Predictive value of Fc gamma receptor IIIa genotype in response to conatumumab in three phase II studies.

Abstract

3103 Background: Conatumumab (AMG 655) is an investigational, fully human monoclonal agonist IgG1 antibody that selectively binds to DR5, activates caspases, and induces apoptosis in cancer cells. Conatumumab requires cross-linking to FcγRIIIa, a receptor for the Fc region of immunoglobulin G, to induce apoptosis in vitro. A polymorphism in the FCGR3A gene leads to high and low affinity forms of the receptor. We investigated whether FCGR3A genotype was predictive of response to conatumumab in three phase II clinical trials. Methods: Samples from randomized, placebo-controlled studies in non-small cell lung cancer (NSCLC), metastatic colorectal cancer (mCRC), and metastatic pancreatic cancer (mPC) were genotyped for the FCGR3A V158F SNP (rs396991) for 55, 137, and 156 subjects, respectively. Cox proportional hazard modeling was used to determine the significance of the interaction between treatment effect and FCGR3A V allele (high affinity) carrier status. Results: After adjusting for major prognostic factors, conatumumab treatment was associated with a trend of better overall survival (OS) than the control patients among the V carriers but not the F allele homozygotes in the NSCLC trial. In mCRC, OS was significantly longer in conatumumab-treated than the control patients among the V carriers, while no OS benefit was observed with conatumumab in the F homozygotes. In the mPC trial, there was no apparent impact of the polymorphism on the treatment effect of conatumumab on OS. Conclusions: FCGR3A V allele carriers trend toward stronger treatment effect on OS, suggesting that the high affinity form of FcγRIIIa may be associated with enhanced responsiveness to conatumumab. The effect of this polymorphism in response to conatumumab and other antibodies reliant on FcγRIIIa cross-linking may be different among different tumor types and needs further validation in additional studies. Cox model for interaction of treatment effect and genotype. Study No. of deaths total patients) Hazard ratio (CI)— V carriers Hazard Ratio (CI)— FF P value (adjusted) NSCLC 93 (137) 0.72 (0.43, 1.23) 1.37 (0.66, 2.86) 0.068 mCRC 38 (156) 0.39 (0.16, 0.93) 2.89 (0.83, 10.07) 0.013 mPC 45 (55) 1.25 (0.58, 2.69) 0.58 (0.21, 1.58) 0.11