Fcγ Receptor Polymorphisms as Biomarkers for Epidermal Growth Factor Receptor Antibodies

Abstract

TO THE EDITOR: With great interest I read the editorial by Shepherd and Tsao on epidermal growth factor receptor (EGFR) biomarkers in non–small-cell lung cancer (NSCLC). In this article, the authors comment on the biomarker analyses of the BMS099 trial, which appear in the same issue of Journal of Clinical Oncology, and similar results from the First-Line Erbitux in Lung Cancer (FLEX) study, which have only been published in abstract form so far. Interestingly, validated biomarkers for EGFR-directed tyrosine kinase inhibitors in NSCLC, such as EGFR or KRAS mutations, were not predictive for responses to EGFR antibodies, suggesting fundamental differences in the therapeutic modes of action between these two classes of EGFR inhibitors. In contrast to tyrosine kinase inhibitors, EGFR antibodies, including the immunoglobulin G2 antibody panitumumab, recruit effector cells for antibody-dependent cellular cytotoxicity (ADCC). In vitro, in vivo, and clinical data, demonstrating an association between functional Fc receptor polymorphisms and response to antibody therapy, have suggested ADCC as a major effector mechanism of other therapeutic antibodies. For cetuximab, two studies reported correlations between Fc receptor polymorphisms and clinical responses in colorectal cancer, suggesting that blockade of signaling is not the only mechanism of action of cetuximab in vivo. Pending data on the impact of these Fc receptor polymorphisms for the outcome of antibody therapy in NSCLC may trigger novel approaches to enhance antibody efficacy in this difficult-to-treat tumor entity because the interactions between Fc receptors and therapeutic antibodies are amenable to antibody engineering. For example, Fc-engineered EGFR antibodies triggered killing of KRAS-mutated tumor cells that were resistant to growth inhibition and ADCC by wild-type EGFR antibodies.