Effect Of EGFR Status And EGFR-TKIs On The Efficacy And Duration Of Pemetrexed In Advanced Lung Adenocarcinoma Postgraduate

Objectives:1.Differences in the efficacy and Duration Of Therapy(DOT)of pemetrexed treatment in patients with advanced lung adenocarcinoma with or without EGFR mutations;2.Differences in the efficacy and DOT of pemetrexed treatment among different types of EGFR initial mutations(19del/21L858 R mutations,rare mutations and compound mutations);3.Whether there is a difference in the efficacy and DOT of subsequent pemetrexed treatment with different types of EGFR-TKIs(first-,second-,and third-generation TKIs)in first-line treatment and with or without T790 M mutations after TKIs resistance.Methods:Patients with advanced lung adenocarcinoma attending Yunnan Cancer Hospital(Third Affiliated Hospital of Kunming Medical University)from September 2016 to September 2021 were collected and divided into study and control groups according to the presence or absence of EGFR mutation.The study group were all EGFR mutated and were treated with pemetrexed-containing regimen after resistance to firstline EGFR-TKIs;the control group were all EGFR wild-type and were treated with pemetrexed-containing regimen as first-line treatment.Baseline demographic characteristics,laboratory test results and imaging indices were collected,and SPSS25.0 statistical software was used to describe and analyze baseline information,pemetrexed efficacy and duration of treatment.In the analysis of curative effect,the factors that were significant in univariate analysis were further analyzed by multivariate binary logistic model.Kaplan-Meier method and log-rank test were used to analyze the duration of treatment.Factors significant in univariate analysis were included in Cox proportional hazard regression for further analysis.Primary study endpoint: pemetrexed DOT in both groups;secondary study endpoint: pemetrexed treatment efficacy(ORR,DCR)in both groups;exploratory endpoint: whether there is a difference in pemetrexed treatment efficacy and DOT after different initial EGFR mutation types and first-line treatment with different EGFR-TKIs.Results:1.DOT analysis of pemetrexed in both groups188 patients progressed after pemetrexed chemotherapy and reached the followup endpoint.The median pemetrexed DOT was 10.1(7.02,14.80)months in 98 patients with EGFR wild type and 5.31(3.54,7.22)months in 90 patients with EGFR mutant type,with a significant difference between the two groups(P< 0.001).2.Analysis of the factors influencing the DOT of pemetrexedThe median DOT of pemetrexed treatment was longer in EGFR wild-type patients than in EGFR mutant patients(10.1 vs.5.31 months),and the difference between the two groups was significant(P<0.001);univariate analysis showed a correlation between EGFR mutation status,smoking status and pemetrexed DOT(P<0.001,P =0.039),and multivariate analysis found that EGFR mutation status was independently associated with pemetrexed DOT.(P < 0.001,HR=0.364,95%CI :0.265-0.500).3.Analysis of the differences in the efficacy of pemetrexed in the two groupsThe efficacy evaluation after pemetrexed chemotherapy was available in 238 patients,26(21.3%)were evaluated as ORR and 224(94.1%)achieved DCR.in the EGFR wild-type and mutation groups,the ORR was 21.3% and 13.8%,respectively,and the difference between the two groups was not statistically significant(P=0.128);the DCR was 100% and 87.9%,respectively,and the difference between the two groups were significant(P=<0.001).4.Exploratory analysis in EGFR mutation subgroups4.1 Pemetrexed DOT AnalysisThe median DOT of pemetrexed was 5.63(3.57,7.93)and 4.63(2.27,6.00)months in patients with EGFR classical sensitive mutations(including 19-del,21-L858R)and rare compound mutations,respectively,and although the median DOT was longer in EGFR sensitive mutations,the difference between the two groups was not statistically significant(P=0.094);between 19-del and 21-L858 R,pemetrexed median DOT was5.30(3.57,7.83)vs.5.63(3.70,8.07)months,respectively,with no statistically significant difference between the two groups(P=0.683).For first-line use of first-and second-generation EGFR-TKIs and third-generation EGFR-TKIs,the median DOT of pemetrexed was 5.68(3.57,7.47)and 3.75(1.82,5.58)months in the two groups,respectively,with longer median DOT in patients with firstand second-line EGFR-TKIs,but the difference was not statistically significant(P=0.088);For T790M-resistant mutations,the median DOT of pemetrexed was6.19(3.57,8.27)and 4.91(3.26,7.17)months in the T790M(+)and T790M(-)groups,respectively,although the DOT was longer in patients with T790 M mutations,but the difference between the two groups was not statistically significant(P=0.383).4.2 Efficacy AnalysisAmong EGFR classical sensitive mutations(including 19-del/21-L858R)and rare and compound mutations,the DCR was 90.8% and 72.2% in the two groups,respectively,with a statistically significant difference(P=0.026),and the difference in ORR between the two groups was not statistically significant(14.3% vs.11.1%,P=0.720).For first-line use of first-and second-generation EGFR-TKIs and third-generation EGFR-TKIs,the differences in ORR(15.0% vs.3.6%)and DCR(89.0% vs.81.3%)between the two pemetrexed groups were not statistically significant(P=0.346,P=0.377,both <0.05);for the presence or absence of T790 M resistance mutations,the differences in ORR(17.6% vs.12.2%)and DCR(85.3% vs.89.0%)between the two pemetrexed groups were also not statistically significant(P=0.438,P=0.575).Conclusion(s):1.Duration of pemetrexed treatment after resistance to EGFR-TKIs in patients with EGFR mutations is shorter than with direct pemetrexed in EGFR wild-type patients,and EGFR mutations are an independent risk factor for shortened pemetrexed DOT in a standardized treatment setting.2.The DCR of pemetrexed after resistance to EGFR-TKIs in patients with EGFR mutations was lower than that of direct pemetrexed in EGFR wild-type patients.3.The DCR of subsequent pemetrexed was higher in patients with classical EGFRsensitive mutations than in patients with rare and compound mutations;there was no significant difference in the efficacy and DOT of subsequent pemetrexed in patients with 19-del and 21-L858R;there was no significant difference in the efficacy and DOT of subsequent pemetrexed after resistance to EGFR-TKIs with or without T790 M mutations with different EGFR-TKIs in first line differences.