsen HJ, Pedersen MW, et al. Preclinical pharmacokinetics and safety of Sym004: a synergistic antibody mixture directed against epidermal growth factor receptor. Clin Cancer Res. 2011;17:5962–72.PubMedCrossRefGoogle Scholar
Iida M, Brand TM, Starr MM, et al. Sym004, a novel EGFR antibody mixture, can overcome acquired resistance to cetuximab. Neoplasia. 2013;15:1196–206.PubMedCentralPubMedGoogle Scholar
Tabernero et al. An Open-label, Multi-center Phase I Dose Escalation Study to Investigate the Safety and Tolerability of Multiple Doses of Sym004 in Patients With Advanced Solid Tumors. ClinicalTrials.gov Identifier: NCT01117428.
Gerdes CA, Nicolini V, Herter S, et al. GA201 (RG7160): a novel, humanized, glycoengineered anti-EGFR antibody with enhanced ADCC and superior in vivo efficacy compared with cetuximab. Clin Cancer Res. 2013;19:1126–38.PubMedCrossRefGoogle Scholar
Delord JP, Tabernero J, Garcıa-Carbonero R, et al. Open-label, multicentre expansion cohort to evaluate imgatuzumab in pre-treated patients with KRAS-mutant advanced colorectal carcinoma. Eur J Cancer. 2014;50:496–505.PubMedCrossRefGoogle Scholar
Paz Ares L, Gomez Roca C, Delord JP, et al. Phase I pharmacokinetic and pharmacodynamic dose-escalation study of RG7160 (GA201), the first glycoengineered monoclonal antibody against the epidermal growth factor receptor (EGFR) in patients with advanced solid tumors. J Clin Oncol. 2011;29:3783–90.PubMedCrossRefGoogle Scholar
Cervantes-Ruiperez A, Markman B, Siena S. et al. The GAIN-C study (BP25438): Randomized phase II trial of RG7160 (GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI alone in second-line KRAS wild type (WT) or mutant metastatic colorectal cancer (mCRC). ASCO Annual Meeting. 2012. J Clin Oncol 30, 2012abstr: TPS3637A).
Friday BB, Adjei AA. Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res. 2008;14:342–6.PubMedCrossRefGoogle Scholar
Akinleye A, Furqan M, Mukhi N, et al. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:27.PubMedCentralPubMedCrossRefGoogle Scholar
Maekawa M, Nishida E, Tanoue T. Identification of the anti-proliferative protein Tob as a MAPK substrate. J Biol Chem. 2002;277:37783–7.PubMedCrossRefGoogle Scholar
Roux PP, Ballif BA, Anjum R, et al. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci U S A. 2004;101:13489–94.PubMedCentralPubMedCrossRefGoogle Scholar
Ledwith BJ, Manam S, Kraynak AR, et al. Antisense-fos RNA causes partial reversion of the transformed phenotypes induced by the c-Ha-ras oncogene. Mol Cell Biol. 1990;10:1545–55.PubMedCentralPubMedGoogle Scholar
Sebolt-Leopold JS. MEK inhibitors: a therapeutic approach to targeting the Ras-MAP kinase pathway in tumors. Curr Pharm Des. 2004; 1907–14.
Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417949–54.
Marks JL, Gong Y, Chitale D, et al. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res. 2008;68:5524–8.PubMedCentralPubMedCrossRefGoogle Scholar
Allen LF, Sebolt-Leopold JS, Meyer MB. CI-1040 (PD-184,352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol. 2003;30:105–16.PubMedCrossRefGoogle Scholar
Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. JCO. 2005;23:5281–93.CrossRefGoogle Scholar
Rinehart J, Adjei AA, Lorusso PM. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non–small-cell Lung, Breast, Colon, and Pancreatic cancer. J Clin Oncol. 2004;22:4456–62.PubMedCrossRefGoogle Scholar
Davies BR, Logie A, McKay JS, et al. AZD6244 (ARRY- 142886), a potent inhibitor of mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther. 2007;6:2209–19.PubMedCrossRefGoogle Scholar
Yeh TC, Marsh V, Bernat BA, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007;13:1576–83.PubMedCrossRefGoogle Scholar
Troiani T, Vecchione L, Martinelli E, et al. Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells. Br J Cancer. 2012;106:1648–59.PubMedCentralPubMedCrossRefGoogle Scholar
Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small- molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26:2139–46.PubMedCentralPubMedCrossRefGoogle Scholar
Kirkwood JM, Bastholt L, Robert C, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18:555–67.PubMedCentralPubMedCrossRefGoogle Scholar
Hainsworth JD, Cebotaru CL, Kanarev V, et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol. 2010;5:1630–6.PubMedCrossRefGoogle Scholar
Bodoky G, Timcheva C, Spigel DR, et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Investig New Drugs. 2012;30:1216–23.CrossRefGoogle Scholar
Bennouna J, Lang I, Valladares-Ayerbes M, et al. A Phase II, open-label, randomized study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Investig New Drugs. 2011;29:1021–8.CrossRefGoogle Scholar
Yoon J, Koo KH, Choi KY. MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. Cancer Res. 2011;71:445–53.PubMedCrossRefGoogle Scholar
SchelmanW et al. Selumetinib and Cetuximab in Treating Patients With Refractory Solid Tumors. ClinicalTrials.gov identifier: NCT01217450.
Azad N et al. Selumetinib and Cixutumumab in Treating Patients With Advanced Solid Malignancies. ClinicalTrials.gov Identifier: NCT01061749.
Iverson C, Larson G, Lai C, et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 2009;69:6839–47.PubMedCrossRefGoogle Scholar
Weekes CD, Von Hoff DD, Adjei AA, et al. Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer. Clin Cancer Res. 2013;19:1232–43.PubMedCrossRefGoogle Scholar
Chang Q, Chapman MS, Miner JN, et al. Antitumor activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts. BMC Cancer. 2010;10:515.PubMedCentralPubMedCrossRefGoogle Scholar
Infante JR, Fecher LA, Nallapareddy S, et al. Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212. J Clin Oncol. 2010;28 abstr:2503.Google Scholar
Infante JR, Fecher LA, Falchook GS, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:773–81.PubMedCrossRefGoogle Scholar
Flaherty KT, Fecher LA, Falchook GS, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14. The authors showed that trametinib improved progression-free and overall survival of patients with advanced melanoma
Wuthrick E et al. Trametinib, Fluorouracil, and Radiation Therapy Before Surgery in Treating Patients With Stage II-III Rectal Cancer.ClinicalTrials.gov Identifier: NCT0174064
Houede N, Faivre SJ, Awada A, et al. Safety and evidence of activity of MSC1936369, an oral MEK1/2 inhibitor, in patients with advanced malignancies. J Clin Oncol. 2011; 2915s, abstr 3019.
Macarulla T, Cervantes A, Roselló S, et al. Phase i/ii study of folfiri plus the mek1/2 inhibitor pimasertib (msc1936369b) as second-line treatment for kras mutated metastatic colorectal cancer. Ann Oncol. 2012;23 suppl 4:iv19–30.Google Scholar
Sidhu SS, Egile C, Malfilatre M et al. Anti-tumor activity of pimasertib in combination with SAR245409 or SAR245408 in human primary colorectal cancer xenograft models bearing PI3K/KRas and KRas mutations. Cancer Research. 2013; Volume 73, Issue 8, Supplement 1 doi: 10.1158/1538-7445.AM2013-4638, AACR 104th Annual Meeting 2013; Apr 6-10; Washington, DC. Abstract 4638
Martinelli E, Troiani T, D’Aiuto E. Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells. Int J Cancer. 2013;133:2089–101.PubMedCrossRefGoogle Scholar
Ishii N, Harada N, Joseph EW, et al. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res. 2013;73:4050–60.PubMedCentralPubMedCrossRefGoogle Scholar
Little AS, Balmanno K, Sale MJ, et al. Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in Colorectal Cancer cells. Sci Signal. 2011;4:170.Google Scholar
Martinez-Garcia M, Banerji U, Albanell J, et al. First-in-human, phase I dose-escalation study of the safety pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res. 2012;18:4806–19.PubMedCrossRefGoogle Scholar
Troiani T, Zappavigna S, Martinelli E, et al. Optimizing treatment of metastatic colorectal cancer patients with anti-EGFR antibodies: overcoming the mechanisms of cancer cell resistance. Expert Opin Biol Ther. 2013;13:241–55.PubMedCrossRefGoogle Scholar
De Roock W, De Vriendt V, Nomanno N, et al. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol. 2011;12:594–603. The authors show that other activating RAS mutations predict poorer outcome for mCRC patients treated with both cetuximab and panitumumab