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

Abstract

Tumor growth in the context of EGFR inhibitor resistance may remain EGFRdependent 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 signifi cant 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 confi rmed marked Sym004-induced EGFR downmodulation. MET gene amplifi cation 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 signifi cant 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. Cancer Discov; 5(6);[598][599][600][601][602][603][604][605][606][607][608][609]

GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands

“…EGFR-targeted antibodies on the market or under development differ in their isotype, binding affinity, and mechanism of EGFR binding, and show different characteristics (23,24). Recently, mixtures of antibodies targeting nonoverlapping epitopes on EGFR (Sym004 and MM-151) were developed and reported to have enhanced inhibitory activity on EGFR signaling and tumor progression (25,26).…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…Moreover, recent clinical data provide evidence of clinical activity in patients with mCRC whose disease progressed while on anti-EGFR therapies. 155 Whether or not anti-HER3 antibodies can collaborate when administered in mixtures of 2 or more antibodies is still an open question. When studying in vitro mixtures of 2 mAbs to HER3/ERBB3, involving one mAb, which inhibits NRG binding, we observed clear benefit of combining 2 anti-HER3 mAbs in terms of inhibition of several cancer cells types.…”

The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer

“…Recently, Sym004 has shown promising responses in a phase I clinical trial involving MCRC patients with disease resistant or refractory to cetuximab and/or panitumumab. Interestingly, an EGFR S492R mutation emerged in a tumor biopsy after progression to cetuximab, and this patient achieved a partial response to Sym004 (19). The aim of the current study was to characterize the efficacy of Sym004 to circumvent resistance to cetuximab driven by the emergence of ECD mutations of EGFR.…”