Format

Send to

Choose Destination
Cancer Discov. 2015 Jun;5(6):598-609. doi: 10.1158/2159-8290.CD-14-1432. Epub 2015 May 11.

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

Author information

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.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01117428.

PMID:
25962717
DOI:
10.1158/2159-8290.CD-14-1432
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center