Features Of Patients With Advanced EGFR-mutated Non-small Cell Lung Cancer Benefiting From Immune Checkpoint Inhibitors

1.Background:According to GLOBOCAN 2020,lung cancer was the second most diagnosed cancer worldwide and remained the leading cause of cancer death.However,lung cancer was still the most common cancer in China,resulting in 0.72 million deaths in 2020.Non-small cell lung cancer(NSCLC)accounts for about 80%-85%of the total number of lung cancers.Epidermal growth factor receptor(EGFR)mutation is the most common driver gene mutations in Asian patients with lung adenocarcinoma,with a mutation rate of about 50%.EGFR-tyrosine kinase inhibitors(EGFR-TKIs)significantly improved the prognosis of patients with EGFR mutation as compared to chemotherapy,especially the third generation(osimertinib)EGFR-TKIs showed a median progress free survival(mPFS)of 18.9 months.Programmed death protein-1(PD-1)and programmed death-ligand 1(PD-L1)inhibitors have shown great anti-tumor efficacy in advanced NSCLC.The main mechanism of immune checkpoint inhibitors(ICIs)was to promote the activity of cytotoxic T lymphocytes(CTLs)in tumors,activate tumor specific CTLs in lymphoid organs,and establish effective and durable anti-tumor immunity.Currently,a variety of ICIs have been approved for use at home and abroad and have become the standard treatment for patients with advanced NSCLC.However,compared with EGFR wild type,clinical evidence suggested that EGFR-mutant lung cancer patients rarely benefit from treatment of ICIs.A meta-analysis of PD-1/PD-L1 inhibitors as the second-line treatment of NSCLC and two large retrospective analysis reported that ICIs did not improve the overall survival(OS)of EGFR-mutated NSCLC patients.As for ICIs-based combined therapy,the combination of ICIs and EGFR-TKIs did not exert a synergistic anti-tumor effect in EGFR-mutated patients but increased the incidence of toxicity.ATLANTIC studies have revealed that in heavily pretreated EGFR-mutated NSCLC,patients with high PD-L1 expression had better overall response rate(ORR)than those with low PD-L1 expression when treated with durvalumab,suggesting that a subgroup of EGFR-mutated NSCLC may benefit from ICIs.In this study,we collected advanced EGFR-mutated NSCLC patients receiving ICIs alone from three previous studies and discovered the features of these patients who may benefit from ICIs.2.Purpose:This study mainly focused on the efficacy of ICIs as a single agent in the treatment of advanced NSCLC with EGFR mutations.Analyze the effects of EGFR mutation subtypes,PD-L1 expression and clinicopathological factors on the efficacy of ICIs alone in patients with EGFR mutations.Find the dominant population of ICIs treatment and explore the treatment paradigm of advanced EGFR-mutated NSCLC patients.3.Methods:This retrospective study collected advanced EGFR mutated NSCLC patients who have received ICIs(anti-PD-1 or anti-PD-L1,with or without CTLA-4 blockade)and 114 patients were finally identified from three previous studies.Sources of data sets include OAK clinical trials,Memorial Sloan Kettering Cancer Center(MSKCC)data sets,and Hastings,K.’s study.The chi-square test was used to analyze the difference of clinical variables based on different PD-L1 expression.The univariate and multivariate logistics regression analysis was applied to analyze the risk factors on PD-L1 positive.Proportions across different groups were compared using Fisher’s exact test.Time-to-event endpoints(PFS,OS)were visualized using Kaplan-Meier curves.Differences between survival curves were examined using the log-rank test.Hazard ratios(HRs)and 95%confidence intervals(CIs)were calculated using the Cox proportional hazards model.The SPSS 26.0 software package and GraphPad Prism 9.0.0 were used to make all statistical analyses.A two-sided P value less than 0.05 was considered statistically significant.4.Results:Clinical characteristics of advanced EGFR-mutated NSCLC patients:Half of the patients PD-L1 expression≥1%,and 12.28%of patients had high PD-L1 expression(PD-L1≥50%).Most patients have received other treatments before ICIs therapy,only 5 patients are treatment naive.The efficacy of ICIs on NSCLC patients with different EGFR mutation subtypes:This study evaluated the efficacy of ICIs among EGFR mutation subtypes.Major EGFR mutations include L858R and/or exon 19 deletion(19De1).Rare mutations include exon 20 insertion(20ins)and G719X.Compared with patients with rare or other EGFR mutations,patients with major EGFR mutations had shorter PFS and poorer ORR.In addition,the analysis of the efficacy of ICIs according to T790M status showed that T790M negative patients had significantly improved ORR as compared to T790M positive.But there was no statistical difference of PFS and OS between T790M positive and T790M negative patients treated with ICIs.The relationship between PD-L1 expression and the efficacy of ICIs:In the overall EGFR mutation population,the OS was longer in PD-L1<1%patients than PD-L1≥1%patients although not statistically significant.The same tendency was found in patients with major EGFR mutations.However,for patients with rare or other mutations,PD-L1 expression had no prognostic value for the efficacy of ICIs.For patients with T790M mutations,PD-L1<1%patients had a prolonged PFS and OS,but because of limited sample sizes,the difference was not statistically significant.No statistical difference was found in PFS,OS and ORR between PD-L1<50%and PD-L1≥50%patients due to lack of patients with high PD-L1 expression(PD-L1≥50%).The relationship between clinical characteristics and the efficacy of ICIs:Clinical characteristics,such as age,gender,smoking history,treatment method(monotherapy or combination therapy),were not risk factors for the efficacy of ICIs.Among the previous treated patients,the overall and major EGFR mutation patients who have received more than 3 lines of treatments before ICIs had shorter mPFS and mOS and poorer ORR.Patients with rare or other EGFR mutation and T790M mutation also had the same trend,but no statistical difference was found.5.Conclusions:This research showed that patients with major EGFR mutations responded poorly to ICIs.In advanced EGFR-mutated NSCLC patients,the efficacy of ICIs had the tendency to be negatively correlated with PD-L1 expression.For previous treated advanced EGFR-mutated NSCLC patients,ICIs should be used as early as possible.