Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer

Abstract

This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m À2 at week 1 and 250 mg m À2 weekly thereafter until disease progression. Oxaliplatin (100 mg m À2 ) and leucovorin (100 mg m À2) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m À2 ) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1 -65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5 -6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-a levels showed a 100% RR compared to 37.0% in the remaining 27 patients (Po0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.

Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

“…These results are supported by the current study in which the median TTP was found to be 7.6 months. A shorter TTP of median 5.5 months, together with a noteworthy response rate of 50%, was reported in the first cetuximab -chemotherapy study published from East Asia (Han et al, 2009).…”

Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method

“…However, the incidence of EGFR overexpression reported in previous studies varies from 2 % to 81 %, probably the result of differences in antibodies, scoring systems, and observers [4,21,[24][25][26][27][28][29][30][31][32]. In contrast, the frequency of EGFR gene amplification in gastric cancers is consistently less variable (2-7 %), although most of these studies lacked a sufficiently large number of patients or a detailed EGFR GCN examination [3,5,22,24,26,29,30].…”

“…The recent REAL3 (panitumumab) [19] and EXPAND (cetuximab) [20] randomized controlled phase III trials failed to demonstrate the efficacy of the anti-EGFR monoclonal antibodies for treating gastric cancer, presumably because precise patient inclusion criteria were not set for the trials. Several studies suggest that EGFR overexpression or gene amplification may serve as a potential biomarker for the efficacies of anti-EGFR therapies in gastric cancer [9,[21][22][23].…”

Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor

“…The current standard of not testing colorectal tumours for EGFR expression may not apply for other epithelial tumour histologies. It is possible that low serum ligand levels of EGF or TGFa would correlate better with response, as suggested by one study (Han et al, 2009). Recent phase II and III trials have shown that the presence of a K-ras mutation in tumours predicts response to EGFR-targeted therapy (Allegra et al, 2009).…”