To Explore The Appropriate Population Of Advanced EGFR-mutant Non-small Cell Lung Cancer Treated With The First-or Second-followed By Third-generation EGFR-TKI

BackgroundThe emergence of different generations of EGFR-TKI has completely changed the treatment model of advanced EGFR-mutant advanced NSCLC,but a new problem has emerged:how to choose an appropriate sequential treatment clinically,in order to achieve the overall survival time and chemotherapy-free survival time extension?About this question,we explored the long-term survival data,the time of occurrence of acquired T790M,the characteristics of tumor gene profile changes,the mechanism of patient resistance,and the aspects of overcoming resistance in different EGFR-TKIs sequential schemes,respectively.ObjectiveTo find out the best targeted treatment sequential program and suitable population in patients with advanced EGFR-mutant NSCLC,to predict the emergence of acquired T790M after first-line treatment with first-and second-generation EGFR-TKI;explore sequential drug resistance mechanisms and strategies to overcome resistance.MethodsWe retrospectively collected 431pqtients with EGFR-mutant advanced NSCLC who received EGFR-TKIs treatment from January 2010 to May 2020.Firstly,Patients with T790M-positive mutations and subsequent use of osimertinib were divided into 1+3 group(136 cases)and 2+3 group(39 cases),according to the EGFR-TKIs used in the first line.The patients with the First-line treatment of Osimertinib were named 3+X group(43 cases),And the survival analysis between the three groups was performed.The follow-up time was February 20,2021,the overall median follow-up was 48.7 months,the data maturity was 60.3%(1+X:75.0%;2+X:46.9%;3+X:32.6%).Secondly,Collected the paired specimens of each group before and after treatment with osimertinib,performed genetic testing,compared the differences in gene profiles in the three groups,and calculated the median time of T790M mutation appearance after the first and second generation EGFR-TKIs were used in the first line;Thirdly,collected tumor specimens from patients with EGFR-positive advanced NSCLC for organoid culture and drug sensitivity test.Results1.The median OS of patients with first-generation and second-generation EGFR-TKI was no significantly different from that of osimertinib in the FLAURA-China cohort(33.6 months vs 33.3 months vs 33.1 months,respectively).However,the median OS was significantly prolonged in the patients who used osimertinib sequentially after first-generation and second-generation drug resistance,which were 45.2 months and 37.7 months,respectively;2.Patients with 19DEL or L858R mutations at baseline and without coexistence of RBI,CTNNBI,PIK3CA gene mutations and MYC amplification are more likely to acquire T790M mutations after drug resistance.Among them,the median time of T790M appearance is 16.2 months.3.Compared with 3+X,1+3 and 2+3 regimens accounted for a greater proportion of patients with clear resistance mechanisms after drug resistance,37.5%vs 90.4%vs 76.9%;the results of organoid drug sensitivity and the resistance mechanism of patients and the clinical efficacy has good consistency,which can be used for the formulation of personalized plans to overcome drug resistance.Conclusions1.There is no difference in overall survival between first-or second-generation EGFR-TKI used in first line.However,the sequential therapy,the first-or second-followed by third-generation EGFR-TKI when T790M mutation appeared after drug resistance,can significantly prolong the overall survival of patients.2.The appropriate population for the sequential therapy may be patients who have 19DEL or L858R mutations at baseline,and do not coexist with RB1,CTNNBI,PIK3CA gene mutations and MYC amplification.The median time to appearance of T790M is 16.2 months.However,more exploration is still needed for the accurate classification of suitable population and the precise prediction of the appearance of T790M mutation;3.Using organoid model to conduct drug sensitivity test before clinical medication based on the patient's gene profile after drug resistance,which is an effective way to achieve the individualized treatment of patients.