2. Academic Validation
  3. Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer

Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer

  • Cancer Discov. 2015 Jun;5(6):598-609. doi: 10.1158/2159-8290.CD-14-1432.
Rodrigo Dienstmann 1,  Amita Patnaik 2,  Rocio Garcia-Carbonero 3,  Andrés Cervantes 4,  Marta Benavent 3,  Susana Roselló 4,  Bastiaan B J Tops 5,  Rachel S van der Post 5,  Guillem Argilés 6,  Niels J Ø Skartved 7,  Ulla H Hansen 7,  Rikke Hald 7,  Mikkel W Pedersen 7,  Michael Kragh 7,  Ivan D Horak 7,  Stephan Braun 7,  Eric Van Cutsem 8,  Anthony W Tolcher 2,  Josep Tabernero 9
Affiliations

Affiliations

  • 1 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.
  • 2 START South Texas Accelerated Research Therapeutics, San Antonio, Texas.
  • 3 Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (HUVR, CSIC, Universidad de Sevilla), Center affiliated to the RTICC (ISCiii), Sevilla, Spain.
  • 4 Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
  • 5 Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 6 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Center affiliated to the RTICC (ISCiii), Spain.
  • 7 Symphogen A/S, Ballerup, Denmark.
  • 8 Digestive Oncology Department, University Hospitals Leuven and KULeuven, Leuven, Belgium.
  • 9 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.
PMID: 25962717 DOI: 10.1158/2159-8290.CD-14-1432
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.

Significance: 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P991508
    抗EGFR抗体
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