Analysis Of The Efficacy And Related Factors Of Osimertinib After The First Generation EGFR-TKIs In Advanced Lung Adenocarcinoma With T790M Positive

Background and ObjectiveLung cancer is a malignant tumor originated from bronchial mucosa or gland,and its incidence and tumor-related mortality are the first in China and the world.This tumor is usually diagnosed in the middle and late stages with poor prognosis and is a serious threat to human health.In China,non-small cell lung cancer is the main pathological type of lung cancer,especially lung adenocarcinoma.In recent years,with the discovery of lung cancer driver genes,targeted therapy has become another important choice for patients with advanced lung adenocarcinoma.Epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKI is targeted therapy for EGFR mutant population.Compared with the traditional platinum-containing dual-drug chemotherapy,it can significantly prolong the progression-free survival time of this population and reduce the incidence of adverse reactions.However,these patients usually develop acquired drug resistance 9-13 months after taking the drug.T790M mutation in exon 20 of EGFR is considered to be the most important mechanism among various drug resistance mechanisms,accounting for about 50%.Osimertinib is a third generation EGFR-TKIs that is effective for both EGFR-sensitive mutations and T790M drug-resistant mutations.Although currently Osimertinib has been recommended as first-line therapy for advanced lung adenocarcinoma patients with EGFR mutation.At present,most of the patients taking Osimertinib in our country are patients with the first generation of EGFR-TKI resistant patients.Based on this situation,The purpose of this study is to analyze the efficacy of second-line administration of Osimertinibr and the factors related to the efficacy of Osimertinib under this sequential treatment mode.MethodsFrom January 2014 to April 2018,142 patients with advanced lung adenocarcinoma who obtained T790M mutation after the first-generation EGFR-TKIs treatment progress were retrospectively analyzed.These patients have classical mutations of EGFR exon 19 or 21,and ALK,ROS-1,HER2,KRAS,BRAF,RET,MET are all negative.The mutation status of the gene was confirmed by Arams-PCR method or(next generation sequencing,NGS)method.The first-line therapy for all the patients enrolled was the first generation EGFR-TKIs drug.The first generation of EGFR-TKIs drugs include gefitinib,erlotinib and eketinib.All of these patients obtained EGFR exon 20 T790M mutation after first-line treatment.The second-line treatment was all Osimertinib.CT was evaluated every 2 months and bone imaging and head MR were evaluated every 6 months during treatment.The curative effect is judged according to(Response Evaluation Criteria in Solid Tumors,RECIST)1.1 for solid tumors.It is evaluated as(complete response,CR),(partial response,PR),(stable disease,SD)and(progressive disease,PD).PFS is defined as PD or time of death recorded from the 1st day of medication to the first time.Follow-up was conducted by telephone and outpatient service.The deadline for follow-up is December 31,2018.SPSS 22.0 statistical software was used.The counting data is described by relative numbers.Kaplan-Meier method and Log-Rank test were used for single factor analysis affecting survival.Cox proportional hazards model was used for multivariate survival analysis.Test level α=0.05(both sides).Results1.The curative effect of 142 cases advanced lung adenocarcinoma with T790M positive after the first generation of EGFR-TKIs:mPFS of 142 patients rec eiving second-line therapy with Osimertinib is llmonths.2.Analysis of Related Factors of Osimertinib efficacy:Univariate analysis sh owed that the median PFS of osimertinib was associated with the PFS of the f irst generation EGFR-TKIs,Ki-67 index.The PFS in patients taking the first gen eration EGFR-TKIs for ≤10.0 months,the median PFS of osimertinib was 8.0 m onths(95%CI:6.718～9.282);the PFS in patients taking the first generation EGF R-TKIs for≥10.0 months,the median PFS of osimertinib was 13.0 months(95%CI:11.367～14.633),the difference was statistically significant,χ2=9.151,P=0.002.T he patients with a Ki-67 index<30%,30%～60%,≥60%respectively have a PFS of 15.0(95%CI:12.642～17.358),11.0(95%CI:9.812～12.188)and 8.0 months(95%CI:5.333～10.667),the difference was statistically significant,χ2=13.667,P=0.001.It is not related to age,gender,smoking history,stage,EGFR mutation site,PD-L1 statu s,the type of the first generation EGFR-TKIs,genetic test specimens and the me thod of genetic testing.Cox multivariate analysis showed that the PFS of the fir st generation EGFR-TKIs(HR=0.448,95%CI:0.290～0.694,P<0.01),Ki-67 index(HR=1.593,95%CI:1.224-2.074,P<0.01)was an independent positive prognostic factor affecting the median PFS of osimertinib.3.Of the 142 patients taking osimertinib,a total of 113 patients were obse rved to progress further.Further genetic testing revealed a total of 30 patients with other mutations,accounting for 26.5%of all patients with progression.The re were 12 new mutations in EGFR(including 6 cis mutations in EGFR C797 S,2 mutations in EGFR L718Q,2 mutations in EGFR G719X,1 mutation in EGFR G724S and 1 mutation in EGFR G873E).There were 17 cases of bypass activation pathway(including MET amplification in 7 cases,HER2 amplificati on in 3 cases,KRAS mutation in 1 case,PIK3CA missense mutation in 4 cas es,BRAF missense mutation in 2 cases).Another patient was converted to sarc omatoid carcinoma after drug resistance.ConclusionsIn advanced lung adenocarcinoma patients with T790M resistance mutations after the first generation EGFR-TKIs,the median PFS of osimertinib was associated with the PFS of the first generation EGFR-TKIs.Patients who developed resistance over time with the first generation EGFR-TKIs benefited more from osimertinib.Meanwhile,the higher the Ki-67 index,the less benefit from osimertinib.