The Pharmacological Study And Phase Ⅰ/Ⅱa Clinical Trial Of Icotinib Hydrochloride In Advanced Non-small Cell Lung Cancer

Background and Objective:Targeted chemotherapies using epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI) is now a well treatment for some kinds of malignancy.Gefitinib and erlotinib are approved for the treatment of patients with metastatic non-small-cell lung cancer(NSCLC).However,only 9-26%of advanced-stage NSCLC patients could benefit from treatment with these agents in clinical trials.Icotinib hydrochloride (BPI-2009H),a new selective EGFR-TKI has already demonstrated active and selective antitumor activities in both in vitro and in vivo preclinical studies.At the cellular level, the study design to assess pharmacological mechanism and cytotoxicity on several lung cancer cell lines.The phaseâ… /â…¡a trial design to assess the safety and tolerability of icotinib,and to explore clinical activity in patients with advanced NSCLC after failure of prior platinum-based chemotherapy.Methods:The evaluation of icotinib hydrochloride toxicity by a real-time cell electroni c sensing(RT-CES),the EGFR,phosphorylated EGFR(p-EGFR) expression of e pidermal growth factor(EGF)-stimulated lung cancer cell line were measured by Western -blot analysis.A phaseâ… /â…¡a,open-label trial(Trial registration ID:ChiC TR-TNRC-00000194 at the Chinese Clinical Trial Register).Oral icotinib(75,10 0,125,or 150 mg) was administered once 8 hours(TID) for 28-continuous day c ycle until disease progression or undue toxicity.Tumor response was assessed by RECIST.Patients continued treatment at the same dose level as long as icotinib was tolerated and there was no evidence of disease progression.Results:In control HCC827 cells the p-EGFR expression are low,after stimulated by EGF, EGFR expression increased markly.Icotinib hydrochloride pretreatment can inhibit EGF-induced highly p-EGFR expressed and showed a good dose-dependent effects. Gefitinib pretreatment produced a similar role.The two drugs on the expression of EGFR had no significant effect.In the cell toxicity test,PC-9 was sensitive to icotinib hydrochloride or gefitinib,even if the 1.25nM concentration,HCC827 also sensitive to both drugs.H1650 was insensitive.95-D,801-D were totally insensitive to both drugs.From Dec 19 2007,we started the trial.The last patient finished recruitment on the Jan 2nd 2009.33 patients were enrolled.The highest treatment-related adverse events (TRAEs) were acne-like(or folliculitis) rash(15/33,45.5%),diarrhea(8/33, 24.2%),,white blood cells decreased(4/33,12.2%) and hepatic transaminases elevated(4/33,12.2%).They were mostly grade 1-2 and reversible on continuous treatment.No change in icotinib safety profile was observed with prolonged administration.None of these TRAEs were grade 4.Grade 3 TRAEs,which occurred in two patients,included hepatic transaminases elevated(one patients) at dose 100mg TID,mouth lceration(one patients) at dose 125mg TID.Maximum-tolerated dose(MTD) was not reached.32 patients were enrolled for clinical activity assess.No complete responses(CR) were observed.At the 24^th weeks,7 patients had PR,7 patients had SD, corresponding to a objective response rate(ORR) of 21.9%(7/32) and disease control rate(DCR) of 43.8%(14/32).Conclusion:Icotinib hydrochloride can inhibit EGF-induced highly p-EGFR expressed in HCC827 cell line with good dose-dependent mananer.Different lung cancer cell lines are with different sensitivity to icotinib hydrochloride.In the presence of mutations in exon 19 of cell is with the high sensitivity to icotinib hydrochloride.Oral icotinib was generally well tolerated,with manageable and reversible AEs in patients with advanced NSCLC.Icotinib showed positive clinical anti-tumor activities in patients with advanced NSCLC.The recommended dose for phaseâ…¡/â…¢study with icotinib is 125mg or 150mg,TID.