Login Register Cart 0
Review Article

A Critical Review of Second-Generation Anti-EGFR Monoclonal Antibodies in Metastatic Colorectal Cancer

Author(s): Daniel Sur*, Andrei Havasi, Alecsandra Gorzo and Claudia Burz

Volume 22, Issue 9, 2021

Published on: 27 July, 2020

Page: [1034 - 1042] Pages: 9

DOI: 10.2174/1389450121666200727121011

Price: $65

Abstract

Background: Anti-EGFR monoclonal antibodies (mAbs) have become a relevant solution for the treatment of patients with metastatic colorectal cancer. Current anti-EGFR monoclonal antibodies face a series of problems, including resistance and non-durable response, and RAS and BRAF mutations serve as exclusion criteria for treatment with anti-EGFR mAbs. Advances in molecular tumor profiling and information on subsequent pathways responsible for disease progression and drug resistance helped develop a new generation of anti-EGFR mAbs. These second-generation mAbs have been developed to overcome existing resistance mechanisms and to limit common side effects. For the moment, existing literature suggests that these novel anti-EGFR mAbs are far from finding their way to clinical practice soon.

Objective: In this review, we summarize and evaluate current data regarding ongoing research and completed clinical trials for different second-generation anti-EGFR monoclonal antibodies.

Conclusion: Anti-EGFR mAbs exhibit efficacy in advanced colorectal cancer, but second-generation mAbs failed to prove their benefit in the treatment of metastatic colorectal cancer. Understanding the biological basis of primary and acquired drug resistance could allow scientists to design better clinical trials and develop improved second-generation mAbs.

Keywords: Colorectal cancer, metastatic, monoclonal antibodies, second-generation, anti-EGFR, therapy, drug targets, trials.

« Previous Next »
Graphical Abstract

[1]
Florea A, Sangaré L, Lowe K. A Multinational Assessment of Gastric, Esophageal, and Colorectal Cancer Burden: A Report of Disease Incidence, Prevalence, and Fatality. J Gastrointest Cancer 2019.
[http://dx.doi.org/10.1007/s12029-019-00328-4] [PMID: 31784876]
[2]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[3]
Brenner H, Chen C. The colorectal cancer epidemic: challenges and opportunities for primary, secondary and tertiary prevention. Br J Cancer 2018; 119(7): 785-92.
[http://dx.doi.org/10.1038/s41416-018-0264-x]
[4]
Bevan R, Rutter MD. Colorectal Cancer Screening-Who, How, and When? Clin Endosc 2018; 51(1): 37-49. [Review
[http://dx.doi.org/10.5946/ce.2017.141] [PMID: 29397655]
[5]
Tabernero J, Cervantes A, van Halteren H, Eds. Gastrointestinal Tract Tumours: Essentials For Clinicians. 2016.
[6]
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. [Practice Guideline
[http://dx.doi.org/10.1093/annonc/mdu260] [PMID: 25190710]
[7]
van Krieken JH, Jung A, Kirchner T, et al. KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch 2008; 453(5): 417-31.
[http://dx.doi.org/10.1007/s00428-008-0665-y] [PMID: 18802721]
[8]
Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A. Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution Cancer Discov 2014.4-80.(11): 1269-80..
[http://dx.doi.org/10.1158/2159-8290.CD-14-0462]
[9]
Arena S, Siravegna G, Mussolin B, Kearns JD, Wolf BB, Misale S, et al. MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations. Sci Transl Med 2016; 8(324)324ra14
[10]
Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer 2001; 92(5): 1331-46.
[http://dx.doi.org/10.1002/1097-0142(20010901)92:5<1331:AID-CNCR1455>3.0.CO;2-M] [PMID: 11571750]
[11]
Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2(2): 127-37.
[http://dx.doi.org/10.1038/35052073]
[12]
Alroy I, Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett 1997; 410(1): 83-6.
[http://dx.doi.org/10.1016/S0014-5793(97)00412-2] [PMID: 9247128]
[13]
Muthuswamy SK, Gilman M, Brugge JS. Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol 1999; 19(10): 6845-57.
[14]
Zhuang H, Xue Z-y, Wang L, Li X-y, Zhang N, Zhang R-x. Efficacy and immune mechanisms of cetuximab for the treatment of metastatic colorectal cancer Clinical Oncology and Cancer Research 2011; 8(4): 207-14.
[http://dx.doi.org/10.1007/s11805-011-0582-8]
[15]
Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006; 6(10): 803-12.
[http://dx.doi.org/10.1038/nrc1970]
[16]
Fakih M, Vincent M. Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer. Curr Oncol 2010; 17(Suppl. 1): S18-30.
[http://dx.doi.org/10.3747/co.v17iS1.615] [PMID: 20680104]
[17]
Dienstmann R, Salazar R, Tabernero J. Overcoming Resistance to Anti-EGFR Therapy in Colorectal Cancer Am Soc Clin Oncol Educ Book 2015.e149-56.
[http://dx.doi.org/10.14694/EdBook_AM.2015.35.e149]
[18]
De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, 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(8): 753-62.
[19]
Bianco R, Rosa R, Damiano V, Daniele G, Gelardi T, Garofalo S, et al. Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. Clin Cancer Res 2008; 14(16): 5069-80.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-4905]
[20]
Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012; 486(7404): 532-6.
[http://dx.doi.org/10.1038/nature11156]
[21]
Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, et al. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med 2012; 18(2): 221-3.
[22]
Braig F, März M, Schieferdecker A, et al. Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer. Oncotarget 2015; 6(14): 12035-47.
[http://dx.doi.org/10.18632/oncotarget.3574] [PMID: 26059438]
[23]
Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov 2013; 3(6): 658-73.
[24]
Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 2011; 1(6): 508-23.
[25]
Mei Z, Shao YW, Lin P, Cai X, Wang B, Ding Y, et al. SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese metastatic colorectal cancer patients. BMC Cancer 2018; 18(1): 479.
[http://dx.doi.org/10.1186/s12885-018-4298-5]
[26]
Georgiou A, Stewart A, Cunningham D, Banerji U, Whittaker SR. Inactivation of NF1 promotes resistance to EGFR inhibition in KRAS/NRAS/BRAFV600-wildtype colorectal cancer. Mol Cancer Res 2020; 18(6): 835-46.
[http://dx.doi.org/10.1158/1541-7786.MCR-19-1201] [PMID: 32098826]
[27]
De Robertis M, Loiacono L, Fusilli C, et al. Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer. Clin Cancer Res 2017; 23(1): 159-70.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0709] [PMID: 27401248]
[28]
Martini G, Cardone C, Vitiello PP, Belli V, Napolitano S, Troiani T, et al. EPHA2 is a predictive biomarker of resistance and a potential therapeutic target for improving antiepidermal growth factor receptor therapy in colorectal cancerMol Cancer Ther 2019.18-55.(4): 845-55.
[http://dx.doi.org/10.1158/1535-7163.MCT-18-0539]
[29]
Giordano G, Remo A, Porras A, Pancione M. Pancione M Immune Resistance and EGFR Antagonists in Colorectal Cancer Cancers (Basel) 2019; 11(8)
[http://dx.doi.org/10.3390/cancers11081089]
[30]
Scartozzi M, Giampieri R, Maccaroni E, Mandolesi A, Giustini L, Silva R, et al. Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab. Ann Oncol 2012; 23(7): 1706-2.
[31]
Sclafani F, Kim TY, Cunningham D, Kim TW, Tabernero J, Schmoll HJ, et al. A Randomized Phase II/III Study of Dalotuzumab in Combination With Cetuximab and Irinotecan in Chemorefractory, KRAS Wild-Type, Metastatic Colorectal Cancer J Natl Cancer Inst 2015; 107(12): djv258
[32]
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(2): 588-97.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1417] [PMID: 20068188]
[33]
Iida M, Brand TM, Starr MM, Li C, Huppert EJ, Luthar N, et al. Sym004, a novel EGFR antibody mixture, can overcome acquired resistance to cetuximab. Neoplasia 2013; 15(10): 1196-206.
[http://dx.doi.org/10.1593/neo.131584]
[34]
Napolitano S, Martini G, Martinelli E, et al. Therapeutic efficacy of SYM004, a mixture of two anti-EGFR antibodies in human colorectal cancer with acquired resistance to cetuximab and MET activation. Oncotarget 2017; 8(40): 67592-604.
[http://dx.doi.org/10.18632/oncotarget.18749] [PMID: 28978055]
[35]
Sánchez-Martín FJ, Bellosillo B, Gelabert-Baldrich M, et al. The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer. Clin Cancer Res 2016; 22(13): 3260-7.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2400] [PMID: 26888827]
[36]
Dienstmann R, Patnaik A, Garcia-Carbonero R, Cervantes A, Benavent M, Rosello S, et al. Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer Cancer Discov 2015; 5(6): 598-609.
[http://dx.doi.org/10.1158/2159-8290.CD-14-1432]
[37]
Montagut C, Argiles G, Ciardiello F, Poulsen TT, Dienstmann R, Kragh M, et al. Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2018; 4(4)e175245
[38]
Kearns JD, Bukhalid R, Sevecka M, Tan G, Gerami-Moayed N, Werner SL, et al. Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic. Mol Cancer Ther 2015; 14(7): 1625-36.
[39]
Lieu CH, Harb WA, Beeram M, Power L, Kearns JD, Nering R, et al. Phase 1 trial of MM-151, a novel oligoclonal anti-EGFR antibody combination in patients with refractory solid tumors. Journal of Clinical Oncology 2014; 32(15): 2518.
[40]
Miyamoto Y, Suyama K, Baba H. Recent Advances in Targeting the EGFR Signaling Pathway for the Treatment of Metastatic Colorectal Cancer. Int J Mol Sci 2017; 18(4)E752
[http://dx.doi.org/10.3390/ijms18040752] [PMID: 28368335]
[41]
Schaefer G, Haber L, Crocker LM, et al. A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell 2011; 20(4): 472-86.
[http://dx.doi.org/10.1016/j.ccr.2011.09.003] [PMID: 22014573]
[42]
Juric D, Dienstmann R, Cervantes A, Hidalgo M, Messersmith W, Blumenschein GR Jr, et al. Safety and Pharmacokinetics /Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors Clin Cancer Res 2015; 21(11): 2462-70
[43]
Hill AG, Findlay MP, Burge ME, Jackson C, Alfonso PG, Samuel L, et al. Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer. Clin Cancer Res 2018; 24(10): 2276-84.
[44]
Gerdes CA, Nicolini VG, Herter S, van Puijenbroek E, Lang S, Roemmele M, 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(5): 1126-38.
[45]
Oppenheim DE, Spreafico R, Etuk A, Malone D, Amofah E, Pena-Murillo C, et al. Glyco-engineered anti-EGFR mAb elicits ADCC by NK cells from colorectal cancer patients irrespective of chemotherapy. Br J Cancer 2014; 110(5): 1221-7.
[http://dx.doi.org/10.1038/bjc.2014.35]
[46]
Paz-Ares LG, Gomez-Roca C, Delord JP, Cervantes A, Markman B, Corral J, et al. Phase I pharmacokinetic and pharmacodynamic dose-escalation study of RG7160 (GA201), the first glycoengineered monoclonal antibody against the epidermal growth factor receptor, in patients with advanced solid tumors. J Clin Oncol 2011; 29(28): 3783-90.
[47]
Delord JP, Tabernero J, Garcia-Carbonero R, Cervantes A, Gomez-Roca C, Berge Y, 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(3): 496-505.
[48]
Bridgewater JA, Cervantes A, Markman B, Siena S, Cubillo A, Carbonero RG, et al. GAIN-(C): Efficacy and safety analysis of imgatuzumab (GA201), a novel dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with FOLFIRI compared to cetuximab plus FOLFIRI in second-line KRAS exon 2 wild type (e2WT) or with FOLFIRI alone in mutated (e2MT) metastatic colorectal cancer (mCRC). Journal of Clinical Oncology 2015; 33(3): 669.
[49]
ClinicalTrials.gov. Sym004 Versus Futuximab or Modotuximab in Patients With mCRC 2020.. https://clinicaltrials.gov/ct2/show/study/ NCT03549338?id=NCT02568046+OR+NCT02083653+OR+NCT 01117428+OR+NCT03549338+OR+NCT02538627+OR+NCT015 20389+OR+NCT01652482+OR+NCT01207323+OR+NCT019554 73&draw=2&rank=1&load=cart
[50]
ClinicalTrials.gov. Sym004 in Combination With FOLFIRI in Metastatic Colorectal Cancer Patients - Full Text View 2019.. https://clinicaltrials.gov/ct2/show/study/NCT03549338?id=NCT02568046+OR+NCT02083653+OR+NCT01117428+OR+NCT03549338+OR+NCT02538627+OR+NCT01520389+OR+NCT01652482+OR+NCT01207323+OR+NCT01955473&draw=2&rank=1&load=cart
[51]
Kojima T, Yamazaki K, Kato K, et al. Phase I dose-escalation trial of Sym004, an anti-EGFR antibody mixture, in Japanese patients with advanced solid tumors. Cancer Sci 2018; 109(10): 3253-62.
[http://dx.doi.org/10.1111/cas.13767] [PMID: 30099818]
[52]
ClinicalTrials.gov. Phase 1 Combination Study of MM-151 With MM-121, MM-141, or Trametinib . 2015.https://clinicaltrials.gov/ct2/show/NCT02538627?id=NCT01520389+OR+NCT01652482+OR+NCT01207323+OR+NCT02538627+OR+NCT01326000+OR+NCT00721266&draw=2&rank=1&load=cart
[53]
Kuenen B, Witteveen PO, Ruijter R, Giaccone G, Dontabhaktuni A, Fox F, et al. A phase I pharmacologic study of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed against EGFR in patients with advanced solid malignancies. Clin Cancer Res 2010; 16(6): 1915-23.
[54]
Elez E, Hendlisz A, Delaunoit T, Sastre J, Cervantes A, Varea R, et al. Phase II study of necitumumab plus modified FOLFOX6 as first-line treatment in patients with locally advanced or metastatic colorectal cancer. Br J Cancer 2016; 114(4): 372-80.
[http://dx.doi.org/10.1038/bjc.2015.480]
[55]
Bagchi A, Haidar JN, Eastman SW, Vieth M, Topper M, Iacolina MD, et al. Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab Resistance Mol Cancer Ther 2018; 17(2): 521-31.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0575]
[56]
Cleary JM, McRee AJ, Shapiro GI, Tolaney SM, O’Neil BH, Kearns JD, et al. A phase 1 study combining the HER3 antibody seribantumab (MM-121) and cetuximab with and without irinotecan. Invest New Drugs 2017; 35(1): 68-78.
[57]
Roovers R, Herpers B, James M, Eppink B, Cortina C, Maussang-Detaille D, Eds. Abstract 32: Preclinical evaluation of MCLA-158: A bispecific antibody targeting LGR5 and EGFR using patientderived colon carcinoma organoids . Proceedings of the AACR Annual Meeting. Apr 1-5, 2017; Washington, DC. 32-2.
[http://dx.doi.org/10.1158/1538-7445.AM2017-32]
[58]
ClinicalTrialsgovA Study of Bispecific Antibody MCLA-158 in Patients With Advanced Solid Tumors https://clinicaltrials.gov/ct2/show/NCT03526835?cond=NCT03526835&draw=2&rank=1
[59]
Menke-van der Houven van Oordt CW, Gootjes EC, Huisman MC, et al. 89Zr-cetuximab PET imaging in patients with advanced colorectal cancer. Oncotarget 2015; 6(30): 30384-93.
[http://dx.doi.org/10.18632/oncotarget.4672] [PMID: 26309164]
[60]
Bellaye PS, Moreau M, Raguin O, et al. Radiolabeled F(ab’)2-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models. Clin Transl Oncol 2018; 20(12): 1557-70.
[http://dx.doi.org/10.1007/s12094-018-1886-4] [PMID: 29777377]
[61]
Guo Y, Parry JJ, Laforest R, Rogers BE, Anderson CJ. The role of p53 in combination radioimmunotherapy with 64Cu-DOTA-cetuximab and cisplatin in a mouse model of colorectal cancer. J Nucl Med 2013; 54(9): 1621-9.

Rights & Permissions Print Cite
Article Metrics
40
1
© 2024 Bentham Science Publishers | Privacy Policy