1. Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer.
- Author
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Dienstmann R, Patnaik A, Garcia-Carbonero R, Cervantes A, Benavent M, Roselló S, Tops BB, van der Post RS, Argilés G, Skartved NJ, Hansen UH, Hald R, Pedersen MW, Kragh M, Horak ID, Braun S, Van Cutsem E, Tolcher AW, and Tabernero J
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal pharmacology, Antineoplastic Agents pharmacology, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Dose-Response Relationship, Drug, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Female, Gene Amplification, Genes, ras, Humans, Ligands, Male, Middle Aged, Mutation, Neoplasm Metastasis, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins B-raf genetics, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy
- Abstract
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., (©2015 American Association for Cancer Research.)
- Published
- 2015
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