Ex Vivo Antibody-Dependent Cellular Cytotoxicity Inducibility Predicts Efficacy of Cetuximab

We conducted in vitro studies and a clinical trial for patients with squamous cell carcinoma of the head and neck (SCCHN) to study the relationship between Fc gamma RIIIa polymorphisms and antibody-dependent cellular cytotoxicity (ADCC). In vitro, Fc gamma RIIIa genotype was correlated with ADCC and innate cytotoxicity using natural killer (NK) cells harvested from healthy donors. In the phase II study, patients with recurrent or metastatic SCCHN were treated with cetuximab (500 mg/m(2) i.v. every 2 weeks) and lenalidomide (25 mg daily). Fc gamma RIIIa genotype and ex vivo ADCC were correlated with clinical response, progressionfree survival (PFS), and overall survival (OS). In vitro, healthy donors with a Fc gamma RIIIa 158-V allele demonstrated more effective ADCC against two colon cancer cell lines HT29 and SW480, mean cytotoxicity: FF 16.1%, VF/VV 24.3% (P = 0.015) and FF 11.7%, VF/VV 21.0% (P = 0.008), respectively. We observed a linear relationship between ADCC response and innate cytotoxicity. In the phase II trial, 40 patients received cetuximab and lenalidomide with median PFS of 7.2 weeks and OS of 16.4 weeks. Thirtysix patients had Fc gamma RIIIa genotype: VV (2), VF (20), and FF (14), and 25 patients had sufficient NK-cell yield to perform ex vivo ADCC. Fc gamma RIIIa genotype was not associated with any clinical outcomes. Patients mounting ex vivo ADCC response had a higher likelihood of stable disease (P = 0.01) and showed a trend toward increased PFS: 14 weeks versus 6.8 weeks, respectively (P = 0.13). Enhanced ex vivo ADCC and innate immunity responses were more predictive of clinical response than Fc gamma RIIIa and may offer a functional assay to select patients suitable for cetuximab therapy. (c) 2015 AACR.