Assessment of the impact of FcγRIIIA single-nucleotide polymorphisms on the efficacy of IgG1 monoclonal antibodies in patients with advanced gastroesophageal adenocarcinoma

Abstract

Background

Immunoglobulin G1 (IgG1) monoclonal antibodies (mAbs), such as trastuzumab and ramucirumab, are utilized in advanced gastroesophageal adenocarcinoma (aGEA). The important mechanism of mAb therapeutic effect is engagement by natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC). Certain high-affinity FcγRIIIA receptor variants (substituting phenylalanine for valine at amino acid 158) on NK cells enhance fragment C receptor’s affinity for the IgG1 fragment crystallizable (Fc) domain, leading to stronger mAb antitumor effects. Three genotypes are possible at amino acid 158 position (V/V, V/F, and F/F). We attempted to determine whether FcγRIIIA genotype affected real-world responses to mAbs in aGEA patients.

Patients and methods

Whole blood was available from 74/80 patients in the PANGEA trial (NCT02213289). We identified 35 additional aGEA patients (‘non-PANGEA patients’) treated with mAbs at our institution. Utilizing PCR, we determined patient allotypes at amino acid position 158 for the FcγRIIIA gene. We calculated/compared 3-year overall survival (OS) rates between the three FcγRIIIA genotypes.

Results

The highest affinity (V/V) and heterozygotic (V/F) variants were present in 18% (20/109) and 50% (55/109) of patients, respectively. Median OS was similar across all three genotypes in PANGEA patients. In non-PANGEA patients, there was a trend towards increased survival in higher-affinity patients (i.e. V/V or V/F patients) compared to low-affinity patients (mOS 43.4 versus 23.1 months, P = 0.07); in non-PANGEA patients, higher-affinity patients had significantly higher 36-month OS (50% versus 13%, P = 0.04) compared to low-affinity patients. Non-F/F patients had an exceptional response to mAbs.

Conclusions

We report the first real-world data analyzing how FcγRIIIA genotype impacts mAb response in aGEA. Other significant molecular/clinical variables affect mAb responses. Results reiterate the importance of ADCC in aGEA. Further work is needed to elucidate why certain patients are ‘exceptional responders’ to mAb.