Related Experiment Video
Updated: Aug 10, 2026
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal
Rodrigo Dienstmann1, Amita Patnaik2, Rocio Garcia-Carbonero3
1Vall 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.
Unlabelled:
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.
Insights
Sym004, a novel antibody mixture, effectively targets epidermal growth factor receptor (EGFR) in metastatic colorectal cancer patients resistant to prior therapies. This approach demonstrated significant tumor shrinkage, validating EGFR dependency in resistant tumors.
Area of Science:
- Oncology
- Pharmacology
Background:
- Tumor growth can persist despite epidermal growth factor receptor (EGFR) inhibitor resistance, often due to compensatory mechanisms like ligand upregulation.
- Sym004 is a dual-action antibody targeting distinct EGFR epitopes, designed to enhance receptor internalization and degradation.
Purpose of the Study:
- To evaluate the safety, tolerability, and preliminary efficacy of Sym004 in patients with metastatic colorectal cancer (mCRC) who have acquired resistance to EGFR inhibitors.
- To assess the pharmacodynamic effects of Sym004 on EGFR signaling in a clinical setting.
Main Methods:
- A Phase I clinical trial involving dose escalation and dose expansion cohorts.
- Patients with mCRC and acquired resistance to cetuximab/panitumumab received weekly doses of Sym004 (9 or 12 mg/kg).
- Tumor response, toxicity, and pharmacodynamic markers (EGFR downmodulation) were assessed.
Main Results:
- Grade 3 skin toxicity and hypomagnesemia were identified as dose-limiting toxicities.
- In the dose-expansion cohorts, 44% (17/39) of patients experienced tumor shrinkage, with 13% (5/39) achieving a partial response.
- Pharmacodynamic analyses confirmed substantial Sym004-induced EGFR downmodulation, supporting the drug's mechanism of action.
Conclusions:
- Sym004 exhibits potent EGFR downmodulation, leading to significant antitumor activity in mCRC patients with acquired resistance.
- These findings validate the hypothesis that a subset of resistant tumors remains dependent on EGFR signaling.
- Further clinical development and correlative studies, particularly focusing on secondary mutations, are warranted.
More Related Videos
15:04Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation
Published on: January 19, 2019
08:12Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
