The Targeted Drugs Cetuximab Combined With Irinotecan For The Treatment Of Gastric Cancer And Clinical Research

Background:Treatment effects of advanced gastric cancer (AGC) are unsatisfactory, and the prognosis of patients suffering from AGC is poor. Thus, novel therapeutic approaches are much needed. The EGFR monoclonal antibody cetuximab inhibits the growth of several human cancer cells but has been tested rarely for the treatment of GC. The synergy between EGFR inhibition and DNA-damaging agents, such as irinotecan, has been reported, but the mechanisms are still not fully clarified. Consequently, we hypothesized cetuximab/irinotecan combination should enhance the antitumor activity of irinotecan in GC cells.Methods:The in vitro antiproliferative, proapoptotic, cell cycle arrest effects and induction of senescence were examined in SGC-7901 and MKN-45 human GC cell lines. The effects of cetuximab or irinotecan as single agents or the combination on p53, p16 and EGFR signaling pathways were also studied.Results:Cetuximab alone did not show any anti-proliferative or pro-apoptotic effect on GC cells but cetuximab combined with irinotecan synergistically inhibits GC cells proliferation and induces apoptosis and G2/M arrest. Irinotecan is capable of inducing phosphorylation of EGFR, MAPK and AKT and decreasing the expression of P27Kip1, which could be all abrogated by its combination with cetuximab.Conclusions:Cetuximab enhances the activities of irinotecan on human gastric cancer cells. Given the lack of curative options for patients with advanced gastric cancer, combination therapy with cetuximab and irinotecan, a novel therapeutic approach, warrants further study.Background:This multicenter, non-randomized phaseⅡstudy was launched to evaluate the efficacy and safety of cetuximab in combination with modified FOLFIRI as second-line treatment for advanced gastric cancer patients and to identify potential predictive biomarkers.Methods:Inclusion criteria were:18-70 years, ECOG PS≤1, histologically confirmed adenocarcinoma of stomach and failure to first-line therapy. Cetuximab was given at an initial dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2. On day 2 of each 14-day period, patients received irinotecan at a dose of 180 mg/m2; CF at a dose of 200 mg/m2; and 5-Fu as a bolus of 400 mg/m2 and then 2400 mg/m2 by continuous infusion for 46 hours. Treatment was continued until disease progression, unacceptable toxic effects, or withdrawal of consent. The primary endpoint was time to progression (TTP). Secondary endpoints included response rate (RR), overall survival (OS) and adverse events. Activating mutations in exon 2 of the K-ras gene and expression of phosphorylated EGFR and AKT in tumor samples and their association with efficacy and prognosis were also analysed.Results:Sixty-one patients were enrolled:34 males (56%),27 females (44%); median age was 52 years (range 26-69).54 patients were evaluable for response and the response rate was 33.3%. In the intention-to-treat analysis, the median TTP was 4.6 months (95% CI:3.5-5.7 months), the median OS was 8.6 months (95% CI:7.3-9.9 months). The major grade 3-4 toxicities were 52.5% neutropenia,29.5% anemia, 8.2% thrombocytopenia,6.6% diarrhea and 9.8% skin reactions. The expression of phosphorylated EGFR and AKT in tumor samples were not associated with RR, TTP or OS. No patient exhibited K-ras mutations.Conclusions:The combination of cetuximab and FOLFIRI was well-tolerated and appears to be active as second-line treatment for advanced gastric cancer patients. The mutation of the K-ras gene, expression of phosphorylated EGFR and AKT in tumor samples can not predict the outcome.