title: The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer.
abstract: Approved anti-EGFR antibodies cetuximab and panitumumab provide significant clinical benefit in patients with metastatic colorectal cancer (MCRC). However, patients ultimately develop disease progression, often driven by acquisition of mutations in the extracellular domain (ECD) of EGFR. Sym004 is a novel 1:1 mixture of two nonoverlapping anti-EGFR mAbs that recently showed promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations.
  
  
  
  Functional studies were performed to assess drug-receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab, and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored EGFR mutation in the post-cetuximab tumor sample.
  
  
  
  Contrary to cetuximab and panitumumab, Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring mutations in EGFR maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As proof-of-principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy.
  
  
  
  Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials. Clin Cancer Res; 22(13); 3260-7. ©2016 AACR.
authors.affiliation: Cancer Research Program, IMIM, Hospital del Mar, Barcelona, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Sánchez-Martín
authors.affiliation: Cancer Research Program, IMIM, Hospital del Mar, Barcelona, Spain. Department of Pathology, Hospital del Mar, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bellosillo
authors.affiliation: Cancer Research Program, IMIM, Hospital del Mar, Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Gelabert-Baldrich
authors.affiliation: Cancer Research Program, IMIM, Hospital del Mar, Barcelona, Spain. Department of Pathology, Hospital del Mar, Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Dalmases
authors.affiliation: Cancer Research Program, IMIM, Hospital del Mar, Barcelona, Spain.
authors.forename: Israel
authors.initials: I
authors.lastname: Cañadas
authors.affiliation: Department of Medical Oncology, Hospital del Mar, Barcelona, Spain.
authors.forename: Joana
authors.initials: J
authors.lastname: Vidal
authors.affiliation: Cancer Research Program, IMIM, Hospital del Mar, Barcelona, Spain. Department of Medical Oncology, Hospital del Mar, Barcelona, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Argilés
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy. Department of Oncology, University of Torino, Candiolo, Torino, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Siravegna
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy. Department of Oncology, University of Torino, Candiolo, Torino, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Koefoed
authors.affiliation: Department of Medical Oncology, Hospital del Mar, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Visa
authors.affiliation: Cancer Research Program, IMIM, Hospital del Mar, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Arpí
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Ivan David
authors.initials: ID
authors.lastname: Horak
authors.affiliation: Department of Pathology, Hospital del Mar, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.affiliation: Merck-Serono, Darmstadt Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Stroh
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Kragh
authors.affiliation: Cancer Research Program, IMIM, Hospital del Mar, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rovira
authors.affiliation: Cancer Research Program, IMIM, Hospital del Mar, Barcelona, Spain. Department of Medical Oncology, Hospital del Mar, Barcelona, Spain. Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy. Department of Oncology, University of Torino, Candiolo, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Cancer Research Program, IMIM, Hospital del Mar, Barcelona, Spain. Department of Medical Oncology, Hospital del Mar, Barcelona, Spain. cmontagut@hospitaldelmar.cat.
authors.forename: Clara
authors.initials: C
authors.lastname: Montagut
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D000077544:Panitumumab; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D000077544:Panitumumab; C569270:futuximab; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab