Cetuximab (Cetuximab, C225) is a humanized IgG1 monoclonal antibody that specifically binds to the extracellular domain of EGFR. This antibody competitively inhibits the binding of EGFR to its natural ligands and blocks the ligand-induced phosphorylation of the tyrosine kinase domain of EGFR. Cetuximab downregulates the expression of cell surface receptors and weakens receptor-related signaling. Cetuximab also kills tumor cells via antibody-dependent cellular cytotoxicity [
9]. Since cetuximab was introduced to the market in 2004 [
10], numerous phase II clinical studies have assessed the efficacy and safety of its combination with other chemotherapy regimens, including FOLFIRI, docetaxel/cisplatin, FOLFOX, and XELOX [
11‐
15]. These clinical trials have identified a tumor response rate of 41.2–52.3 % and a median OS time of 5.4–16 months for patients with advanced gastric cancer. Based on data from multiple studies, there is no significant difference in the results between first-line treatment with a combination treatment of cetuximab and other chemotherapy regimens and the use of a single-agent chemotherapeutic regimen; however, the former treatment represents an alternative choice for first-line treatment because of its relatively lower toxicity. As a second-line treatment, combination regimens including cetuximab are clearly advantageous in terms of reduced toxicity. However, whether this regimen can be regarded as the standard regimen depends on economic factors. Many Phase II and III clinical trials to investigate the effects of combination regimens including cetuximab are ongoing [
16]. Cetuximab in combination with capecitabine and cisplatin in advanced esophagogastric cancer (EXPAND), a phase III clinical trial, evaluated the efficacy of cetuximab in combination with capecitabine and cisplatin as a first-line treatment for advanced gastric cancer [
17]. However, no significant difference in the median OS time or median progression-free survival (PFS) was identified between the experimental and control groups (4.4 vs 5.6 months, respectively,
p = 0.32 and 9.4 vs 10.7 months,
p = 0.95, respectively), although the incidence of adverse reactions was increased in the experimental group compared with the control group. Multivariate analysis indicated that mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) and PIK3CA were poor prognostic factors. In colon cancer, the efficacy of cetuximab was increased in patients who carried wild-type KRAS; patients who carried the mutant KRAS were resistant to cetuximab treatment. However, the relationship between KRAS expression and treatment efficacy in gastric cancer patients has not been established.
In contrast to cetuximab, panitumumab is a completely humanized monoclonal antibody. Panitumumab is beneficial for colorectal cancer patients who have failed FOLFOX treatment. In REAL3, a phase II/III clinical trial, treatment with panitumumab combined with modified epirubicin, oxaliplatin, and capecitabine did not improve the condition of patients with esophageal, gastroesophageal junction or gastric cancer or with undifferentiated carcinoma [
18]. The median OS time using this regimen was significantly shorter than the standard regimen of epirubicin, oxaliplatin, and platinum (median OS time of 11.3 months); furthermore, the median PFS was shorter in the experimental group compared with the control group (6.0 vs 7.4 months, respectively,
p = 0.068). The tendency toward shorter survival may have been a result of inadequate chemotherapy drug doses, accelerated cancer progression after drug withdrawal or an inability to continue therapy because of the deterioration of the host’s condition. The failure of the EXPAND and REAL3 trials suggested that EGFR may not be the primary oncogenic driver in advanced gastric cancer. Therefore, the identification of predictive markers of anti-EGFR treatment outcome to determine the population that would most likely benefit from this therapy is crucial for therapeutic efficacy.