Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer

Self Cite

Purpose: In a recent randomized phase III clinical trial in metastatic colorectal cancer patients, the addition of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab to bevacizumab and chemotherapy resulted in decreased progression-free survival, in particular for patients with the high-affinity FcgRIIIA.Experimental Design: The presence of natural killer (NK) cells and type 2 (M2) macrophages in colorectal cancer was determined by immunohistochemistry, using antibodies to lineage-specific markers NKp46 and CD68 with CD163, respectively. Influence of tumor-bound cetuximab on M2 macrophages was carried out in vitro with EGFR-expressing tumor cells and short-term differentiated monocytes from blood donors, who were typed for the FcgRIIIA polymorphism (CD16).Results: Antibody-dependent cellular cytotoxicity by NK cells is generally proposed as one of the antitumor mechanisms of mAbs. We found that CD163-positive M2 macrophages are much more abundant in colorectal carcinomas. In vitro analysis of M2 macrophages revealed high levels of Fc-gamma receptors (FcgR) and PD-L1 and production of IL-10 and VEGF but not IL-12. These anti-inflammatory and tumor-promoting mediators were released upon coculture with EGFR-positive tumor cells loaded with low concentrations of cetuximab. Macrophage activation depended on EGFR expression on the tumor cells, FcgRs, target specificity of the mAb and mobility of antibody complexes. Cetuximab-induced macrophage responses were more pronounced for FCGR3A 158-Val (high-affinity) carriers.Conclusion: These results suggest that tumor-promoting M2 macrophages are activated by the therapeutic mAb cetuximab in the local tumor microenvironment and argue that this immune mechanism should be taken into account for the application of therapeutic antibodies.

Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 91%

Activation of Tumor-Promoting Type 2 Macrophages by EGFR-Targeting Antibody Cetuximab

Pander

Heusinkveld

Straaten

et al. 2011

Self Cite

“…Polymorphisms in FcgRIIA and FcgRIIIA affect the affinity with which mAbs bind to these effector cells (30). These polymorphisms have been shown to influence the efficacy of cetuximab; progression-free survival is significantly shorter in patients with the low-affinity variants compared with those homozygous for the high-affinity variants (23,31,32). Similar correlations between Fcg receptor polymorphism and response have been reported for rituximab and trastuzumab (33,34).…”

Section: Introductionsupporting

confidence: 57%

GA201 (RG7160): A Novel, Humanized, Glycoengineered Anti-EGFR Antibody with Enhanced ADCC and Superior In Vivo Efficacy Compared with Cetuximab

Gerdes

Nicolini

Herter

et al. 2013

111

109

Purpose: Anti-EGF receptor (EGFR) antibodies and small-molecule tyrosine kinase inhibitors have shown activity in epithelial tumors; however, agents that work by blocking the EGFR growth signal are ineffective when the oncogenic stimulus arises downstream, such as in tumors with KRAS mutations. Antibodies of the IgG 1 subclass can also kill tumor cells directly through antibody-dependent cell-mediated cytotoxicity (ADCC), and the efficacy of this is determined by the interaction of the Fc portion of the target cell-bound antibody and Fc receptors present on immune effector cells.Experimental Design: We report the development of GA201, a novel anti-EGFR monoclonal antibody with enhanced ADCC properties. GA201 was derived by humanization of the rat ICR62 antibody. The Fc region of GA201 was glycoengineered to contain bisected, afucosylated carbohydrates for enhanced binding to FcgRIIIA.Results: In vitro binding of GA201 to EGFR inhibited EGF ligand binding, EGFR/HER2 heterodimerization, downstream signaling, and cell proliferation to a similar extent as cetuximab. However, GA201 exhibited superior binding to both the low-and high-affinity variants of FcgRIIIA. This resulted in significantly enhanced induction of ADCC compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines. This enhanced ADCC translated into superior in vivo efficacy in a series of mouse xenograft models. Efficacy of GA201 was further increased when administered in combination with chemotherapy (irinotecan).Conclusions: These data suggest that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors.

“…However, it is reasonable to argue that given the interference from several confounding factors, including the immune-suppression effect of the accompanying chemotherapy agents, the interaction between immune effector cells, monoclonal antibodies, and cancer cells in vivo, may be by far more complex than that simulated in in vitro conditions (41,42). Moreover, it is worth noting that preclinical studies demonstrated that the different binding affinity of the FcgRIIIa genotypes was maintained at low concentrations but abolished at saturating concentrations of IgG (15,43), and the 158F allele was found to be predictive of cetuximab benefit in previous retrospective and prospective series (20)(21)(22)28).…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of the in vitro data suggesting an increased binding affinity of FcgRIIa and FcgRIIIa for IgG when amino acid changes occur at specific positions in the IgG binding domain, several studies have investigated the predictive role of genetic polymorphisms of these FcgRs in patients treated with cetuximab for metastatic colorectal cancer (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Possibly due to the retrospective design, small numbers, variable endpoints, heterogeneity of patient populations and treatments received in association with cetuximab, and methodological issues, the findings of these studies have been inconsistent (11).…”

Section: Discussionmentioning

confidence: 99%

FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Sclafani

Castro

Cunningham

et al. 2014

Purpose: FcgR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX AE cetuximab in high-risk, locally advanced rectal cancer.Experimental Design: FcgRIIa-H131R and FcgRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX ¼ 54, CAPOX-C ¼ 51). No deviation from the Hardy-Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. FcgRIIa-131R (HR, 0.38; P ¼ 0.058) and FcgRIIIa-158F alleles (HR, 0.21; P ¼ 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P ¼ 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P ¼ 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P ¼ 0.017) and remained significant after adjusting for prognostic variables (P ¼ 0.003).Conclusion: This is the first study investigating FcgRIIa and FcgRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.