title: Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer.
abstract: Tumor growth in the context of EGFR inhibitor resistance may remain EGFR-dependent and is mediated by mechanisms including compensatory ligand upregulation and de novo gene alterations. Sym004 is a two-antibody mixture targeting nonoverlapping EGFR epitopes. In preclinical models, Sym004 causes significant EGFR internalization and degradation, which translates into superior growth inhibition in the presence of ligands. In this phase I trial, we observed grade 3 skin toxicity and hypomagnesemia as mechanism-based dose-limiting events during dose escalation. In dose-expansion cohorts of 9 and 12 mg/kg of Sym004 weekly, patients with metastatic colorectal cancer and acquired EGFR inhibitor resistance were enrolled; 17 of 39 patients (44%) had tumor shrinkage, with 5 patients (13%) achieving partial response. Pharmacodynamic studies confirmed marked Sym004-induced EGFR downmodulation. MET gene amplification emerged in 1 patient during Sym004 treatment, and a partial response was seen in a patient with EGFR(S492R) mutation that is predictive of cetuximab resistance.
  
  
  CONCLUSIONS
  Potent EGFR downmodulation with Sym004 in patients with metastatic colorectal cancer and acquired resistance to cetuximab/panitumumab translates into significant antitumor activity and validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling. Further clinical development and expanded correlative analyses of response patterns with secondary RAS/EGFR mutations are warranted.
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Center affiliated to the RTICC (ISCiii), Spain. Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Dienstmann
authors.affiliation: START South Texas Accelerated Research Therapeutics, San Antonio, Texas.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (HUVR, CSIC, Universidad de Sevilla), Center affiliated to the RTICC (ISCiii), Sevilla, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Garcia-Carbonero
authors.affiliation: Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (HUVR, CSIC, Universidad de Sevilla), Center affiliated to the RTICC (ISCiii), Sevilla, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Benavent
authors.affiliation: Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Roselló
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Bastiaan B J
authors.initials: BB
authors.lastname: Tops
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: van der Post
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Center affiliated to the RTICC (ISCiii), Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Argilés
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Niels J Ø
authors.initials: NJ
authors.lastname: Skartved
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Ulla H
authors.initials: UH
authors.lastname: Hansen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Hald
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Mikkel W
authors.initials: MW
authors.lastname: Pedersen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Kragh
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Horak
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Stephan
authors.initials: S
authors.lastname: Braun
authors.affiliation: Digestive Oncology Department, University Hospitals Leuven and KULeuven, Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: START South Texas Accelerated Research Therapeutics, San Antonio, Texas.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Center affiliated to the RTICC (ISCiii), Spain. jtabernero@vhio.net.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D011905:Genes, ras; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D008024:Ligands; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; C569270:futuximab; C484760:PIK3CA protein, human