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

Rodrigo Dienstmann,Guillem Argilés,Rocio Garcia-Carbonero,Niels J.Ø Skartved,Rachel S Van Der Post,Marta Benavent,Eric Van Cutsem,Amita Patnaik,Susana Roselló,Ulla H Hansen,Stephan Braun,Bastiaan B.J Tops,Rikke Hald,Mikkel W Pedersen,Josep Tabernero,Anthony W Tolcher,Michael Kragh,Ivan D Horak,Andrés Cervantes

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. 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.

Highlights

Metastatic colorectal cancer is expected to cause 50,000 deaths in the United States alone in 2015 [1]
Preclinical findings point to conservation of EGFR dependency of tumors that progressed upon cetuximab or panitumumab therapy [7], even in the case of acquired mutations in RAS genes [8, 9], with EGFR ligands playing a central role in autocrine and paracrine resistance networks [10,11,12]
We did observe that the cells stimulated by EGFR ligands were those that responded to EGFR inhibition, supporting the notion that EGFR dependency in colorectal cancer is largely driven by the various EGFR ligands

Summary

Introduction

Metastatic colorectal cancer is expected to cause 50,000 deaths in the United States alone in 2015 [1]. Other mechanisms of acquired cetuximab resistance include mutations in the extracellular domain of EGFR and EGFR interactions with the receptor kinases HER3 (ERBB3) or MET [10, 13,14,15,16]. These findings raise the question of whether more effective EGFR targeting, e.g., more potent receptor downmodulation, could overcome resistance to available anti-EGFR therapy [17]. Preclinical studies with Sym showed both superior induction of tumor regression as compared with other EGFR-targeting antibodies and antitumor activity in models of acquired cetuximab resistance [7, 17]. Toxicology studies in cynomolgus monkeys showed a toxicity profile consistent with other drugs of the same class, including dermatologic and gastrointestinal events [19]

Methods

Results

Conclusion