Optimal Treatment Strategies for EGFR Mutant Advanced Lung Adenocarcinoma Patients with Targeted Therapy Resistance and Correlation Analysis of PD-L1 Expression with ICI Efficacy

Optimal Treatment Strategies for EGFR Mutant Advanced Lung Adenocarcinoma Patients with Targeted Therapy Resistance and Correlation Analysis of PD-L1 Expression with ICI Efficacy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Optimal Treatment Strategies for EGFR Mutant Advanced Lung Adenocarcinoma Patients with Targeted Therapy Resistance and Correlation Analysis of PD-L1 Expression with ICI Efficacy Jiling Niu, Xuquan Jing, zhongyu Shi, zhuoran Sun, hui Zhu, zhaidong Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7774591/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Third-generation tyrosine kinase inhibitors (TKIs) have become the standard treatment for advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. Currently, after developing resistance to third-generation EGFR-TKIs, treatment regimens based on platinum-based dual-agent chemotherapy yield limited clinical benefit. Method This retrospective study analyzed patients who progressed on first-line third-generation EGFR-TKIs between March 2019 and September 2024 and received second-line chemotherapy-based regimens. Patients were further stratified based on PD-L1 expression status and immune checkpoint inhibitor (ICI) use to assess the correlation between PD-L1 expression and ICI efficacy. Results Among 107 patients who progressed on third-generation TKIs as first-line therapy, 35 received chemotherapy (CP), 29 received chemotherapy combined with anti-angiogenic (BCP), 22 received chemoimmunotherapy (ACP), and 21 received chemoimmunotherapy combined with anti-angiogenic therapy (ABCP). Second-line median progression-free survival (mPFS2) were 4.89 months, 6.74 months, 7.80 months, and 8.00 months, respectively. Non-ICIs group vs. ICIs group: mPFS2 was 5.06 months vs. 8.00 months, P = 0.031. In PD-L1-negative, positive, and strong subgroups, the Non-ICIs group vs. ICIs group showed mPFS2 of 5.32 months vs. 6.68 months, P = 0.724; 4.89 months vs. 8.63 months, P = 0.009, and 3.11 months vs. 13.52 months, P < 0.001. Conclusion Among patients with EGFR-TKI resistance, combination immunochemotherapy with or without anti-angiogenic therapy demonstrates distinct advantages over chemotherapy alone. Adding ICIs in PD-L1-positive patients improves progression-free survival, with greater clinical benefit observed at higher PD-L1 expression levels. Within the immunotherapy cohort, PD-L1-high patients show a trend toward more pronounced benefit from ICIs. non-small cell lung cancer EGFR mutations tyrosine kinase inhibitors programmed death ligand 1 immunotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Lung cancer, as the cancer with the highest incidence and mortality rates worldwide, severely impacts human survival and health [ 1 ] . Non-small cell lung cancer (NSCLC) accounts for approximately 80–85% of cases [ 2 ] . EGFR mutations are the most common mutation type in NSCLC, accounting for approximately 30% of cases [ 3 , 4 ] . In adenocarcinomas, this proportion can reach as high as 40–60% [ 4 – 6 ] . With the advancement of EGFR-TKIs, the mPFS for patients with EGFR-mutated lung cancer has increased from 9.2 months to 22.1 months [ 7 , 8 ] , median overall survival (OS) has exceeded 36 months [ 9 – 12 ] . Today, third-generation EGFR-TKIs have become the preferred first-line treatment for advanced EGFR-mutated lung adenocarcinoma. The resistance to EGFR-TKIs is inevitable. Among patients receiving third-generation EGFR-TKIs, approximately half experience disease progression between 17.8 and 22.1 months [ 9 – 13 ] . Treatment options for targeted therapy resistance vary, with differing degrees of benefit. The IMPRESS study demonstrated that extending TKI therapy after EGFR-TKI resistance did not improve PFS or OS [ 14 , 15 ] . Currently, platinum-based dual-agent chemotherapy is the primary treatment following EGFR-TKI resistance, but clinical benefits remain limited, with a mPFS of only 4–5 months [ 14 , 16 , 17 ] . With the advent of ICIs, these agents have also been explored in patients who develop resistance to EGFR-TKIs. However, monotherapy with ICIs demonstrates low response rates [ 18 , 19 ] . ICIs combined with EGFR-TKI treatment did not significantly improve efficacy, yet adverse reactions markedly increased [ 20 , 21 ] , An optimal combination therapy regimen for immunotherapy is urgently needed. With the successive emergence of various immunotherapy combination regimens, the CHECKMATE-722 study demonstrated a trend toward survival benefit with the BCP approach [ 22 ] . The ORIENT-31 and ATTLAS studies further indicated that the ABCP regimen could deliver significant survival benefits for NSCLC patients after EGFR-TKI resistance [ 23 – 25 ] . Compared to wild-type EGFR, the mutated form exhibits distinct immunogenicity, with heterogeneity in PD-L1 expression levels, tumor mutational burden, and other immune microenvironment characteristics. PD-L1 expression serves as a key predictor of treatment efficacy with ICIs. Clarifying its role in EGFR-TKI-resistant populations may help identify advantageous groups for immunotherapy in post-TKI resistance settings, warranting further investigation. Therefore, this study will further explore optimal treatment strategies for patients with targeted resistance to EGFR-TKIs and analyze the correlation between PD-L1 expression status and ICI efficacy to identify a favorable population for immunotherapy. 2. Patients & methods 2.1. Study design & patients This retrospective study analyzed patients treated at our hospital between March 2019 and September 2024 who progressed on third-generation EGFR-TKIs as first-line therapy and received second-line chemotherapy-based regimens (Fig. 1 ). Demographic characteristics and clinical data were extracted from the electronic medical record system. This study was reviewed by the Ethics Review Committee of Shandong First Medical University Affiliated Cancer Hospital (Ethical approval number: SDTHEC202504008) and conducted in accordance with the Declaration of Helsinki. 2.2 Pathological & Imaging Analysis EGFR gene mutations were analyzed in paraffin-embedded tissue using the ARMS fluorescence quantitative PCR method. In this study, EGFR-sensitive mutations were defined as those associated with EGFR-TKI sensitivity, including: Exon 19 DEL and Exon 21 L858R. A 10-gene panel was employed, excluding patients with co-mutations. PD-L1 expression levels were assessed using the DAKO LINK 48 assay system with the 22C3 antibody or the VENTANA assay system with the SP263 antibody. PD-L1 expression was interpreted based on the tumor proportion score (TPS). Imaging assessments used baseline reference data from initial imaging and clinically relevant information at the time of progression on third-generation EGFR-TKI therapy. Tumor response evaluation followed the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 2.3. Statistical analysis The primary endpoints of this study were PFS1 and PFS2, with OS as the secondary endpoint. PFS1 was defined as the time interval from initiation of EGFR-TKI treatment to disease progression (PD) or death from any cause, or to the last known follow-up date. PFS2 was defined as the time interval from initiation of second-line therapy following progression on EGFR-TKIs to the next detected PD or death from any cause; OS was defined as the time interval from initiation of EGFR-TKIs to death from any cause. Analysis was performed using the Kaplan-Meier method. The log-rank test was used to compare differences in survival curves between groups. Multivariate analysis was performed using a logistic regression model, including age, sex, smoking history, KPS score, baseline metastatic status, and PD-L1 expression. Univariate and multivariate analyses were conducted using Cox proportional hazards models to identify potential prognostic factors. Clinically significant variables ( P < 0.10) from univariate analysis were incorporated into the multivariate model to assess independent prognostic factors associated with survival. Statistical analyses were performed using SPSS Statistics version 26.0 (IBM Corporation) and Prism software version 8.0.2 (GraphPad). All reported P values were two-sided, with confidence intervals (CI) of 95%. P values ≤ 0.05 were considered statistically significant. 3 Results 3.1 Population Baseline Characteristics of EGFR-TKI-Resistant Patients This retrospective study analyzed 107 patients who progressed on third-generation EGFR-TKIs as first-line therapy between March 2019 and September 2024. Baseline patient characteristics are presented in Table 1 . The median age was 60 years (range: 34–75 years), with 58 (54.21%) patients were female. 78 (72.90%) were never-smokers, and 56 (52.34%) had a KPS score > 80. Furthermore, 60 (56.07%) patients had an exon 19 deletion, 47 (43.93%) had an exon 21 L858R mutation, 58 (54.21%) were treated with Osimertinib, 43 (40.19%) were treated with Aumolertinib and 6 (5.60%) were treated with Furmonertinib. Baseline metastatic sites primarily included: 36 (33.64%) with brain metastases, 44 (41.12%) with bone metastases, and 21 (19.63%) with liver metastases. Second-line treatment modalities were: 35 (32.71%) CP group, 29 (27.10%) BCP group, 22 (20.56%) ACP group, and 21 (19.63%) ABCP group. PD-L1 expression status: 45 (42.06%) negative, 40(37.38%) weak expression, and 22 (20.56%) strong expression. Table 1 Baseline characteristics of patients Characteristic Number of patients (%) Characteristic Number of patients (%) Age(years), n (%) Brain metastases at diagnosis, n (%) <65 71( 66.36 ) Metastasis 36 ( 33.64 ) ≥ 65 36( 33.64 ) No metastasis 71 ( 66.36 ) Median (range) 60( 34–75 ) Bone metastases at diagnosis, n (%) Gender, n (%) Metastasis 44 ( 41.12 ) Female 58( 54.21 ) No metastasis 63 ( 58.88 ) Male 49( 45.79 ) liver metastases at diagnosis, n (%) Smoking history, n (%) Metastasis 21 ( 19.63 ) Never 78( 72.90 ) No metastasis 86 ( 80.37 ) Current/former 29( 27.10 ) Second-line treatment methods, n (%) KPS, n (%) CP group 35( 32.71 ) >80 56( 52.34 ) BCP group 29 ( 27.10 ) ≤ 80 51( 47.66 ) ACP group 22 ( 20.56 ) EGFR mutation, n (%) ABCP group 21 ( 19.63 ) Exon 19 DEL 60 ( 56.07 ) PD-L1 expression status, n (%) Exon 21 L858R 47 ( 43.93 ) Negative 45 ( 42.06 ) Three generations EGFR-TKIs, n (%) Weak 40 ( 37.38 ) Osimertinib 58 ( 54.21 ) Strong 22 ( 20.56 ) Almonertinib 43 ( 40.19 ) Furmonertinib 6 ( 5.60 ) EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PD-L1, programmed death-ligand 1; TPS, tumor proportion score; KPS, Karnofsky performance status; CP, chemotherapy; BCP, chemotherapy combined with anti-angiogenic therapy; ACP, chemoimmunotherapy; ABCP, chemoimmunotherapy combined with anti-angiogenic therapy. 3.2 Efficacy Analysis of Second-Line Therapy in EGFR-TKI-Progressed Patients The median follow-up duration for the entire cohort was 31.27 months (95% CI: 23.36–39.19). with mPFS1 at 11.24 months (95% CI: 8.67–13.81), mPFS2 at 6.68 months (95% CI: 5.38–7.98), and mOS at 30.78 months (95% CI: 27.31–34.24) (Fig. 2 ). In the efficacy analysis of second-line treatment for EGFR-TKI-resistant patients, the CP group demonstrated mPFS2 of 4.89 months (95% CI: 3.82–5.97) and OS of 29.46 months (95% CI: 24.39–34.52); the BCP group had a mPFS2 of 6.74 months (95% CI: 4.44–9.05) and an OS of 33.85 months (95% CI: 28.25–39.45); the ACP group had a mPFS2 of 7.80 months (95% CI: 4.38–11.23) and OS of 36.40 months (95% CI: 24.89–47.90); the mPFS2 for the ABCP group was 8.00 months (95% CI: 3.82–12.18) and OS was 30.08 months (95% CI: 15.14–45.03) (Fig. 3 A,B). Among different chemotherapy-based regimens, the addition of anti-angiogenic agents showed a trend toward improving PFS2 but without significant statistical difference. The incorporation of ICIs reduced the risk of disease progression and significantly prolonged PFS2. CP group vs. BCP group: PFS2 (4.89 months vs. 6.74 months), HR: 0.619 (95% CI: 0.344–1.116), P = 0.092; CP group vs. ACP group PFS2: (4.89 months vs. 7.80 months), HR: 0.532 (95% CI: 0.282–1.006), P = 0.048; CP group vs. ABCP group PFS2: (4.89 months vs. 8.00 months), HR: 0.429 (95% CI: 0.226–0.817), P = 0.007 (Fig. 3 A). Among the four chemotherapy-based second-line regimens, no statistically significant differences were observed in overall survival analysis (Fig. 3 B). In a multivariable Cox regression model, after adjusting for age, sex, smoking status, KPS score, EGFR mutation type, PD-L1 expression status, brain, bone, and liver metastasis status, and second-line treatment modality, second-line treatment regimen and KPS score emerged as significant factors influencing PFS2. Patients with a KPS score > 80 demonstrated significantly longer PFS2 compared to those with a score ≤ 80 (HR: 0.45; 95% CI: 0.26–0.80; P = 0.006). Compared with CP group, BCP group (HR: 0.43; 95% CI: 0.22–0.83; P = 0.012), ACP group (HR: 0.21; 95% CI: 0.09–0.50; P = 0.001), and ABCP group (HR: 0.35; 95% CI: 0.17–0.72; P = 0.005) all extended PFS2 in patients. Table 2 Univariate and multivariate analysis of clinical pathological features and second-line progression free survival Characteristic Univariate analysis Multivariate analysis HR 95%CI P HR 95%CI P Age(years) 80 0.48 0.29 ~ 0.79 0.004 0.45 0.26 ~ 0.80 0.006 EGFR mutation Exon 21L858R Reference Exon 19DEL 1.47 0.91 ~ 2.37 0.118 PD-L1 expression status Negative Reference Weak 1.07 0.63 ~ 1.82 0.798 Strong 1.07 0.60 ~ 1.94 0.810 Brain metastases at diagnosis No metastasis Reference Metastasis 0.95 0.59 ~ 1.53 0.882 Bone metastases at diagnosis No metastasis Reference Metastasis 1.48 0.92 ~ 2.40 0.108 liver metastases at diagnosis No metastasis Reference Metastasis 1.27 0.71 ~ 2.27 0.418 Second-line treatment methods CP group Reference Reference BCP group 0.58 0.32 ~ 1.04 0.066 0.43 0.22 ~ 0.83 0.012 ACP group 0.46 0.23 ~ 0.92 0.028 0.21 0.09 ~ 0.50 0.001 ABCP group 0.41 0.21 ~ 0.81 0.010 0.35 0.17 ~ 0.72 0.005 EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PD-L1, programmed death-ligand 1; TPS, tumor proportion score; KPS, Karnofsky performance status; CP, chemotherapy; BCP, chemotherapy combined with anti-angiogenic therapy; ACP, chemoimmunotherapy; ABCP, chemoimmunotherapy combined with anti-angiogenic therapy. Hazard Ratio, CI: Confidence Interval 3.3 Non-ICIs Group & ICIs Group In second-line therapy, the overall population was divided into Non-ICIs Group and ICIs Group based on the inclusion of ICIs. Patients' mPFS2 were 5.06 months (95% CI: 4.01–6.11) and 8.00 months (95% CI: 6.43–9.57), P = 0.031 (Fig. 4 A); The mOS was 30.78 months (95% CI: 26.28–35.27) and 30.58 months (95% CI: 22.06–39.10), P = 0.748 (Fig. 4 B). The addition of ICIs improved PFS2 but did not significantly alter OS. In the ICIs group, we further analyzed treatment benefits using TPS = 1% and TPS = 50% as cut-off points. The mPFS2 for patients with PD-L1 < 1% and PD-L1 ≥ 1% were 7.24 months (95% CI: 3.02–10.33) and 8.63 months (95% CI: 4.75–12.50), P = 0.587 (Fig. 4 C); For PD-L1 < 50% and PD-L1 ≥ 50% patients, mPFS2 was 7.24 months (95% CI: 4.43–10.04) and 13.52 months (95% CI: 8.11–18.93), P = 0.126 (Fig. 4 D). Statistical analysis using PD-L1 expression thresholds of TPS = 1% and TPS = 50% showed no significant differences, but both demonstrated a trend toward greater benefit from ICIs in patients with high PD-L1 expression. The impact of PD-L1 expression on immunotherapy outcomes in EGFR-TKI resistant patients requires validation through large-scale retrospective or prospective clinical studies. We subsequently conducted a subgroup analysis of PFS2 between the Non-ICIs Group and ICIs Group, including age, gender, smoking status, KPS score, brain, bone, and liver metastasis status, PD-L1 expression status, and EGFR mutation type. Nearly all subgroups demonstrated a benefit for the ICIs Group relative to the Non-ICIs Group in patients with first-line third-generation EGFR-TKI resistance. Notably, significant advantages were observed in patients: KPS ≤ 80 (HR: 0.44, 95% CI: 0.24–0.83, P = 0.011), bone metastases (HR: 0.38, 95% CI: 0.17–0.86, P = 0.020), no liver metastases (HR: 0.50, 95% CI: 0.29–0.88, P = 0.016), and strong PD-L1 expression (HR: 0.16, 95% CI: 0.05–0.51, P = 0.002) (Fig. 5 ). 3.4 Classification of Immunologically Advantageous Populations Based on PD-L1 Expression Levels In the PD-L1-negative population, the mPFS2 for patients in the non-ICIs group and ICIs group were 5.32 months (95% CI: 4.10–6.55) and 6.68 months (95% CI: 3.02–10.33), P = 0.724 (Fig. 6 A). In the PD-L1-positive population, the mPFS2 for the non-ICIs group and the ICIs group were 4.89 months (95% CI: 3.56–6.22) and 8.63 months (95% CI: 4.75–12.50), P = 0.009 (Fig. 6 B). In the PD-L1-strong cohort, the mPFS2 for the non-ICIs group and ICIs group were 3.11 months (95% CI: 2.67–3.95) and 13.52 months (95% CI: 8.11–18.93), P < 0.001 (Fig. 6 C). The addition of ICIs in PD-L1-positive patients improves PFS2, with greater clinical benefit observed at higher PD-L1 expression levels. 4 Discussion In our study, CP group vs. ACP group PFS2: (4.89 months vs. 7.80 months), HR: 0.532 (95% CI: 0.282–1.006), P = 0.048; CP group vs. ABCP group PFS2: (4.89 months vs. 8.00 months), HR: 0.429 (95% CI: 0.226–0.817), P = 0.007. This is similar to the findings of the ORIENT-31 study: CP group vs. ACP group PFS2: (4.3 months vs. 5.5 months), P = 0.016; CP group vs. ABCP group PFS2: (4.3 months vs. 7.2 months), P <0.0001 [ 24 ] . The addition of ICIs improved PFS2 in patients. The ORIENT-31 protocol did not analyze the impact of anti-angiogenic agents on patients. In our study, vs. BCP group PFS2: (4.89 months vs. 6.74 months), HR: 0.619 (95% CI: 0.344–1.116), P = 0.092. Chemotherapy serves as the cornerstone, and the addition of anti-angiogenic agents shows a trend toward improving PFS2 in patients with EGFR-TKI resistance, though no statistically significant difference was observed. Preclinical studies indicate that EGFR-TKI resistance is associated with elevated tumor vascular endothelial growth factor (VEGF) levels. The addition of anti-angiogenic agents can enhance antitumor activity against such resistant tumors, thereby prolonging patients' progression-free survival [ 29 , 30 ] . The ABCP four-drug combination regimen has demonstrated unique advantages and has emerged as the preferred treatment option for EGFR-mutated NSCLC patients who have failed EGFR-TKI therapy [ 31 ] . Research indicates that the mechanisms underlying the benefits of the ABCP regimen primarily include the following aspects: 1. Alterations in the tumor microenvironment following EGFR-TKI resistance favor immunotherapy. The expression status of PD-L1 differs before and after EGFR-TKI treatment, with PD-L1 expression levels increasing post-treatment [ 32 – 34 ] . Acquired EGFR-TKI resistance promotes lung cancer immune escape by upregulating PD-L1 expression through PI3K-Akt, MAPK, AP-1, and NF-kappa B signaling pathways [ 33 ] . Mutant NSCLC exhibits a low tumor mutational burden (TMB), which significantly increases following TKI treatment [ 35 ] . 2. Chemotherapy can enhance immunogenicity and improve the tumor immunosuppressive microenvironment. The cytotoxic effects of chemotherapeutic agents induce tumor cell apoptosis, releasing neoantigens that increase tumor immunogenicity. Additionally, through direct or indirect immune activation, chemotherapy can improve the immunosuppressive microenvironment surrounding tumor cells [ 36 ] . 3. Anti-angiogenic drugs play a crucial role in enhancing immune sensitivity. By normalizing tumor vasculature, these agents activate the immune state, promote immune cell differentiation, and enhance immune cell function [ 37 , 38 ] . Both the Impower-150 study and multicenter retrospective studies demonstrated that ACP therapy did not show a significant survival benefit compared to BCP therapy [ 39 , 40 ] . The optimal patient population for ICIs in EGFR-TKI-resistant patients warrants further investigation. PD-L1 expression status serves as a crucial predictor of ICI efficacy. In our study, we found that the use of ICIs did not improve PFS2 in PD-L1-negative patients. In PD-L1-positive patients, the addition of ICIs extended PFS2 by approximately 4 months, with a HR = 0.464, P = 0.009. In PD-L1-strong patients, the addition of ICIs extended PFS2 by approximately 10 months, HR = 0.227, P <0.001. The addition of ICIs in PD-L1-positive patients improves PFS2, with greater clinical benefit observed at higher PD-L1 expression levels. Among patients in the immunotherapy group, those with high PD-L1 expression showed a trend toward benefit from ICIs. Our study has certain limitations. First, compared to prospective clinical trials, this is a single-center retrospective study with inherent biases. Second, we did not differentiate between different ICIs, and our findings lack specificity. Third, we did not evaluate adverse reactions across different treatment regimens. Previous studies indicate that the safety profiles of the four treatment regimens are manageable. Therefore, caution is warranted before drawing conclusions. Given these limitations, a large-scale, multicenter prospective study is needed to further validate our findings. Exploring the correlation between PD-L1 expression and the efficacy of ICIs in later-line settings following EGFR-TKI resistance could help identify patient populations likely to benefit from these agents, thereby aiding clinicians in decision-making. 5 Conclusion In conclusion, among patients with EGFR-TKI resistance, combination immunochemotherapy with or without anti-angiogenic therapy demonstrates distinct advantages over chemotherapy alone. Adding ICIs in PD-L1-positive patients improves progression-free survival, with greater clinical benefit observed at higher PD-L1 expression levels. Within the immunotherapy cohort, PD-L1-high patients show a trend toward more pronounced benefit from ICIs. Declarations Ethics approval and consent to participate: This study was approved by the Ethical Review Committee of the Affiliated Cancer Hospital of Shandong First Medical University and was conducted in accordance with the Declaration of Helsinki (Ethical approval number: SDTHEC202504008). Informed consent was obtained from all patients or their legal guardians. Competing interests: The authors declare no competing interests Funding: This work was sponsored in part by Shandong University of Traditional Chinese Medicine Scientific Research Fund, KYZK2024M05; Shandong Provincial Traditional Chinese Medicine Science and Technology Project, 2020M015 Author Contribution L. Z., Z.H. are responsible for research and design; N.J., S.Z., S.Z., and J.X. were responsible for data collation and statistical analysis. N.J. wrote this manuscript; L. Z., Z.H. checked the manuscript; All authors contributed to the article and approved the submitted version. Acknowledgement The authors thank all the patients and their fami-lies. Data Availability All the data generated or analyzed during this study are included in this published article. The datasets used and/or analyzed during the current study are available from the corresponding author. References BRAY F, LAVERSANNE M, SUNG H, et al. 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SEQUIST L V, YANG J C, YAMAMOTO N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations [J]. J Clin Oncol, 2013, 31(27): 3327-34. NAUMOV G N, NILSSON M B, CASCONE T, et al. Combined Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor (EGFR) Blockade Inhibits Tumor Growth in Xenograft Models of EGFR Inhibitor Resistance [J]. Clinical Cancer Research, 2009, 15(10): 3484-94. NILSSON M B, ROBICHAUX J, HERYNK M H, et al. Altered Regulation of HIF-1alpha in Naive- and Drug-Resistant EGFR-Mutant NSCLC: Implications for a Vascular Endothelial Growth Factor-Dependent Phenotype [J]. J Thorac Oncol, 2021, 16(3): 439-51. ZHAO Y, HE Y, WANG W, et al. Efficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review, meta-analysis, and network meta-analysis [J]. Lancet Oncol, 2024, 25(10): 1347-56. SUDA K, ROZEBOOM L, FURUGAKI K, et al. Increased EGFR Phosphorylation Correlates with Higher Programmed Death Ligand-1 Expression: Analysis of TKI-Resistant Lung Cancer Cell Lines [J]. Biomed Res Int, 2017, 2017: 7694202. PENG S, WANG R, ZHANG X, et al. EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression [J]. Mol Cancer, 2019, 18(1): 165. ISOMOTO K, HARATANI K, HAYASHI H, et al. Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in EGFR Mutation-Positive Non-Small Cell Lung Cancer [J]. Clin Cancer Res, 2020, 26(8): 2037-46. OFFIN M, RIZVI H, TENET M, et al. Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers [J]. Clin Cancer Res, 2019, 25(3): 1063-9. GALLUZZI L, ZITVOGEL L, KROEMER G. Immunological Mechanisms Underneath the Efficacy of Cancer Therapy [J]. Cancer Immunol Res, 2016, 4(11): 895-902. KHAN K A, KERBEL R S. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa [J]. Nat Rev Clin Oncol, 2018, 15(5): 310-24. FUKUMURA D, KLOEPPER J, AMOOZGAR Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges [J]. Nat Rev Clin Oncol, 2018, 15(5): 325-40. NOGAMI N, BARLESI F, SOCINSKI M A, et al. IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain [J]. J Thorac Oncol, 2022, 17(2): 309-23. YU X, LI J, YE L, et al. Real-world outcomes of chemo-antiangiogenesis versus chemo-immunotherapy combinations in EGFR-mutant advanced non-small cell lung cancer patients after failure of EGFR-TKI therapy [J]. Transl Lung Cancer Res, 2021, 10(9): 3782-92. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7774591","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":542064585,"identity":"8b56924a-ff9f-4fcd-9609-1382ed08652a","order_by":0,"name":"Jiling 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06:29:55","extension":"html","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":123138,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7774591/v1/badacc0587538eba00e9cc3d.html"},{"id":96048947,"identity":"51cf73e7-a642-4d9a-943a-8a2f59a82db6","added_by":"auto","created_at":"2025-11-17 06:29:54","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":133529,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart\u003c/p\u003e\n\u003cp\u003eNSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PD-L1, programmed death-ligand 1; ICIs, Immune checkpoint inhibitors; CP, chemotherapy; BCP, chemotherapy combined with anti-angiogenic therapy; ACP, chemoimmunotherapy; ABCP, chemoimmunotherapy combined with anti-angiogenic therapy.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7774591/v1/98afaa0dbd115c5ff1ba5b9b.jpeg"},{"id":96048950,"identity":"de56c07e-cb0e-4c42-accd-948cb1d7935a","added_by":"auto","created_at":"2025-11-17 06:29:54","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":108411,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival analysis of all patients\u003c/p\u003e\n\u003cp\u003emPFS, median progression-free survival; mOS, median overall survival; CI, confidence interval.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7774591/v1/3dd6f334f3fb7b56f797a1c2.jpeg"},{"id":96247606,"identity":"7500a4ab-304c-4382-a51b-a93e20ccf35e","added_by":"auto","created_at":"2025-11-19 07:27:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":212485,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival analysis of second-line treatment for overall patients\u003c/p\u003e\n\u003cp\u003e(A) Kaplan-Meier curve for PFS2 in all patients receiving second-line therapy. (B) Kaplan-Meier curve for OS in all patients receiving second-line therapy. mPFS2, median progression-free survival after second-line therapy; mOS, median overall survival; CI, confidence interval; HR, hazard ratio; NA, not reached.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7774591/v1/29d394fddf6266ffcc49cc0b.png"},{"id":96247397,"identity":"bf11af56-03fa-4e43-92a1-be66da132cc5","added_by":"auto","created_at":"2025-11-19 07:27:27","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":362058,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival analysis of non-immunotherapy group and immunotherapy group population\u003c/p\u003e\n\u003cp\u003e(A) Kaplan-Meier curves for PFS2 comparing the Non-ICIs Group and ICIs Group. (B) Kaplan-Meier curves for PFS2 comparing the Non-ICIs Group and ICIs Group. (C) Kaplan-Meier curves comparing PFS2 between the TPS \u0026lt; 1% and TPS ≥ 1% in the ICI groups. (D) Kaplan-Meier curves comparing PFS2 between the TPS \u0026lt; 50% and TPS ≥ 50% in the ICI groups. mPFS, median progression-free survival; mOS, median overall survival; CI, confidence interval; HR, hazard ratio.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7774591/v1/a881081f68bb4527b492ad8e.jpeg"},{"id":96048957,"identity":"f222a6bf-e6b0-42e0-b28b-3ddc71311d40","added_by":"auto","created_at":"2025-11-17 06:29:55","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":209945,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariate analysis and forest plot of second-line progression free survival between non immunotherapy group and immunotherapy group\u003c/p\u003e\n\u003cp\u003eICIs, Immune checkpoint inhibitors; PD-L1, programmed death-ligand 1; KPS, Karnofsky performance status; CI, confidence interval; HR, hazard ratio.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7774591/v1/22c6bff9b6b65abcee01a1d9.jpeg"},{"id":96048965,"identity":"22fdcfec-2404-4aff-8ee8-39140427a3ad","added_by":"auto","created_at":"2025-11-17 06:29:55","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":127121,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival analysis of different PD-L1 expression states\u003c/p\u003e\n\u003cp\u003e(A) Kaplan-Meier curves for PFS2 comparing the non-ICIs group and ICIs group in PD-L1-negative patients. (B) Kaplan-Meier curves for PFS2 comparing the non-ICIs group and ICIs group in PD-L1-positive patients. (C) Kaplan-Meier curves for PFS2 in the non-ICIs group and ICIs group in PD-L1- strongpatients. mPFS2, median progression-free survival in second-line therapy; CI, confidence interval; HR, hazard ratio.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7774591/v1/db6ff070cd76d721f70f8b59.png"},{"id":100741744,"identity":"a46563c9-6871-44fb-b61a-b3b6766a837a","added_by":"auto","created_at":"2026-01-21 01:58:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2129371,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7774591/v1/bcf0a1ce-5797-49d5-a91d-4ac4a0e88ee4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Optimal Treatment Strategies for EGFR Mutant Advanced Lung Adenocarcinoma Patients with Targeted Therapy Resistance and Correlation Analysis of PD-L1 Expression with ICI Efficacy","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eLung cancer, as the cancer with the highest incidence and mortality rates worldwide, severely impacts human survival and health\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Non-small cell lung cancer (NSCLC) accounts for approximately 80\u0026ndash;85% of cases\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. EGFR mutations are the most common mutation type in NSCLC, accounting for approximately 30% of cases\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. In adenocarcinomas, this proportion can reach as high as 40\u0026ndash;60%\u003csup\u003e[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. With the advancement of EGFR-TKIs, the mPFS for patients with EGFR-mutated lung cancer has increased from 9.2 months to 22.1 months\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, median overall survival (OS) has exceeded 36 months\u003csup\u003e[\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Today, third-generation EGFR-TKIs have become the preferred first-line treatment for advanced EGFR-mutated lung adenocarcinoma.\u003c/p\u003e\u003cp\u003eThe resistance to EGFR-TKIs is inevitable. Among patients receiving third-generation EGFR-TKIs, approximately half experience disease progression between 17.8 and 22.1 months\u003csup\u003e[\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Treatment options for targeted therapy resistance vary, with differing degrees of benefit. The IMPRESS study demonstrated that extending TKI therapy after EGFR-TKI resistance did not improve PFS or OS \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Currently, platinum-based dual-agent chemotherapy is the primary treatment following EGFR-TKI resistance, but clinical benefits remain limited, with a mPFS of only 4\u0026ndash;5 months\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. With the advent of ICIs, these agents have also been explored in patients who develop resistance to EGFR-TKIs. However, monotherapy with ICIs demonstrates low response rates \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. ICIs combined with EGFR-TKI treatment did not significantly improve efficacy, yet adverse reactions markedly increased \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e, An optimal combination therapy regimen for immunotherapy is urgently needed. With the successive emergence of various immunotherapy combination regimens, the CHECKMATE-722 study demonstrated a trend toward survival benefit with the BCP approach \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. The ORIENT-31 and ATTLAS studies further indicated that the ABCP regimen could deliver significant survival benefits for NSCLC patients after EGFR-TKI resistance \u003csup\u003e[\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eCompared to wild-type EGFR, the mutated form exhibits distinct immunogenicity, with heterogeneity in PD-L1 expression levels, tumor mutational burden, and other immune microenvironment characteristics. PD-L1 expression serves as a key predictor of treatment efficacy with ICIs. Clarifying its role in EGFR-TKI-resistant populations may help identify advantageous groups for immunotherapy in post-TKI resistance settings, warranting further investigation.\u003c/p\u003e\u003cp\u003eTherefore, this study will further explore optimal treatment strategies for patients with targeted resistance to EGFR-TKIs and analyze the correlation between PD-L1 expression status and ICI efficacy to identify a favorable population for immunotherapy.\u003c/p\u003e"},{"header":"2. Patients \u0026 methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Study design \u0026amp; patients\u003c/h2\u003e\u003cp\u003eThis retrospective study analyzed patients treated at our hospital between March 2019 and September 2024 who progressed on third-generation EGFR-TKIs as first-line therapy and received second-line chemotherapy-based regimens (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Demographic characteristics and clinical data were extracted from the electronic medical record system. This study was reviewed by the Ethics Review Committee of Shandong First Medical University Affiliated Cancer Hospital (Ethical approval number: SDTHEC202504008) and conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Pathological \u0026amp; Imaging Analysis\u003c/h2\u003e\u003cp\u003eEGFR gene mutations were analyzed in paraffin-embedded tissue using the ARMS fluorescence quantitative PCR method. In this study, EGFR-sensitive mutations were defined as those associated with EGFR-TKI sensitivity, including: Exon 19 DEL and Exon 21 L858R. A 10-gene panel was employed, excluding patients with co-mutations. PD-L1 expression levels were assessed using the DAKO LINK 48 assay system with the 22C3 antibody or the VENTANA assay system with the SP263 antibody. PD-L1 expression was interpreted based on the tumor proportion score (TPS).\u003c/p\u003e\u003cp\u003eImaging assessments used baseline reference data from initial imaging and clinically relevant information at the time of progression on third-generation EGFR-TKI therapy. Tumor response evaluation followed the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Statistical analysis\u003c/h2\u003e\u003cp\u003eThe primary endpoints of this study were PFS1 and PFS2, with OS as the secondary endpoint. PFS1 was defined as the time interval from initiation of EGFR-TKI treatment to disease progression (PD) or death from any cause, or to the last known follow-up date. PFS2 was defined as the time interval from initiation of second-line therapy following progression on EGFR-TKIs to the next detected PD or death from any cause; OS was defined as the time interval from initiation of EGFR-TKIs to death from any cause. Analysis was performed using the Kaplan-Meier method. The log-rank test was used to compare differences in survival curves between groups. Multivariate analysis was performed using a logistic regression model, including age, sex, smoking history, KPS score, baseline metastatic status, and PD-L1 expression. Univariate and multivariate analyses were conducted using Cox proportional hazards models to identify potential prognostic factors. Clinically significant variables (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.10) from univariate analysis were incorporated into the multivariate model to assess independent prognostic factors associated with survival. Statistical analyses were performed using SPSS Statistics version 26.0 (IBM Corporation) and Prism software version 8.0.2 (GraphPad). All reported P values were two-sided, with confidence intervals (CI) of 95%. \u003cem\u003eP\u003c/em\u003e values\u0026thinsp;\u0026le;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Population Baseline Characteristics of EGFR-TKI-Resistant Patients\u003c/h2\u003e\n \u003cp\u003eThis retrospective study analyzed 107 patients who progressed on third-generation EGFR-TKIs as first-line therapy between March 2019 and September 2024. Baseline patient characteristics are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age was 60 years (range: 34\u0026ndash;75 years), with 58 (54.21%) patients were female. 78 (72.90%) were never-smokers, and 56 (52.34%) had a KPS score\u0026thinsp;\u0026gt;\u0026thinsp;80. Furthermore, 60 (56.07%) patients had an exon 19 deletion, 47 (43.93%) had an exon 21 L858R mutation, 58 (54.21%) were treated with Osimertinib, 43 (40.19%) were treated with Aumolertinib and 6 (5.60%) were treated with Furmonertinib. Baseline metastatic sites primarily included: 36 (33.64%) with brain metastases, 44 (41.12%) with bone metastases, and 21 (19.63%) with liver metastases. Second-line treatment modalities were: 35 (32.71%) CP group, 29 (27.10%) BCP group, 22 (20.56%) ACP group, and 21 (19.63%) ABCP group. PD-L1 expression status: 45 (42.06%) negative, 40(37.38%) weak expression, and 22 (20.56%) strong expression.\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics of patients\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNumber of patients (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNumber of patients (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge(years), n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eBrain metastases at diagnosis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71( 66.36 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 ( 33.64 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36( 33.64 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71 ( 66.36 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60( 34\u0026ndash;75 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eBone metastases at diagnosis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 ( 41.12 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58( 54.21 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63 ( 58.88 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49( 45.79 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eliver metastases at diagnosis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSmoking history, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 ( 19.63 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78( 72.90 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86 ( 80.37 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCurrent/former\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29( 27.10 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSecond-line treatment methods, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKPS, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCP group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35( 32.71 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e56( 52.34 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBCP group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 ( 27.10 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51( 47.66 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eACP group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 ( 20.56 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEGFR mutation, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eABCP group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 ( 19.63 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExon 19 DEL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 ( 56.07 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003ePD-L1 expression status, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExon 21 L858R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47 ( 43.93 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 ( 42.06 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eThree generations EGFR-TKIs, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeak\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 ( 37.38 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOsimertinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58 ( 54.21 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStrong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 ( 20.56 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlmonertinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 ( 40.19 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFurmonertinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 ( 5.60 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eEGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PD-L1, programmed death-ligand 1; TPS, tumor proportion score; KPS, Karnofsky performance status; CP, chemotherapy; BCP, chemotherapy combined with anti-angiogenic therapy; ACP, chemoimmunotherapy; ABCP, chemoimmunotherapy combined with anti-angiogenic therapy.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Efficacy Analysis of Second-Line Therapy in EGFR-TKI-Progressed Patients\u003c/h2\u003e\n \u003cp\u003eThe median follow-up duration for the entire cohort was 31.27 months (95% CI: 23.36\u0026ndash;39.19). with mPFS1 at 11.24 months (95% CI: 8.67\u0026ndash;13.81), mPFS2 at 6.68 months (95% CI: 5.38\u0026ndash;7.98), and mOS at 30.78 months (95% CI: 27.31\u0026ndash;34.24) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). In the efficacy analysis of second-line treatment for EGFR-TKI-resistant patients, the CP group demonstrated mPFS2 of 4.89 months (95% CI: 3.82\u0026ndash;5.97) and OS of 29.46 months (95% CI: 24.39\u0026ndash;34.52); the BCP group had a mPFS2 of 6.74 months (95% CI: 4.44\u0026ndash;9.05) and an OS of 33.85 months (95% CI: 28.25\u0026ndash;39.45); the ACP group had a mPFS2 of 7.80 months (95% CI: 4.38\u0026ndash;11.23) and OS of 36.40 months (95% CI: 24.89\u0026ndash;47.90); the mPFS2 for the ABCP group was 8.00 months (95% CI: 3.82\u0026ndash;12.18) and OS was 30.08 months (95% CI: 15.14\u0026ndash;45.03) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA,B). Among different chemotherapy-based regimens, the addition of anti-angiogenic agents showed a trend toward improving PFS2 but without significant statistical difference. The incorporation of ICIs reduced the risk of disease progression and significantly prolonged PFS2. CP group vs. BCP group: PFS2 (4.89 months vs. 6.74 months), HR: 0.619 (95% CI: 0.344\u0026ndash;1.116), P\u0026thinsp;=\u0026thinsp;0.092; CP group vs. ACP group PFS2: (4.89 months vs. 7.80 months), HR: 0.532 (95% CI: 0.282\u0026ndash;1.006), P\u0026thinsp;=\u0026thinsp;0.048; CP group vs. ABCP group PFS2: (4.89 months vs. 8.00 months), HR: 0.429 (95% CI: 0.226\u0026ndash;0.817), P\u0026thinsp;=\u0026thinsp;0.007 (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). Among the four chemotherapy-based second-line regimens, no statistically significant differences were observed in overall survival analysis (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e\n \u003cp\u003eIn a multivariable Cox regression model, after adjusting for age, sex, smoking status, KPS score, EGFR mutation type, PD-L1 expression status, brain, bone, and liver metastasis status, and second-line treatment modality, second-line treatment regimen and KPS score emerged as significant factors influencing PFS2. Patients with a KPS score\u0026thinsp;\u0026gt;\u0026thinsp;80 demonstrated significantly longer PFS2 compared to those with a score\u0026thinsp;\u0026le;\u0026thinsp;80 (HR: 0.45; 95% CI: 0.26\u0026ndash;0.80; P\u0026thinsp;=\u0026thinsp;0.006). Compared with CP group, BCP group (HR: 0.43; 95% CI: 0.22\u0026ndash;0.83; P\u0026thinsp;=\u0026thinsp;0.012), ACP group (HR: 0.21; 95% CI: 0.09\u0026ndash;0.50; P\u0026thinsp;=\u0026thinsp;0.001), and ABCP group (HR: 0.35; 95% CI: 0.17\u0026ndash;0.72; P\u0026thinsp;=\u0026thinsp;0.005) all extended PFS2 in patients.\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eUnivariate and multivariate analysis of clinical pathological features and second-line progression free survival\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.86\u0026thinsp;~\u0026thinsp;2.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.68\u0026thinsp;~\u0026thinsp;1.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.741\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmoking history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCurrent/former\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.49\u0026thinsp;~\u0026thinsp;1.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.487\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.29\u0026thinsp;~\u0026thinsp;0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.26\u0026thinsp;~\u0026thinsp;0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEGFR mutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExon 21L858R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExon 19DEL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.91\u0026thinsp;~\u0026thinsp;2.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003ePD-L1 expression status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeak\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.63\u0026thinsp;~\u0026thinsp;1.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.798\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStrong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.60\u0026thinsp;~\u0026thinsp;1.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.810\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"8\"\u003e\n \u003cp\u003eBrain metastases at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.59\u0026thinsp;~\u0026thinsp;1.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.882\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eBone metastases at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.92\u0026thinsp;~\u0026thinsp;2.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eliver metastases at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.71\u0026thinsp;~\u0026thinsp;2.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.418\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eSecond-line treatment methods\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCP group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBCP group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.32\u0026thinsp;~\u0026thinsp;1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.22\u0026thinsp;~\u0026thinsp;0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eACP group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.23\u0026thinsp;~\u0026thinsp;0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.028\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09\u0026thinsp;~\u0026thinsp;0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eABCP group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.21\u0026thinsp;~\u0026thinsp;0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.010\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.17\u0026thinsp;~\u0026thinsp;0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\"\u003eEGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PD-L1, programmed death-ligand 1; TPS, tumor proportion score; KPS, Karnofsky performance status; CP, chemotherapy; BCP, chemotherapy combined with anti-angiogenic therapy; ACP, chemoimmunotherapy; ABCP, chemoimmunotherapy combined with anti-angiogenic therapy. Hazard Ratio, CI: Confidence Interval\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Non-ICIs Group \u0026amp; ICIs Group\u003c/h2\u003e\n \u003cp\u003eIn second-line therapy, the overall population was divided into Non-ICIs Group and ICIs Group based on the inclusion of ICIs. Patients\u0026apos; mPFS2 were 5.06 months (95% CI: 4.01\u0026ndash;6.11) and 8.00 months (95% CI: 6.43\u0026ndash;9.57), P\u0026thinsp;=\u0026thinsp;0.031 (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA); The mOS was 30.78 months (95% CI: 26.28\u0026ndash;35.27) and 30.58 months (95% CI: 22.06\u0026ndash;39.10), P\u0026thinsp;=\u0026thinsp;0.748 (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eB). The addition of ICIs improved PFS2 but did not significantly alter OS.\u003c/p\u003e\n \u003cp\u003eIn the ICIs group, we further analyzed treatment benefits using TPS\u0026thinsp;=\u0026thinsp;1% and TPS\u0026thinsp;=\u0026thinsp;50% as cut-off points. The mPFS2 for patients with PD-L1\u0026thinsp;\u0026lt;\u0026thinsp;1% and PD-L1\u0026thinsp;\u0026ge;\u0026thinsp;1% were 7.24 months (95% CI: 3.02\u0026ndash;10.33) and 8.63 months (95% CI: 4.75\u0026ndash;12.50), P\u0026thinsp;=\u0026thinsp;0.587 (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eC); For PD-L1\u0026thinsp;\u0026lt;\u0026thinsp;50% and PD-L1\u0026thinsp;\u0026ge;\u0026thinsp;50% patients, mPFS2 was 7.24 months (95% CI: 4.43\u0026ndash;10.04) and 13.52 months (95% CI: 8.11\u0026ndash;18.93), P\u0026thinsp;=\u0026thinsp;0.126 (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eD). Statistical analysis using PD-L1 expression thresholds of TPS\u0026thinsp;=\u0026thinsp;1% and TPS\u0026thinsp;=\u0026thinsp;50% showed no significant differences, but both demonstrated a trend toward greater benefit from ICIs in patients with high PD-L1 expression. The impact of PD-L1 expression on immunotherapy outcomes in EGFR-TKI resistant patients requires validation through large-scale retrospective or prospective clinical studies.\u003c/p\u003e\n \u003cp\u003eWe subsequently conducted a subgroup analysis of PFS2 between the Non-ICIs Group and ICIs Group, including age, gender, smoking status, KPS score, brain, bone, and liver metastasis status, PD-L1 expression status, and EGFR mutation type. Nearly all subgroups demonstrated a benefit for the ICIs Group relative to the Non-ICIs Group in patients with first-line third-generation EGFR-TKI resistance. Notably, significant advantages were observed in patients: KPS\u0026thinsp;\u0026le;\u0026thinsp;80 (HR: 0.44, 95% CI: 0.24\u0026ndash;0.83, P\u0026thinsp;=\u0026thinsp;0.011), bone metastases (HR: 0.38, 95% CI: 0.17\u0026ndash;0.86, P\u0026thinsp;=\u0026thinsp;0.020), no liver metastases (HR: 0.50, 95% CI: 0.29\u0026ndash;0.88, P\u0026thinsp;=\u0026thinsp;0.016), and strong PD-L1 expression (HR: 0.16, 95% CI: 0.05\u0026ndash;0.51, P\u0026thinsp;=\u0026thinsp;0.002) (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Classification of Immunologically Advantageous Populations Based on PD-L1 Expression Levels\u003c/h2\u003e\n \u003cp\u003eIn the PD-L1-negative population, the mPFS2 for patients in the non-ICIs group and ICIs group were 5.32 months (95% CI: 4.10\u0026ndash;6.55) and 6.68 months (95% CI: 3.02\u0026ndash;10.33), P\u0026thinsp;=\u0026thinsp;0.724 (Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eA). In the PD-L1-positive population, the mPFS2 for the non-ICIs group and the ICIs group were 4.89 months (95% CI: 3.56\u0026ndash;6.22) and 8.63 months (95% CI: 4.75\u0026ndash;12.50), P\u0026thinsp;=\u0026thinsp;0.009 (Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eB). In the PD-L1-strong cohort, the mPFS2 for the non-ICIs group and ICIs group were 3.11 months (95% CI: 2.67\u0026ndash;3.95) and 13.52 months (95% CI: 8.11\u0026ndash;18.93), P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 (Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eC). The addition of ICIs in PD-L1-positive patients improves PFS2, with greater clinical benefit observed at higher PD-L1 expression levels.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eIn our study, CP group vs. ACP group PFS2: (4.89 months vs. 7.80 months), HR: 0.532 (95% CI: 0.282\u0026ndash;1.006), P\u0026thinsp;=\u0026thinsp;0.048; CP group vs. ABCP group PFS2: (4.89 months vs. 8.00 months), HR: 0.429 (95% CI: 0.226\u0026ndash;0.817), P\u0026thinsp;=\u0026thinsp;0.007. This is similar to the findings of the ORIENT-31 study: CP group vs. ACP group PFS2: (4.3 months vs. 5.5 months), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016; CP group vs. ABCP group PFS2: (4.3 months vs. 7.2 months), \u003cem\u003eP\u003c/em\u003e\u0026lt;0.0001\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. The addition of ICIs improved PFS2 in patients. The ORIENT-31 protocol did not analyze the impact of anti-angiogenic agents on patients. In our study, vs. BCP group PFS2: (4.89 months vs. 6.74 months), HR: 0.619 (95% CI: 0.344\u0026ndash;1.116), P\u0026thinsp;=\u0026thinsp;0.092. Chemotherapy serves as the cornerstone, and the addition of anti-angiogenic agents shows a trend toward improving PFS2 in patients with EGFR-TKI resistance, though no statistically significant difference was observed. Preclinical studies indicate that EGFR-TKI resistance is associated with elevated tumor vascular endothelial growth factor (VEGF) levels. The addition of anti-angiogenic agents can enhance antitumor activity against such resistant tumors, thereby prolonging patients' progression-free survival\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe ABCP four-drug combination regimen has demonstrated unique advantages and has emerged as the preferred treatment option for EGFR-mutated NSCLC patients who have failed EGFR-TKI therapy\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Research indicates that the mechanisms underlying the benefits of the ABCP regimen primarily include the following aspects: 1. Alterations in the tumor microenvironment following EGFR-TKI resistance favor immunotherapy. The expression status of PD-L1 differs before and after EGFR-TKI treatment, with PD-L1 expression levels increasing post-treatment\u003csup\u003e[\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. Acquired EGFR-TKI resistance promotes lung cancer immune escape by upregulating PD-L1 expression through PI3K-Akt, MAPK, AP-1, and NF-kappa B signaling pathways\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. Mutant NSCLC exhibits a low tumor mutational burden (TMB), which significantly increases following TKI treatment\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. 2. Chemotherapy can enhance immunogenicity and improve the tumor immunosuppressive microenvironment. The cytotoxic effects of chemotherapeutic agents induce tumor cell apoptosis, releasing neoantigens that increase tumor immunogenicity. Additionally, through direct or indirect immune activation, chemotherapy can improve the immunosuppressive microenvironment surrounding tumor cells\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. 3. Anti-angiogenic drugs play a crucial role in enhancing immune sensitivity. By normalizing tumor vasculature, these agents activate the immune state, promote immune cell differentiation, and enhance immune cell function\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e .\u003c/p\u003e\u003cp\u003eBoth the Impower-150 study and multicenter retrospective studies demonstrated that ACP therapy did not show a significant survival benefit compared to BCP therapy\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. The optimal patient population for ICIs in EGFR-TKI-resistant patients warrants further investigation. PD-L1 expression status serves as a crucial predictor of ICI efficacy.\u003c/p\u003e\u003cp\u003eIn our study, we found that the use of ICIs did not improve PFS2 in PD-L1-negative patients. In PD-L1-positive patients, the addition of ICIs extended PFS2 by approximately 4 months, with a HR\u0026thinsp;=\u0026thinsp;0.464, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009. In PD-L1-strong patients, the addition of ICIs extended PFS2 by approximately 10 months, HR\u0026thinsp;=\u0026thinsp;0.227,\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001. The addition of ICIs in PD-L1-positive patients improves PFS2, with greater clinical benefit observed at higher PD-L1 expression levels. Among patients in the immunotherapy group, those with high PD-L1 expression showed a trend toward benefit from ICIs.\u003c/p\u003e\u003cp\u003eOur study has certain limitations. First, compared to prospective clinical trials, this is a single-center retrospective study with inherent biases. Second, we did not differentiate between different ICIs, and our findings lack specificity. Third, we did not evaluate adverse reactions across different treatment regimens. Previous studies indicate that the safety profiles of the four treatment regimens are manageable. Therefore, caution is warranted before drawing conclusions. Given these limitations, a large-scale, multicenter prospective study is needed to further validate our findings. Exploring the correlation between PD-L1 expression and the efficacy of ICIs in later-line settings following EGFR-TKI resistance could help identify patient populations likely to benefit from these agents, thereby aiding clinicians in decision-making.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eIn conclusion, among patients with EGFR-TKI resistance, combination immunochemotherapy with or without anti-angiogenic therapy demonstrates distinct advantages over chemotherapy alone. Adding ICIs in PD-L1-positive patients improves progression-free survival, with greater clinical benefit observed at higher PD-L1 expression levels. Within the immunotherapy cohort, PD-L1-high patients show a trend toward more pronounced benefit from ICIs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the Ethical Review Committee of the Affiliated Cancer Hospital of Shandong First Medical University and was conducted in accordance with the Declaration of Helsinki (Ethical approval number: SDTHEC202504008). Informed consent was obtained from all patients or their legal guardians.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe authors declare no competing interests\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eThis work was sponsored in part by Shandong University of Traditional Chinese Medicine Scientific Research Fund, KYZK2024M05; Shandong Provincial Traditional Chinese Medicine Science and Technology Project, 2020M015\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eL. Z., Z.H. are responsible for research and design; N.J., S.Z., S.Z., and J.X. were responsible for data collation and statistical analysis. N.J. wrote this manuscript; L. Z., Z.H. checked the manuscript; All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eThe authors thank all the patients and their fami-lies.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eAll the data generated or analyzed during this study are included in this published article. The datasets used and/or analyzed during the current study are available from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA Cancer J Clin, 2024, 74(3): 229-63.\u003c/li\u003e\n\u003cli\u003eLEITER A, VELUSWAMY R R, WISNIVESKY J P. The global burden of lung cancer: current status and future trends [J]. 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Lancet, 2017, 389(10066): 255-65.\u003c/li\u003e\n\u003cli\u003eOXNARD G R, YANG J C H, YU H, et al. TATTON: a multi-arm, phase lb trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in -mutant lung cancer [J]. Annals of Oncology, 2020, 31(4): 507-16.\u003c/li\u003e\n\u003cli\u003eYANG J C H, SHEPHERD F A, KIM D W, et al. Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report [J]. Journal of Thoracic Oncology, 2019, 14(5): 933-9.\u003c/li\u003e\n\u003cli\u003eMOK T, NAKAGAWA K, PARK K, et al. Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722 [J]. J Clin Oncol, 2024, 42(11): 1252-64.\u003c/li\u003e\n\u003cli\u003eLU S, WU L, JIAN H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial [J]. Lancet Oncol, 2022, 23(9): 1167-79.\u003c/li\u003e\n\u003cli\u003eLU S, WU L, JIAN H, et al. Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial [J]. Lancet Respir Med, 2023, 11(7): 624-36.\u003c/li\u003e\n\u003cli\u003ePARK S, KIM T M, HAN J Y, et al. Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04) [J]. 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Cancer Immunol Res, 2016, 4(11): 895-902.\u003c/li\u003e\n\u003cli\u003eKHAN K A, KERBEL R S. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa [J]. Nat Rev Clin Oncol, 2018, 15(5): 310-24.\u003c/li\u003e\n\u003cli\u003eFUKUMURA D, KLOEPPER J, AMOOZGAR Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges [J]. Nat Rev Clin Oncol, 2018, 15(5): 325-40.\u003c/li\u003e\n\u003cli\u003eNOGAMI N, BARLESI F, SOCINSKI M A, et al. IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain [J]. J Thorac Oncol, 2022, 17(2): 309-23.\u003c/li\u003e\n\u003cli\u003eYU X, LI J, YE L, et al. Real-world outcomes of chemo-antiangiogenesis versus chemo-immunotherapy combinations in EGFR-mutant advanced non-small cell lung cancer patients after failure of EGFR-TKI therapy [J]. Transl Lung Cancer Res, 2021, 10(9): 3782-92.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"non-small cell lung cancer, EGFR mutations, tyrosine kinase inhibitors, programmed death ligand 1, immunotherapy","lastPublishedDoi":"10.21203/rs.3.rs-7774591/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7774591/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThird-generation tyrosine kinase inhibitors (TKIs) have become the standard treatment for advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. Currently, after developing resistance to third-generation EGFR-TKIs, treatment regimens based on platinum-based dual-agent chemotherapy yield limited clinical benefit.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e\u003cp\u003eThis retrospective study analyzed patients who progressed on first-line third-generation EGFR-TKIs between March 2019 and September 2024 and received second-line chemotherapy-based regimens. Patients were further stratified based on PD-L1 expression status and immune checkpoint inhibitor (ICI) use to assess the correlation between PD-L1 expression and ICI efficacy.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAmong 107 patients who progressed on third-generation TKIs as first-line therapy, 35 received chemotherapy (CP), 29 received chemotherapy combined with anti-angiogenic (BCP), 22 received chemoimmunotherapy (ACP), and 21 received chemoimmunotherapy combined with anti-angiogenic therapy (ABCP). Second-line median progression-free survival (mPFS2) were 4.89 months, 6.74 months, 7.80 months, and 8.00 months, respectively. Non-ICIs group vs. ICIs group: mPFS2 was 5.06 months vs. 8.00 months, P\u0026thinsp;=\u0026thinsp;0.031. In PD-L1-negative, positive, and strong subgroups, the Non-ICIs group vs. ICIs group showed mPFS2 of 5.32 months vs. 6.68 months, P\u0026thinsp;=\u0026thinsp;0.724; 4.89 months vs. 8.63 months, P\u0026thinsp;=\u0026thinsp;0.009, and 3.11 months vs. 13.52 months, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eAmong patients with EGFR-TKI resistance, combination immunochemotherapy with or without anti-angiogenic therapy demonstrates distinct advantages over chemotherapy alone. Adding ICIs in PD-L1-positive patients improves progression-free survival, with greater clinical benefit observed at higher PD-L1 expression levels. Within the immunotherapy cohort, PD-L1-high patients show a trend toward more pronounced benefit from ICIs.\u003c/p\u003e","manuscriptTitle":"Optimal Treatment Strategies for EGFR Mutant Advanced Lung Adenocarcinoma Patients with Targeted Therapy Resistance and Correlation Analysis of PD-L1 Expression with ICI Efficacy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-17 06:29:49","doi":"10.21203/rs.3.rs-7774591/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1b35390e-938d-4687-9643-fdeeee6e2691","owner":[],"postedDate":"November 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-21T01:57:08+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-17 06:29:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7774591","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7774591","identity":"rs-7774591","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}