FCGR2A H131R and FCGR3A V158F polymorphism status in mCRC patients treated with single-agent cetuximab (IMCL 0144 and CA225045) or with second-line irinotecan plus cetuximab (EPIC): A pooled statistical analysis.

Abstract

e14025 Background: Beyond K-RAS mutation status, additional positive predictive markers are needed to identify patients who will benefit from cetuximab treatment. Recent studies demonstrate antibody-dependent cell-mediated cytotoxicity (ADCC) may be one of the modes of action for cetuximab. Previous data suggest two Fc gamma receptor polymorphisms (FCGR2A H131R/FCGR3A V158F) may predict efficacy of cetuximab. Here we present analyses of these 2 polymorphisms in 3 phase II trials of mCRC patients treated with either single agent cetuximab (IMCL0144 and CA225045 [045]) or with second-line irinotecan plus cetuximab (EPIC). Methods: A total of 317 patients (133 from IMCL 0144; 84 from EPIC; 100 from 045) had been tested for FCGR2A H131 R and FCGR3A V158F polymorphisms. FCGR2A/3A polymorphisms were tested by PCR-RFLP or allele-specific PCR technique. Results: In a pooled analysis of IMCL 0144 and EPIC, we found patients with FCGR2A 131 HH genotype had shorter PFS (median PFS=1.3 months (95%C.I: 1.2-2.4) compared to those with HR/RR genotypes. (median PFS= 2.5 months [95%CI: 1.5-3.0] p=0.036, log-rank test). No statistically significant associations were observed between FCGR2A/3A polymorphisms and tumor response rate in either all evaluable patients or in the wild-type KRAS subgroup. (p>0.05, Fisher’s exact test). There are no associations between FCGR3A polymorphisms and OS, PFS. In a separate analysis of 045, no statistically significant associations were observed between FCGR2A/3A genotype and the assessed endpoints (response rate or PFS). Conclusions: Our pooled analysis suggested that the FCGR2A polymorphism may be associated with PFS in patients with mCRC, however FCGR3A polymorphism was not associated with efficacy of cetuximab-based treatment. Further larger statistically powered studies to evaluate the significance of FCGR polymorphisms are needed, and international collaborations are necessary to address the need for larger studies to validate molecular markers in the future.