{"paper_id":"1abcb43d-362d-452d-a49e-f22eaeb1cb4e","body_text":"Clinical outcomes and predictive factors of immunotherapy efficacy in non-small cell lung cancer brain metastases: A comparative study | 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 Clinical outcomes and predictive factors of immunotherapy efficacy in non-small cell lung cancer brain metastases: A comparative study Yuxi Wei, Rongzhen Li, Xiaoyan Liu, Yuequan Shi, Xu Yan, Jing Zhao, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7676603/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Dec, 2025 Read the published version in BMC Cancer → Version 1 posted 10 You are reading this latest preprint version Abstract Background Brain metastases (BMs) are common in patients with non-small cell lung cancer (NSCLC) and remain a major therapeutic challenge. While immune checkpoint inhibitors (ICIs) have improved systemic outcomes, their Intracranial efficacy and prognostic determinants in patients with BMs, particularly in comparison with chemotherapy, remain insufficiently characterized. Methods We conducted a multi-center, retrospective cohort study including NSCLC patients with BMs who received ICIs or chemotherapy alone. Propensity score matching was performed to balance baseline characteristics between treatment groups. Intracranial and extracranial responses, intracranial progression-free survival (iPFS), extracranial PFS (ePFS), and overall survival (OS) were compared. Logistic regression and Cox proportional hazards models were used to identify clinical and treatment-related prognostic factors associated with treatment response and survival. Results In the matched cohort, patients treated with immunotherapy achieved significantly longer median OS than those receiving chemotherapy (18.9 vs. 13.3 months, p = 0.001), while intracranial and extracranial PFS were numerically but not significantly prolonged. The intracranial objective response rate (iORR) was 31.4% in the matched subset of immunotherapy cohort, comparable to 33.9% in the matched chemotherapy cohort. Concordance between intracranial and extracranial responses was about 70% across groups. In the immunotherapy cohort, development of immune-related adverse events (irAEs), receipt of stereotactic radiotherapy (SRT), and prior radiotherapy were associated with improved OS. Patients receiving intracranial radiotherapy before ICIs achieved a median OS of 32.3 months versus 19.0 months with concurrent therapy. In the chemotherapy cohort, age ≥ 65 years and multiple brain metastases were associated with inferior survival. Conclusions This real-world study suggests that immunotherapy may confer a survival advantage over chemotherapy in NSCLC patients with brain metastases, with efficacy less dependent on baseline factors such as age or performance status. Radiotherapy administered before ICIs appeared associated with favorable outcomes, although this observation remains hypothesis-generating given the study limitations. NSCLC brain metastases immune checkpoint inhibitors radiotherapy intracranial objective response rate intracranial progression-free survival Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Background As of 2022, lung cancer remained the most commonly diagnosed malignancy and the leading cause of cancer-related death worldwide [ 1 ]. Non‑small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases [ 2 ]. Brain metastases (BMs) are a common metastastic site in advanced NSCLC, occurring in up to 40% of patients during the disease course. Brain metastases occur in approximately 20–40% of NSCLC patients during their disease course, with 5–10% presenting at diagnosis [ 3 ]. In the pre-immunotherapy era, the prognosis of NSCLC patients with brain metastases was dismal, with a median overall survival (OS) ranging from 3 to 8 months, despite conventional treatment with chemotherapy and radiotherapy [ 4 ]. The advent of immune checkpoint inhibitors (ICIs) has markedly transformed the prevailing therapeutic paradigm of advanced NSCLC, extending the survival of patients with brain metastases to approximately 13–24 months [ 5 ] across various subgroups. Nonetheless, detailed data regarding their intracranial efficacy—such as objective response rates, intracranial progression-free survival (iPFS), and associated determinants remain limited. Furthermore, although local therapies, particularly radiotherapy are frequently combined with ICIs in clinical practice[ 6 ], the potential influence of radiotherapy modality and treatment sequencing on intracranial response and long-term outcomes has not been fully elucidated. In this multi-center retrospective study, we evaluated intracranial and extracranial responses as well as survival outcomes of NSCLC patients with brain metastases treated with ICIs, and compared them with a matched cohort receiving chemotherapy alone to assess the real-world clinical benefits of immunotherapy. We also investigated whether radiotherapy modality and timing in relation to immunotherapy were associated with variations in treatment response and prognosis. Methods Patients This was a multi-center, retrospective cohort study conducted in accordance with the Declaration of Helsinki. A retrospective review was conducted on patients with NSCLC and BMs who received ICIs between July, 2016 and April, 2024 at multiple centers in Beijing including Peking Union Medical College Hospital, Beijing Cancer Hospital and Cancer Hospital Chinese Academy of Medical Sciences. For comparison, patients with NSCLC and BMs who were treated exclusively with chemotherapy during a similar period at Peking Union Medical College Hospital between June, 2013 and April, 2022 were also reviewed. The common inclusion criteria for both cohorts were: (1) histopathological or cytological confirmation of NSCLC; (2) stage IV disease with radiologically confirmed brain metastases; (3) receipt of at least two cycles of systemic therapy (ICIs for the immunotherapy cohort or chemotherapy for the chemotherapy cohort); and (4) availability of measurable intracranial lesions on baseline imaging. Patients were excluded if they had pathologically confirmed large cell carcinoma or small cell transformation during the disease course, multiple primary lung cancers, or absence of measurable intracranial lesions. For the chemotherapy cohort, additional exclusion criteria included exposure to ICIs at any point during the disease course and receipt of concurrent tyrosine kinase inhibitors (TKIs) alongside chemotherapy. The study protocol was approved by the Ethics Committee of Peking Union Medical College Hospital. Propensity score matching To minimize baseline imbalances between treatment groups, propensity score matching (PSM) was performed using key clinical variables, including sex, age, Eastern Cooperative Oncology Group (ECOG) performance status, histological subtype, Epidermal growth factor receptor (EGFR) mutation status, line of systemic treatment, receipt of brain radiotherapy, and number of brain metastases. The flow of patient selection and matching is presented in Fig. 1 . A 1:1 nearest-neighbor matching without replacement was conducted with a caliper width of 0.2 of the standard deviation of the logit of the propensity score. Covariate balance before and after matching was assessed using standardized mean differences (SMDs), with values <0.1 considered indicative of adequate balance. The SMDs of covariates before and after matching are summarized in Supplementary Table S1. The matched cohort was used for comparative analyses of survival and response outcomes, while the entire chemotherapy cohort was retained for exploratory analyses of prognostic factors. Definitions and assessments Mutations at baseline were identified using either amplification refractory mutation system (ARMS) or next-generation sequencing (NGS). All patients were tested negative for ALK rearrangements, HER2 and other oncogenic driver alterations except EGFR. Patients harboring EGFR 19del, L858R, T790M, S768I, L861Q, and/or G719X mutations were classified as EGFR mutation positive. Baseline information related to brain metastases was collected before treatment, including presence of neurological symptoms, the number of brain metastases, and the maximum diameter of intracranial lesions based on imaging findings. Neurological symptoms included headache, dizziness, muscle weakness, nausea, and other symptoms attributable to brain metastases. The number of brain metastases was categorized as oligo metastases (≤3 lesions) and multiple metastases (≥4 lesions). Prior radiotherapy was defined as radiotherapy completed before the initiation of systemic therapy (either immunotherapy or chemotherapy). Concurrent radiotherapy referred to intracranial radiotherapy delivered during the course of immunotherapy, regardless of whether it was started in the first cycle or subsequent cycles, typically for symptom control or management of cerebral edema. Palliative radiotherapy was defined as salvage intracranial radiotherapy administered after documented intracranial progression or insufficient local control during systemic therapy. The primarily endpoint was OS and secondary endpoints included the intracranial objective response rate (iORR), intracranial progression-free survival (iPFS) and extracranial progression-free survival (ePFS). Intracranial responses were assessed according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, while extracranial lesions were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Radiologic assessments were scheduled every 6 weeks until disease progression or death and were performed by experienced oncologists at each participating center. The data cutoff date for survival analysis was April 30th, 2025. Objective response was defined as partial response (PR) or complete response (CR). iPFS was defined as the interval from systemic therapy initiation to the first radiological confirmation of intracranial progression or death, whichever occurred first. Extracranial PFS (ePFS) was similarly defined as the interval from systemic therapy initiation to radiological confirmation of extracranial progression or death, whichever occurred first. OS was calculated from the date of first immune checkpoint inhibitors (ICI) or chemotherapy administration to death from any cause or last follow-up. Intracranial lesions were evaluated using brain magnetic resonance imaging (MRI), while extracranial lesions were assessed through contrast-enhanced computed tomography (CT) scans of the chest, abdomen, and pelvis. Statistical analysis Continuous variables were summarized using clinically relevant cut-offs or median values, and categorical variables were presented as frequencies and percentages. Baseline characteristics between groups were compared using the chi-squared test or Fisher’s exact test for categorical variables. For treatment response analyses, univariate logistic regression was first performed to identify potential predictors; variables with p < 0.05 were subsequently entered into multivariate logistic regression models. For time-to-event outcomes, Kaplan–Meier estimators were used to generate survival curves, and group differences were evaluated with the log-rank test. Cox proportional hazards regression models were applied to assess the association of clinical factors with progression-free survival (PFS) and overall survival (OS). Univariate Cox analyses were initially performed, and variables with p < 0.05 were included in multivariate models to adjust for potential confounding. All statistical analyses were performed in R (version 4.3.1; R Foundation for Statistical Computing, Vienna, Austria). Propensity score matching was performed using the ‘ MatchIt’ package. Covariate balance was assessed with standardized mean differences and visualized using the ‘ cobalt’ package. Baseline characteristics were summarized with the ‘ tableone’ package. Survival analyses, including Kaplan–Meier estimation and Cox proportional hazards models, were conducted with the ‘ survival’ and ‘ survminer’ packages. Logistic regression analyses were performed using the ‘ stats’ package. Forest plots were generated using the ‘ forestploter’ package, and additional data processing and visualization were carried out with the ‘ dplyr’ and ‘ ggplot2’ packages. Missing data were not imputed, and patients with incomplete follow-up were excluded from corresponding analyses. All statistical tests were two-sided, and a p-value < 0.05 was considered statistically significant. RESULTS Patient characteristics As shown in Fig. 1 , 126 patients were included in the immunotherapy cohort, of whom 104 had evaluable intracranial and extracranial responses, and 85 patients were included in the chemotherapy cohort. The baseline characteristics of patients receiving immunotherapy stratified by intracranial response are summarized in Table 1. Among the immunotherapy group, 103 (81.7%) had non-squamous histology, 29 (23.0%) harbored EGFR mutations, 59 (46.8%) received ICIs as first-line treatment, and 93 (73.8%) were treated with immunotherapy in combination with chemotherapy. Radiotherapy for brain metastases was administered in 60 patients (47.6%). Baseline characteristics were further compared among subgroups with different intracranial. Significant differences were observed for treatment line and radiotherapy timing. Patients treated with ICIs in the first line had higher intracranial response rates than those treated in later lines (66.7% vs. 27.7%, p < 0.001), and prior radiotherapy was associated with improved responses compared to no radiotherapy, whereas palliative radiotherapy was linked to inferior responses compared with prior or concurrent radiotherapy. After propensity score matching, baseline characteristics of the matched immunotherapy and chemotherapy cohorts are presented in Supplementary Table S2 , showing well-balanced covariates between groups. The total chemotherapy cohort is described in Supplementary Table S3. Table 1 Baseline characteristics of immunotherapy cohort Characteristics Level Overall Intracranial Response P value Yes No Number 126 39 (31.0%) 65 (51.6%) Sex (%) Female 34 (27.0%) 8 (20.5%) 19 (29.2%) 0.453 Male 92 (73.0%) 31 (79.5%) 46 (70.8%) Age (%) <65 70 (55.6%) 23 (59.0%) 36 (55.4%) 0.878 >=65 56 (44.4%) 16 (41.0%) 29 (44.6%) Smoking history (%) No 51 (40.5%) 12 (30.8%) 31 (47.7%) 0.136 Yes 75 (59.5%) 27 (69.2%) 34 (52.3%) ECOG (%) 0 or1 97 (77.0%) 28 (71.8%) 48 (73.8%) 1 >=2 29 (23.0%) 11 (28.2%) 17 (26.2%) Liver metastases (%) No 102 (81.0%) 33 (84.6%) 51 (78.5%) 0.607 Yes 24 (19.0%) 6 (15.4%) 14 (21.5%) Pathological subtype (%) Non-squamous 103 (81.7%) 33 (84.6%) 53 (81.5%) 0.894 Squamous 23 (18.3%) 6 (15.4%) 12 (18.5%) EGFR mutation No 97 (77.0%) 32 (82.1%) 46 (70.8%) 0.293 Yes 29 (23.0%) 7 (17.9%) 19 (29.2%) Line of immunotherapy First 59 (46.8%) 26 (66.7%) 18 (27.7%) <0.001 Non-first 67 (53.2%) 13 (33.3%) 47 (72.3%) Combined chemotherapy No 33 (26.2%) 11 (28.2%) 20 (30.8%) 0.956 Yes 93 (73.8%) 28 (71.8%) 45 (69.2%) irAE (%) No 94 (74.6%) 26 (66.7%) 51 (78.5%) 0.273 Yes 32 (25.4%) 13 (33.3%) 14 (21.5%) Neurological symptom (%) No 82 (65.1%) 22 (56.4%) 42 (64.6%) 0.532 Yes 44 (34.9%) 17 (43.6%) 23 (35.4%) Number of brain metastases (%) Multiple 53 (42.4%) 14 (35.9%) 34 (52.3%) 0.155 Oligo 72 (57.6%) 25 (64.1%) 31 (47.7%) Leptomeningeal metastases (%) No 121 (96.0%) 36 (92.3%) 64 (98.5%) 0.292 Yes 5 (4.0%) 3 (7.7%) 1 (1.5%) Radiotherapy (%) No 66 (52.4%) 15 (38.5%) 36 (55.4%) 0.142 Yes 60 (47.6%) 24 (61.5%) 29 (44.6%) Radiotherapy modality (%) No 66 (52.4%) 15 (38.5%) 36 (55.4%) 0.104 SRT 34 (27.0%) 15 (38.5%) 13 (20.0%) WBRT 26 (20.6%) 9 (23.1%) 16 (24.6%) Radiotherapy timing (%) No 66 (52.4%) 15 (38.5%) 36 (55.4%) 0.002 Before 23 (18.3%) 13 (33.3%) 9 (13.8%) Concurrent 18 (14.3%) 10 (25.6%) 7 (10.8%) Palliative 19 (15.1%) 1 (2.6%) 13 (20.0%) ECOG, Eastern Cooperative Oncology Group Performance Status; SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy. Comparison of efficacy and survival outcomes between immunotherapy and chemotherapy in patients with brain metastases In the propensity score–matched cohort, patients treated with immunotherapy had a significantly longer median OS than those receiving chemotherapy (18.9 vs. 13.3 months, p = 0.001), as illustrated in Fig. 2 . Intracranial and extracranial PFS were numerically prolonged in the immunotherapy cohort but did not reach statistical significance. The median iPFS was 10.4 months in the immunotherapy group versus 9.6 months in the chemotherapy group (p = 0.09), while the median ePFS was 7.8 versus 7.1 months, respectively (p = 0.06). In terms of intracranial response, the objective response rate was 31.4% (16/51) in the immunotherapy group and 33.9% (19/56) in the chemotherapy group. No significant difference was observed between ICI monotherapy and chemo-immunotherapy combinations in terms of intracranial response ( p = 0.374). Among 104 patients who were accessible of intracranial efficacy the iORR was 37.5% (39/104) and the eORR was 45.2% (57/126). Patients treated with ICI plus chemotherapy and those receiving ICI monotherapy achieved comparable intracranial responses. Patients treated with ICI plus chemotherapy and those receiving ICI monotherapy achieved comparable intracranial responses（38.4 verse 35.5%, p = 0.374). The concordance rate between intracranial and extracranial response was 71.2% (74/104). Among the 30 patients with discordant responses, 20 showed response in extracranial lesions only, while 10 responded intracranially only. Notably, 4 of these 10 patients had not received brain radiotherapy. In the chemotherapy cohort (n = 85), the iORR was 28.8% (23/80), and the eORR was 21.2% (18/85). The concordance rate between intracranial and extracranial responses was 70% (56/80). Among the 24 patients showing discordant responses, 15 showed intracranial response only, of whom 10 had received brain radiotherapy, while 9 showed extracranial response only. Clinical factors associated with intracranial and extracranial responses In the immunotherapy cohort, several clinical factors were associated with intracranial response as shown in Fig. 3 . A significantly higher intracranial response rate was observed in patients who received ICI as first-line treatment [Odds Ratio (OR) 5.22, p=0.0002], in those who received stereotactic radiotherapy (SRT) versus no radiotherapy (OR 2.77, p = 0.037), and in those who received radiotherapy prior to (OR 3.47, p = 0.019) or concurrently with (OR 3.43, p = 0.034) ICI compared with no radiotherapy. However, only the line of immunotherapy remained an independent predictive factor in multivariate analysis. Fig. 4 demonstrated that extracranial response was significantly associated with first-line ICI treatment (OR 2.98, p=0.003) and the occurrence of immune-related adverse events (irAEs) (OR 3.08, p=0.001). Nevertheless, only the line of treatment was retained as an independent influencing factor in multivariate analysis. In the chemotherapy cohort, intracranial response was associated with receipt of SRT (OR 5.42, p = 0.017) or radiotherapy administered prior to chemotherapy (OR 3.87, p = 0.023), compared to those without radiotherapy ( Supplementary Fig. S1 ). The presence of neurological symptoms related to brain metastases (OR 0.087, p = 0.021), and receiving chemotherapy as non-first line treatment (OR 0.276, p = 0.027) was associated with a reduced extracranial response ( Supplementary Fig. S2 ). Prognostic factors for progression-free survival and overall survival As displayed in Fig. 5 , in the immunotherapy cohort, overall survival was significantly prolonged in patients who developed irAEs [Hazard Ratio (HR) 0.614, p=0.039], received SRT (HR 0.622, p=0.046), or underwent radiotherapy prior to immunotherapy (HR 0.530, p=0.021). Among pairwise comparisons of timing of radiotherapy, only prior radiotherapy conferred a significant survival advantage compared with no radiotherapy ( p = 0.014) or palliative radiotherapy ( p = 0.018). As shown in Fig. 6 , patients who received intracranial radiotherapy prior to immunotherapy achieved a median overall survival of up to 32.3 months, whereas those who underwent concurrent radiotherapy and immunotherapy had a median survival of 19.0 months. As shown in Fig. 7 , administration of whole-brain radiotherapy (WBRT) (HR 2.22, p=0.006) and palliative radiotherapy (HR 4.86, p<0.001) were significantly associated with shorter iPFS. In contrast, as illustrated in Fig. 8, male sex (HR 0.528, p=0.005), the occurrence of irAEs (HR 0.548, p=0.020), and receipt of SRT (HR 0.54, p=0.029) were significantly associated with prolonged ePFS. In the chemotherapy-only cohort, patients aged ≥ 65 years (HR 2.45, p < 0.001) had significantly shorter overall, while patients with an ECOG performance status of 2 or higher (HR 1.96, p=0.083) or with multiple brain metastases (HR 1.46, p=0.100) tended to have shorter survival. (Supplementary Fig. S3). Multiple brain metastases showed a trend toward shorter iPFS (HR 1.54, p=0.084), while palliative radiotherapy was significantly associated with reduced iPFS (HR 2.37, p=0.010) compared to those without radiotherapy (Supplementary Fig. S4). Regarding ePFS, patients aged ≥ 65 years (HR 1.69, p=0.042) had earlier extracranial progression ( Supplementary Fig. S5 ). Discussion This study provides exploratory, real-world insights into the intracranial and extracranial efficacy of immunotherapy in NSCLC patients with brain metastases. Our matched analysis suggested a potential survival advantage with immunotherapy over chemotherapy, although these findings should be interpreted with caution given the retrospective design and limited sample size. Among potential prognostic indicators, the occurrence of immune-related adverse events, and prior brain radiotherapy particularly stereotactic radiotherapy (SRT) appeared most consistently associated with improved survival outcomes in patients receiving immunotherapy. In terms of intracranial efficacy, the iORR of the overall immunotherapy cohort was 37.5%, and 31.4% in the matched immunotherapy cohort, which was comparable to 33.9% in the matched chemotherapy cohort. In real-world settings, the iORR of ICI monotherapy has been reported as 24.2% (n = 33), regardless of PD-L1 levels [ 7 ], while that of immunotherapy combined with chemotherapy generally ranges from 20% to 40% [ 8 – 10 ]. In our study, approximately 70% of patients demonstrated concordant intracranial and extracranial responses, consistent across treatment groups. While discordant responses were observed in the remainder, including cases with greater intracranial than extracranial responses. Similar discordance has been reported in 21% (n = 44) of patients receiving ICI monotherapy[ 8 ] and 26.8% (n = 41) regardless of combination with chemotherapy. These findings suggest that, beyond immune microenvironmental differences, tumor-intrinsic heterogeneity may also contribute to divergent responses. Recent evidence indicates that increased genomic instability and intratumor heterogeneity in brain metastases facilitate immune remodeling and local immune escape [ 11 ], underscoring the need to tailor immunotherapy strategies to both immune and genomic features of metastatic lesions. The median OS for patients receiving ICIs was 18.9 months, significantly longer than that of patients treated with chemotherapy, and comparable to the 18.8 months reported in the KEYNOTE-189 trial [ 12 ]. By analyzing clinical factors related to treatment response and survival, we found that in the chemotherapy cohort, long-term survival was more closely associated with baseline features such as age, ECOG performance status, and the number of intracranial lesions, although some of these associations did not reach statistical significance. In contrast, such baseline factors showed less influence in the immunotherapy cohort, consistent with previous studies suggesting that even elderly or functionally impaired patients may still derive benefit from ICIs [ 12 , 13 ]. These findings though preliminary, support the possibility that immunotherapy could provide a potential survival benefit even in vulnerable patient populations traditionally considered less fit for systemic therapy. We also noted that patients with EGFR mutations who received immunotherapy after tyrosine kinase inhibitor (TKI) progression achieved clinical benefits comparable to those with EGFR wild-type disease, in terms of treatment response and survival outcomes. This aligns with prior reports suggesting that ICIs combined with chemotherapy may retain activity in NSCLC with EGFR-sensitive mutations post-TKI progression [ 14 ]. In our cohort, the line of immunotherapy administration influenced intracranial and extracranial responses but was not significantly associated with progression-free survival or overall survival likely due to the relatively high proportion (23%) of EGFR-mutant patients receiving ICIs as later-line therapy. Nevertheless, earlier-line administration has been associated with improved survival in pivotal trials and real-world studies[ 15 , 16 ], although benefit persists across treatment lines. As unique adverse events of immune checkpoint blockade, the development of irAEs was significantly associated with improved extracranial efficacy and prolonged survival in our cohort, in line with growing evidence that irAEs may serve as a surrogate marker of ICI response [ 17 , 18 ]. With regard to radiotherapy, we observed that intracranial radiotherapy administered prior to systemic treatment was associated with improved intracranial response in both immunotherapy and chemotherapy cohorts In the immunotherapy cohort, patients who received radiotherapy before ICIs tended to have longer survival, while such an association was not observed in the chemotherapy group. Patients who received intracranial radiotherapy prior to immunotherapy achieved a median overall survival of up to 32.3 months, significantly longer than 19.0 months for those treated concurrently with radiotherapy and immunotherapy. These findings may suggest a potential interaction between radiotherapy and immune checkpoint blockade. Previous studies have indicated that combining radiotherapy with immunotherapy may improve intracranial response [ 19 , 20 ], whereas its effect on long-time survival remains inconclusive [ 21 ]. Translational data further suggest that radiotherapy delivered during or after ICIs may compromise the immune microenvironment by eliminating infiltrating lymphocytes [ 22 ] and disrupting tertiary lymphoid structures (TLS), which serve as immunological hubs facilitating adaptive immune activation and predict favorable immunotherapy outcomes [ 23 ]. Remarkably, TLS have also been identified within brain metastases originating from lung cancer, albeit often in an immature form [ 24 ]. Clinical trial data also highlight the complex interplay between radiotherapy and immunotherapy: In the original PACIFIC study[ 25 ], immunotherapy administered sequentially after completion of chemoradiation significantly improved survival, whereas the PACIFIC-2 trial [ 26 ], which evaluated concurrent delivery of immunotherapy with chemoradiation, did not demonstrate such benefit. These contrasting outcomes suggest that treatment timing may be critical although remains incompletely defined. Similarly, a real-world analysis reported improved survival when radiotherapy was delivered within 14 days before or after programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) inhibition, compared with delayed radiotherapy (≥ 14 days after ICI) [ 27 ]. The biological effects of radiotherapy persist long after therapy ends, including ongoing tumor cell apoptosis, vascular injury [ 28 ], and modulation of the immune landscape - such as antigen release, dendritic cell recruitment, and upregulation of PD-L1 on tumor and myeloid cells [ 29 ], thereby supporting the rationale for administering immunotherapy sequentially after radiotherapy. This study had several limitations. First, its retrospective and relatively small sample size inherently carries the risk of selection bias and limits the strength of causal inferences, underscoring the need for validation in larger, multi-institutional cohorts. Second, part of the chemotherapy cohort was treated during an earlier period, which may have introduced heterogeneity in molecular testing methods and radiotherapy techniques compared with the immunotherapy group. Third, the frequency of follow-up imaging was not uniform, as intracranial assessments were generally performed at longer intervals than extracranial evaluations, and some patients did not undergo brain MRI strictly at predefined timepoints. Conclusions This analysis provides exploratory, real-world insights into the management of NSCLC with brain metastases. Our matched comparisons suggest that immunotherapy may be associated with improved survival outcomes compared with chemotherapy, and that these benefits appear less dependent on baseline characteristics such as age and performance status. Our finding that intracranial radiotherapy administered before immunotherapy was associated with longer survival suggests a sequence-dependent interplay between radiotherapy and immunotherapy. Nevertheless, these results arise from a retrospective analysis with limited sample size and without external validation and should therefore be considered exploratory. Prospective, larger-scale studies will be needed to clarify the clinical relevance of treatment sequencing and to define optimal strategies for NSCLC patients with brain metastases. Abbreviations NSCLC: Non-small cell lung cancer BMs: Brain metastases ICIs: Immune checkpoint inhibitors OS: Overall survival iPFS: Intracranial progression-free survival ePFS: Extracranial progression-free survival ORR: Objective response rate iORR: Intracranial objective response rate eORR: Extracranial objective response rate PSM: Propensity score matching SMDs: Standardized mean differences PD-1: Programmed death-1 PD-L1: Programmed death-ligand 1 MRI: Magnetic resonance imaging CIs: Confidence intervals CR: Complete response PR: Partial response CT: Computed tomography HR: Hazard ratio ECOG: Eastern Cooperative Oncology Group EGFR: Epidermal growth factor receptor TKIs: Tyrosine kinase inhibitors ARMS: Amplification refractory mutation system NGS: Next-generation sequencing SRT: Stereotactic radiotherapy WBRT: Whole-brain radiotherapy irAEs: Immune-related adverse events RANO-BM: Response Assessment in Neuro-Oncology Brain Metastases RECIST: Response Evaluation Criteria in Solid Tumors TLS: Tertiary lymphoid structures Declarations Ethics approval and consent to participate This study was conducted in accordance with the Helsinki Declaration and was approved by the Institutional Review Board of Peking Union Medical College Hospital. The requirement for informed consent was waived by the Institutional Review Board of Peking Union Medical College Hospital. Availability of data The datasets generated and/or analysed during the current study are provided in the Supplementary Information. Competing interest The authors declare no conflicts of interest. Funding Not applicable. CRediT authorship contribution statement MZW contributed to the conception and design of the study. MJC contributed to the critical review, commentary, or revision of the manuscript. YXW contributed to the drafting of the article. RZL performed data visualization. XYL, YQS and XYF participated in data analysis and interpretation. YX and JZ provided supervision and guidance throughout the study. All authors reviewed and approved the final manuscript. Acknowledgements We gratefully acknowledge the technical support provided by Gaohui Bian and his engineering team for database services. References The Lancet O. Curbing the climb in cancer incidence. Lancet Oncol. 2024;25(5):529. http://dx.doi.org/10.1016/S1470-2045(24)00217-1 Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584-94. http://dx.doi.org/10.4065/83.5.584 Naresh G, Malik PS, Khurana S, Pushpam D, Sharma V, Yadav M, et al. Assessment of Brain Metastasis at Diagnosis in Non-Small-Cell Lung Cancer: A Prospective Observational Study From North India. JCO Glob Oncol. 2021;7:593-601. http://dx.doi.org/10.1200/GO.20.00629 Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):655-61. http://dx.doi.org/10.1016/j.ijrobp.2009.08.025 Nigen B, Goronflot T, Herbreteau G, Mathiot L, Sagan C, Raimbourg J, et al. Impact of first-line immunotherapy on survival and intracranial outcomes in a cohort of non-small cell lung cancer patients with brain metastases at diagnosis. Lung Cancer (Amsterdam, Netherlands). 2023;184:107321. http://dx.doi.org/10.1016/j.lungcan.2023.107321 Le Rhun E, Guckenberger M, Smits M, Dummer R, Bachelot T, Sahm F, et al. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol. 2021;32(11):1332-47. http://dx.doi.org/10.1016/j.annonc.2021.07.016 Skribek M, Rounis K, Makrakis D, Agelaki S, Mavroudis D, De Petris L, et al. Outcome of Patients with NSCLC and Brain Metastases Treated with Immune Checkpoint Inhibitors in a 'Real-Life' Setting. Cancers (Basel). 2020;12(12). http://dx.doi.org/10.3390/cancers12123707 Kang S, Jeong H, Park JE, Kim HS, Kim YH, Lee DH, et al. Central nervous systemic efficacy of immune checkpoint inhibitors and concordance between intra/extracranial response in non-small cell lung cancer patients with brain metastasis. J Cancer Res Clin Oncol. 2022;10.1007/s00432-022-04251-3. http://dx.doi.org/10.1007/s00432-022-04251-3 Sun C, Zhou F, Li X, Zhao C, Li W, Li J, et al. PD-1/PD-L1 Inhibitor Combined with Chemotherapy Can Improve the Survival of Non-Small Cell Lung Cancer Patients with Brain Metastases. Onco Targets Ther. 2020;13:12777-86. http://dx.doi.org/10.2147/OTT.S286600 Sheng J, Li H, Yu X, Yu S, Chen K, Pan G, et al. Efficacy of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer and brain metastases: A real-world retrospective study in China. Thorac Cancer. 2021;12(22):3019-31. http://dx.doi.org/10.1111/1759-7714.14171 Wang X, Bai H, Zhang J, Wang Z, Duan J, Cai H, et al. Genetic Intratumor Heterogeneity Remodels the Immune Microenvironment and Induces Immune Evasion in Brain Metastasis of Lung Cancer. Journal of Thoracic Oncology : Official Publication of the International Association For the Study of Lung Cancer. 2024;19(2):252-72. http://dx.doi.org/10.1016/j.jtho.2023.09.276 Yang F, Markovic SN, Molina JR, Halfdanarson TR, Pagliaro LC, Chintakuntlawar AV, et al. Association of Sex, Age, and Eastern Cooperative Oncology Group Performance Status With Survival Benefit of Cancer Immunotherapy in Randomized Clinical Trials: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020;3(8):e2012534. http://dx.doi.org/10.1001/jamanetworkopen.2020.12534 Gomes F, Wong M, Battisti NML, Kordbacheh T, Kiderlen M, Greystoke A, et al. Immunotherapy in older patients with non-small cell lung cancer: Young International Society of Geriatric Oncology position paper. Br J Cancer. 2020;123(6):874-84. http://dx.doi.org/10.1038/s41416-020-0986-4 Zhou S, Ren F, Meng X. Efficacy of immune checkpoint inhibitor therapy in EGFR mutation-positive patients with NSCLC and brain metastases who have failed EGFR-TKI therapy. Front Immunol. 2022;13:955944. http://dx.doi.org/10.3389/fimmu.2022.955944 Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-33. Brown LJ, Khou V, Brown C, Alexander M, Jayamanne D, Wei J, et al. First-line chemoimmunotherapy and immunotherapy in patients with non-small cell lung cancer and brain metastases: a registry study. Front Oncol. 2024;14:1305720. http://dx.doi.org/10.3389/fonc.2024.1305720 Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R, et al. Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer. JAMA Oncol. 2018;4(3):374-8. http://dx.doi.org/10.1001/jamaoncol.2017.2925 Shi Y, Fang J, Zhou C, Liu A, Wang Y, Meng Q, et al. Immune checkpoint inhibitor-related adverse events in lung cancer: Real-world incidence and management practices of 1905 patients in China. Thorac Cancer. 2022;13(3):412-22. http://dx.doi.org/10.1111/1759-7714.14274 Kim DY, Kim PH, Suh CH, Kim KW, Kim HS. Immune Checkpoint Inhibitors with or without Radiotherapy in Non-Small Cell Lung Cancer Patients with Brain Metastases: A Systematic Review and Meta-Analysis. Diagnostics (Basel). 2020;10(12). http://dx.doi.org/10.3390/diagnostics10121098 Porte J, Saint-Martin C, Frederic-Moreau T, Massiani M-A, Bozec L, Cao K, et al. Efficacy and Safety of Combined Brain Stereotactic Radiotherapy and Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer with Brain Metastases. Biomedicines. 2022;10(9). http://dx.doi.org/10.3390/biomedicines10092249 Chu X, Niu L, Xiao G, Peng H, Deng F, Liu Z, et al. The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis. Front Immunol. 2022;13:875488. http://dx.doi.org/10.3389/fimmu.2022.875488 Saddawi-Konefka R, O'Farrell A, Faraji F, Clubb L, Allevato MM, Jensen SM, et al. Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC. Nat Commun. 2022;13(1):4298. http://dx.doi.org/10.1038/s41467-022-31941-w Sautès-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19(6):307-25. http://dx.doi.org/10.1038/s41568-019-0144-6 Nohira S, Kuramitsu S, Ohno M, Fujita M, Yamashita K, Nagasaka T, et al. Tertiary Lymphoid Structures in Brain Metastases of Lung Cancer: Prognostic Significance and Correlation With Clinical Outcomes. Anticancer Res. 2024;44(8):3615-21. http://dx.doi.org/10.21873/anticanres.17184 Chaft JE, Rimner A, Weder W, Azzoli CG, Kris MG, Cascone T. Evolution of systemic therapy for stages I-III non-metastatic non-small-cell lung cancer. Nat Rev Clin Oncol. 2021;18(9):547-57. http://dx.doi.org/10.1038/s41571-021-00501-4 Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2022;40(12):1301-11. http://dx.doi.org/10.1200/JCO.21.01308 Yu Y, Chen H, Tian Z, Zhang Q, Shui Y, Shen L, et al. Improved survival outcome with not-delayed radiotherapy and immediate PD-1/PD-L1 inhibitor for non-small-cell lung cancer patients with brain metastases. J Neurooncol. 2023;165(1):127-37. http://dx.doi.org/10.1007/s11060-023-04459-4 Carvalho HdA, Villar RC. Radiotherapy and immune response: the systemic effects of a local treatment. Clinics (Sao Paulo). 2018;73(suppl 1):e557s. http://dx.doi.org/10.6061/clinics/2018/e557s Guo S, Yao Y, Tang Y, Xin Z, Wu D, Ni C, et al. Radiation-induced tumor immune microenvironments and potential targets for combination therapy. Signal Transduct Target Ther. 2023;8(1):205. http://dx.doi.org/10.1038/s41392-023-01462-z Additional Declarations No competing interests reported. Supplementary Files chemotherapycohort.csv immunotherapycohort.csv Supplementaryinformation.docx Cite Share Download PDF Status: Published Journal Publication published 07 Dec, 2025 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 23 Oct, 2025 Reviews received at journal 18 Oct, 2025 Reviewers agreed at journal 16 Oct, 2025 Reviews received at journal 08 Oct, 2025 Reviewers agreed at journal 02 Oct, 2025 Reviewers invited by journal 01 Oct, 2025 Editor assigned by journal 30 Sep, 2025 Editor invited by journal 29 Sep, 2025 Submission checks completed at journal 27 Sep, 2025 First submitted to journal 27 Sep, 2025 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-7676603\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":528832911,\"identity\":\"708a2462-e765-4e1d-80eb-718f03964145\",\"order_by\":0,\"name\":\"Yuxi Wei\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Chinese Academy of Medical Sciences \\u0026 Peking Union Medical College\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yuxi\",\"middleName\":\"\",\"lastName\":\"Wei\",\"suffix\":\"\"},{\"id\":528832912,\"identity\":\"e9ae1b5b-c932-4687-bbd8-f0f7693c6787\",\"order_by\":1,\"name\":\"Rongzhen Li\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Chinese Academy of Medical Sciences \\u0026 Peking Union Medical College\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Rongzhen\",\"middleName\":\"\",\"lastName\":\"Li\",\"suffix\":\"\"},{\"id\":528832913,\"identity\":\"00d2a7b5-f122-49d0-8758-71ed4946c4c5\",\"order_by\":2,\"name\":\"Xiaoyan Liu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Chinese Academy of Medical Sciences \\u0026 Peking Union Medical College\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xiaoyan\",\"middleName\":\"\",\"lastName\":\"Liu\",\"suffix\":\"\"},{\"id\":528832914,\"identity\":\"f292c75e-7b23-4915-91f5-9ae3eea1e52f\",\"order_by\":3,\"name\":\"Yuequan Shi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Chinese Academy of Medical Sciences \\u0026 Peking Union Medical College\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yuequan\",\"middleName\":\"\",\"lastName\":\"Shi\",\"suffix\":\"\"},{\"id\":528832915,\"identity\":\"5f1d41d6-b738-404a-9b2f-fb28a491174d\",\"order_by\":4,\"name\":\"Xu Yan\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Chinese Academy of Medical Sciences \\u0026 Peking Union Medical College\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xu\",\"middleName\":\"\",\"lastName\":\"Yan\",\"suffix\":\"\"},{\"id\":528832916,\"identity\":\"3e9bc396-e727-4914-91e4-80fe1626ed67\",\"order_by\":5,\"name\":\"Jing Zhao\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Chinese Academy of Medical Sciences \\u0026 Peking Union Medical College\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jing\",\"middleName\":\"\",\"lastName\":\"Zhao\",\"suffix\":\"\"},{\"id\":528832917,\"identity\":\"8576480a-a103-4df5-92ed-a9bcb63a5cd1\",\"order_by\":6,\"name\":\"Minjiang Chen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Chinese Academy of Medical Sciences \\u0026 Peking Union Medical College\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Minjiang\",\"middleName\":\"\",\"lastName\":\"Chen\",\"suffix\":\"\"},{\"id\":528832918,\"identity\":\"694fb7a0-e959-4745-973d-242723a867d8\",\"order_by\":7,\"name\":\"Mengzhao Wang\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYLACxgYo4wODBIlaGGeQrIWZhxjVuu29h1/+3GEnZ3D87OHXNn8s8vgbmB8+uoFHi9mZc2kWkmeSjQ3O5KVZ57ZJFEscYDM2zsGn5UaOmYFhG3PitgM5Zsa5DRKJDQd42KTxarn/xswgsa0+cdv5N2bGFn8kEucT1HKDx/jBwbbDidtu5Bg/ZmCTSNxAUMuZHDPGxrbjxvY33pgx9rZJJG48TMgvx88Yf/zZVi0n2Z9j/OHHn7rEecebHz7GpwUI2CRQGcz4lYOVfEBnjIJRMApGwShAAQB+olFLgjCrtwAAAABJRU5ErkJggg==\",\"orcid\":\"\",\"institution\":\"Chinese Academy of Medical Sciences \\u0026 Peking Union Medical College\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Mengzhao\",\"middleName\":\"\",\"lastName\":\"Wang\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-09-22 13:23:49\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-7676603/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-7676603/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1186/s12885-025-15327-x\",\"type\":\"published\",\"date\":\"2025-12-07T15:58:29+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":93610478,\"identity\":\"41d2fb1c-2037-4d92-898e-551d8d61b1ba\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:42\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":107463,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Manuscript.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/58e1186dd78b1e5a815e5601.docx\"},{\"id\":93610488,\"identity\":\"be611658-1ec6-4249-b702-2fe50348cd79\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:42\",\"extension\":\"json\",\"order_by\":9,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":9820,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"43893a98d9ed4ebe8e8563227fe703bc.json\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/d752f720f8985b6ff2e6f87a.json\"},{\"id\":93613346,\"identity\":\"d9e247a4-1343-49bd-8d17-a8e78eba59ed\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:26:43\",\"extension\":\"eps\",\"order_by\":10,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":1027290,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.S1.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/2a12a0373216242ec3c8951c.eps\"},{\"id\":93610497,\"identity\":\"a6256435-5e1c-4520-a2dc-6d085c44e049\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:43\",\"extension\":\"eps\",\"order_by\":11,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":1032026,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.S2.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/02f51ce5fa369f661840118c.eps\"},{\"id\":93610495,\"identity\":\"ba39eaa7-8923-461b-a3cc-64126e30a18e\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:43\",\"extension\":\"eps\",\"order_by\":12,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":990990,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.S3.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/509c47327c3dbfbf9d1a4411.eps\"},{\"id\":93612393,\"identity\":\"dd94f900-ffdc-43f6-a64d-26a916178518\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:18:42\",\"extension\":\"eps\",\"order_by\":13,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":981390,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.S4.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/8db6a8a8e410c107a3487a7e.eps\"},{\"id\":93610499,\"identity\":\"89b31598-bf47-469f-ab5e-9eb7f671768b\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:43\",\"extension\":\"eps\",\"order_by\":14,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":995842,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.S5.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/cc3cc4baaf6f02cf9da9af4e.eps\"},{\"id\":93612395,\"identity\":\"bb733ec5-4c19-493f-9aa3-76edb6b4a437\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:18:42\",\"extension\":\"docx\",\"order_by\":15,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":33472,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Supplementaryinformation.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/8cc2e0ce4fd4fb6c513720b0.docx\"},{\"id\":93610492,\"identity\":\"c5407355-a653-4212-a0db-ae15c87e1a1c\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:42\",\"extension\":\"csv\",\"order_by\":16,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":10084,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"chemotherapycohort.csv\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/1c887a02041204b72e472aac.csv\"},{\"id\":93613345,\"identity\":\"5473c180-5add-4dee-9ecf-d80ff198d8dc\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:26:42\",\"extension\":\"csv\",\"order_by\":17,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":15771,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"immunotherapycohort.csv\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/b8decd84ac29d3b71393bb4c.csv\"},{\"id\":93612397,\"identity\":\"3a4789e9-854b-4e71-b6d0-9442d41e880d\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:18:43\",\"extension\":\"xml\",\"order_by\":18,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":122918,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"43893a98d9ed4ebe8e8563227fe703bc1enriched.xml\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/a0cad6e73cd29af74d5f8e60.xml\"},{\"id\":93610490,\"identity\":\"18e03e23-d518-437f-81b7-d13f07a0c279\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:42\",\"extension\":\"pdf\",\"order_by\":19,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":26230,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.1.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/c574cdebc6dd3437129e30ba.pdf\"},{\"id\":93612398,\"identity\":\"e097022a-5cad-4216-955b-15ae97aea7af\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:18:43\",\"extension\":\"eps\",\"order_by\":20,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":1389674,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.2.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/b81e5fd57929450db0d8e9b5.eps\"},{\"id\":93613347,\"identity\":\"aa895b69-0f05-4a39-a933-8785c5cf1b54\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:26:43\",\"extension\":\"eps\",\"order_by\":21,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":1067506,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.3.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/d08bd4b2ab57019045092782.eps\"},{\"id\":93612400,\"identity\":\"74d9dfaa-8ea1-43f5-9c2d-c505b62a3450\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:18:43\",\"extension\":\"eps\",\"order_by\":22,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":1064986,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.4.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/50345d3ae9209c34905b0a84.eps\"},{\"id\":93612401,\"identity\":\"1faf7630-ae1d-42ee-86d6-13915c70b982\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:18:43\",\"extension\":\"eps\",\"order_by\":23,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":1058682,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.5.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/b9a1c1205eeaeb3725ef885b.eps\"},{\"id\":93610506,\"identity\":\"18c49ff7-a19a-4840-a1a5-807c5e829985\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:43\",\"extension\":\"eps\",\"order_by\":24,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":544114,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.6.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/b432e8f04846b92611297878.eps\"},{\"id\":93613884,\"identity\":\"b0db1c65-df05-4ea0-822c-00af75be1d39\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:34:43\",\"extension\":\"eps\",\"order_by\":25,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":1053294,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.7.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/8ffb1fc17261c6cd5fb89f51.eps\"},{\"id\":93610505,\"identity\":\"414127fb-ae63-492c-a9e6-88057e275e96\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:43\",\"extension\":\"eps\",\"order_by\":26,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":1054142,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Fig.8.eps\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/11be5d7c73a53de2dab5e01d.eps\"},{\"id\":93610501,\"identity\":\"32c03cbe-fe3a-40a5-879b-54ea10217f60\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:43\",\"extension\":\"xml\",\"order_by\":27,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":120109,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"43893a98d9ed4ebe8e8563227fe703bc1structuring.xml\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/8c14007262530beb3b487150.xml\"},{\"id\":93613348,\"identity\":\"e607681b-0237-4eb6-88bb-4348b145482e\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:26:43\",\"extension\":\"html\",\"order_by\":28,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":131308,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"earlyproof.html\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/16be3cb2bf37fa726e7dd430.html\"},{\"id\":93612385,\"identity\":\"90e897c3-3a36-47d2-b096-42a610c3e684\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:18:42\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":22852,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eFlowchart of patient enrollment and analysis. NSCLC, non-small cell lung cancer; ICIs, immune checkpoint inhibitor; SCLC, small cell lung cancer.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"fig1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/0adb264f3d8a3a3dde43bda0.png\"},{\"id\":93612386,\"identity\":\"cd978dd7-bbb3-4f6a-8bc7-adecc05fd324\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:18:42\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":31724,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eKaplan–Meier curves for overall survival, intracranial and extracranial progression-free survival in matched patients. (a) Kaplan–Meier curves for overall survival. (b) Kaplan–Meier curves intracranial progression-free survival. (c) Kaplan–Meier curves extracranial progression-free survival. The vertical dashed lines indicate the time point at which 50% of patients remain at risk, corresponding to the median overall survival. The p-value shown is derived from the log-rank test. Number at risk is displayed below the time axis. iPFS, intracranial progression-free survival; ePFS, extracranial progression-free survival.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"fig2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/182b9dafd40834f89f0de153.png\"},{\"id\":93613883,\"identity\":\"c1f62476-4b4f-45cd-bf2b-a3742cb2f4a4\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:34:42\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":64632,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eUnivariate logistic regression analysis of clinical factors associated with intracranial response in immunotherapy cohort. The blue dots represent the odds ratios (ORs) for each variable, and the blue horizontal lines indicate the corresponding 95% confidence intervals (CIs). SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"fig3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/126203bf582edf5882b92872.png\"},{\"id\":93610482,\"identity\":\"3c28e36e-eeda-4668-8dd9-9f211d7f18f8\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:42\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":64466,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eUnivariate logistic regression analysis of clinical factors associated with extracranial response in immunotherapy cohort. The blue dots represent the odds ratios (ORs) for each variable, and the blue horizontal lines indicate the corresponding 95% confidence intervals (CIs). SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"fig4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/d91ff2e7bee92676dd113fbd.png\"},{\"id\":93613343,\"identity\":\"bb95314b-cd04-4f39-8456-f5ce39f24b7e\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:26:42\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":64151,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eUnivariate cox regression analysis of prognostic factors for overall survival in immunotherapy cohort. The blue dots represent the hazard ratios (HRs) for each variable, and the blue horizontal lines indicate the corresponding 95% confidence intervals (CIs). SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy; irAEs, immune-related adverse events.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"fig5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/1989e44e73452a853bbacd7b.png\"},{\"id\":93613882,\"identity\":\"f9ff4a67-de43-4148-a556-41cde72d0d24\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:34:42\",\"extension\":\"png\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":14902,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eKaplan–Meier curves for overall survival in immunotherapy cohort stratified by timing of intracranial. OS, overall survival. Number at risk is displayed below the time axis.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"fig6.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/858150b7fa28eee49d20592d.png\"},{\"id\":93612388,\"identity\":\"9a281d1a-1833-49bc-b080-aa6c81906e74\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:18:42\",\"extension\":\"png\",\"order_by\":7,\"title\":\"Figure 7\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":64424,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eUnivariate cox regression analysis of prognostic factors for intracranial progression-free survival in immunotherapy cohort. The blue dots represent the hazard ratios (HRs) for each variable, and the blue horizontal lines indicate corresponding 95% confidence intervals (CIs). SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"fig7.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/80047f2c2e5d1d414390128c.png\"},{\"id\":93613341,\"identity\":\"676c11b4-a5fe-401c-a4ae-39f48b98523c\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:26:42\",\"extension\":\"png\",\"order_by\":8,\"title\":\"Figure 8\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":62656,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eUnivariate cox regression analysis of prognostic factors for extracranial progression-free survival in immunotherapy cohort. The blue dots represent the hazard ratios (HRs) for each variable, and the blue horizontal lines indicate the corresponding 95% confidence intervals (CIs). SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"fig8.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/3d89eab04265290a8e643122.png\"},{\"id\":97724906,\"identity\":\"9fd30a2f-6156-4680-92eb-50f4fb1ccd2a\",\"added_by\":\"auto\",\"created_at\":\"2025-12-08 16:13:53\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1227705,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/5af3db77-e38b-4113-b992-665a2b85b7e6.pdf\"},{\"id\":93610475,\"identity\":\"03a30699-5309-4451-8736-0248a886b3cb\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:42\",\"extension\":\"csv\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":10084,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"chemotherapycohort.csv\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/16e1acf8f0e9eb0d27a9d740.csv\"},{\"id\":93610477,\"identity\":\"c9949ad7-0538-43ba-b83e-3ea2315e70aa\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:42\",\"extension\":\"csv\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":15771,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"immunotherapycohort.csv\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/d71b3f03fb5f9b4303de2b66.csv\"},{\"id\":93610487,\"identity\":\"98b2a168-571c-4e8c-a8f5-f5cd0290738b\",\"added_by\":\"auto\",\"created_at\":\"2025-10-15 16:10:42\",\"extension\":\"docx\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":33472,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Supplementaryinformation.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7676603/v1/b3895bcfde2f89c5da0c7f7c.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Clinical outcomes and predictive factors of immunotherapy efficacy in non-small cell lung cancer brain metastases: A comparative study\",\"fulltext\":[{\"header\":\"Background\",\"content\":\"\\u003cp\\u003eAs of 2022, lung cancer remained the most commonly diagnosed malignancy and the leading cause of cancer-related death worldwide [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. Non‑small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Brain metastases (BMs) are a common metastastic site in advanced NSCLC, occurring in up to 40% of patients during the disease course. Brain metastases occur in approximately 20\\u0026ndash;40% of NSCLC patients during their disease course, with 5\\u0026ndash;10% presenting at diagnosis [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. In the pre-immunotherapy era, the prognosis of NSCLC patients with brain metastases was dismal, with a median overall survival (OS) ranging from 3 to 8 months, despite conventional treatment with chemotherapy and radiotherapy [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eThe advent of immune checkpoint inhibitors (ICIs) has markedly transformed the prevailing therapeutic paradigm of advanced NSCLC, extending the survival of patients with brain metastases to approximately 13\\u0026ndash;24 months [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e] across various subgroups. Nonetheless, detailed data regarding their intracranial efficacy\\u0026mdash;such as objective response rates, intracranial progression-free survival (iPFS), and associated determinants remain limited. Furthermore, although local therapies, particularly radiotherapy are frequently combined with ICIs in clinical practice[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e], the potential influence of radiotherapy modality and treatment sequencing on intracranial response and long-term outcomes has not been fully elucidated.\\u003c/p\\u003e\\u003cp\\u003eIn this multi-center retrospective study, we evaluated intracranial and extracranial responses as well as survival outcomes of NSCLC patients with brain metastases treated with ICIs, and compared them with a matched cohort receiving chemotherapy alone to assess the real-world clinical benefits of immunotherapy. We also investigated whether radiotherapy modality and timing in relation to immunotherapy were associated with variations in treatment response and prognosis.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003ePatients\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis was a multi-center, retrospective cohort study conducted in accordance with the Declaration of Helsinki. A retrospective review was conducted on patients with NSCLC and BMs who received ICIs between July, 2016 and April, 2024 at multiple centers in Beijing including Peking Union Medical College Hospital, Beijing Cancer Hospital and Cancer Hospital Chinese Academy of Medical Sciences. For comparison, patients with NSCLC and BMs who were treated exclusively with chemotherapy during a similar period at Peking Union Medical College Hospital between June, 2013 and April, 2022 were also reviewed. The common inclusion criteria for both cohorts were: (1) histopathological or cytological confirmation of NSCLC; (2) stage IV disease with radiologically confirmed brain metastases; (3) receipt of at least two cycles of systemic therapy (ICIs for the immunotherapy cohort or chemotherapy for the chemotherapy cohort); and (4) availability of measurable intracranial lesions on baseline imaging. Patients were excluded if they had pathologically confirmed large cell carcinoma or small cell transformation during the disease course, multiple primary lung cancers, or absence of measurable intracranial lesions. For the chemotherapy cohort, additional exclusion criteria included exposure to ICIs at any point during the disease course and receipt of concurrent tyrosine kinase inhibitors (TKIs) alongside chemotherapy. The study protocol was approved by the Ethics Committee of Peking Union Medical College Hospital.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003ePropensity score matching\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eTo minimize baseline imbalances between treatment groups, propensity score matching (PSM) was performed using key clinical variables, including sex, age, Eastern Cooperative Oncology Group (ECOG)\\u0026nbsp;performance status, histological subtype, Epidermal growth factor receptor (EGFR) mutation status, line of systemic treatment, receipt of brain radiotherapy, and number of brain metastases. The flow of patient selection and matching is presented in \\u003cstrong\\u003eFig. 1\\u003c/strong\\u003e. A 1:1 nearest-neighbor matching without replacement was conducted with a caliper width of 0.2 of the standard deviation of the logit of the propensity score. Covariate balance before and after matching was assessed using standardized mean differences (SMDs), with values \\u0026lt;0.1 considered indicative of adequate balance. \\u003cstrong\\u003eThe SMDs of covariates before and after matching are summarized in Supplementary Table S1.\\u003c/strong\\u003e The matched cohort was used for comparative analyses of survival and response outcomes, while the entire chemotherapy cohort was retained for exploratory analyses of prognostic factors.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eDefinitions and assessments\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eMutations at baseline were identified using either amplification refractory mutation system (ARMS) or next-generation sequencing (NGS). All patients were tested negative for ALK rearrangements, HER2 and other oncogenic driver alterations except EGFR. Patients harboring EGFR 19del, L858R, T790M, S768I, L861Q, and/or G719X mutations were classified as EGFR mutation positive. Baseline information related to brain metastases was collected before treatment, including\\u0026nbsp;presence of neurological symptoms, the number of brain metastases, and the maximum diameter of intracranial lesions\\u0026nbsp;based on imaging findings. Neurological symptoms included headache, dizziness, muscle weakness, nausea, and other symptoms attributable to brain metastases.\\u0026nbsp;The number of brain metastases was categorized as oligo metastases (\\u0026le;3 lesions) and multiple metastases (\\u0026ge;4 lesions). Prior radiotherapy was defined as radiotherapy completed before the initiation of systemic therapy (either immunotherapy or chemotherapy). Concurrent radiotherapy referred to intracranial radiotherapy delivered during the course of immunotherapy,\\u0026nbsp;regardless of whether it was started in the first cycle or subsequent cycles,\\u0026nbsp;typically for symptom control or management of cerebral edema.\\u0026nbsp;Palliative radiotherapy was defined as salvage intracranial radiotherapy administered after documented intracranial progression or insufficient local control during systemic therapy.\\u003c/p\\u003e\\n\\u003cp\\u003eThe primarily endpoint was OS and secondary endpoints included the intracranial objective response rate (iORR), intracranial progression-free survival (iPFS) and\\u0026nbsp;extracranial progression-free survival (ePFS). Intracranial responses were assessed according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, while extracranial lesions were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.\\u0026nbsp;Radiologic assessments were scheduled every 6 weeks until disease progression or death and were performed by experienced oncologists at each participating center. The data cutoff date for survival analysis was April 30th, 2025.\\u0026nbsp;Objective response was defined as\\u0026nbsp;partial response (PR) or complete response (CR). iPFS was defined as the interval from systemic therapy initiation to the first radiological confirmation of intracranial progression or death, whichever occurred first. Extracranial PFS (ePFS) was similarly defined as the interval from systemic therapy initiation to radiological confirmation of extracranial progression or death, whichever occurred first. OS was calculated from the date of first immune checkpoint inhibitors (ICI) or chemotherapy administration to death from any cause\\u0026nbsp;or last follow-up.\\u0026nbsp;Intracranial lesions were evaluated using brain magnetic resonance imaging (MRI), while extracranial lesions were assessed through contrast-enhanced computed tomography (CT) scans of the chest, abdomen, and pelvis.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eStatistical analysis\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eContinuous variables were summarized using clinically relevant cut-offs or median values, and categorical variables were presented as frequencies and percentages. Baseline characteristics between groups were compared using the chi-squared test or Fisher\\u0026rsquo;s exact test for categorical variables.\\u003c/p\\u003e\\n\\u003cp\\u003eFor treatment response analyses, univariate logistic regression was first performed to identify potential predictors; variables with p \\u0026lt; 0.05 were subsequently entered into multivariate logistic regression models. For time-to-event outcomes, Kaplan\\u0026ndash;Meier estimators were used to generate survival curves, and group differences were evaluated with the log-rank test. Cox proportional hazards regression models were applied to assess the association of clinical factors with progression-free survival (PFS) and overall survival (OS). Univariate Cox analyses were initially performed, and variables with p \\u0026lt; 0.05 were included in multivariate models to adjust for potential confounding.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAll statistical analyses were performed in R (version 4.3.1; R Foundation for Statistical Computing, Vienna, Austria).\\u0026nbsp;Propensity score matching was performed using the \\u0026lsquo;\\u003cem\\u003eMatchIt\\u0026rsquo;\\u003c/em\\u003e package. Covariate balance was assessed with standardized mean differences and visualized using the \\u0026lsquo;\\u003cem\\u003ecobalt\\u0026rsquo;\\u003c/em\\u003e package. Baseline characteristics were summarized with the \\u0026lsquo;\\u003cem\\u003etableone\\u0026rsquo;\\u003c/em\\u003e package. Survival analyses, including Kaplan\\u0026ndash;Meier estimation and Cox proportional hazards models, were conducted with the \\u0026lsquo;\\u003cem\\u003esurvival\\u0026rsquo;\\u003c/em\\u003e and \\u0026lsquo;\\u003cem\\u003esurvminer\\u0026rsquo;\\u003c/em\\u003e packages. Logistic regression analyses were performed using the \\u0026lsquo;\\u003cem\\u003estats\\u0026rsquo;\\u003c/em\\u003e package. Forest plots were generated using the \\u0026lsquo;\\u003cem\\u003eforestploter\\u0026rsquo;\\u003c/em\\u003e package, and additional data processing and visualization were carried out with the \\u0026lsquo;\\u003cem\\u003edplyr\\u0026rsquo;\\u003c/em\\u003e and \\u0026lsquo;\\u003cem\\u003eggplot2\\u0026rsquo;\\u003c/em\\u003e packages. Missing data were not imputed, and patients with incomplete follow-up were excluded from corresponding analyses. All statistical tests were two-sided, and a p-value \\u0026lt; 0.05 was considered statistically significant.\\u003c/p\\u003e\"},{\"header\":\"RESULTS\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003ePatient characteristics\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAs shown in \\u003cstrong\\u003eFig. 1\\u003c/strong\\u003e, 126 patients were included in the immunotherapy cohort, of whom 104 had evaluable intracranial and extracranial responses, and 85 patients were included in the chemotherapy cohort. The baseline characteristics of patients receiving immunotherapy stratified by intracranial response are summarized in Table 1. Among the immunotherapy group, 103 (81.7%) had non-squamous histology, 29 (23.0%) harbored EGFR mutations, 59 (46.8%) received ICIs as first-line treatment, and 93 (73.8%) were treated with immunotherapy in combination with chemotherapy. Radiotherapy for brain metastases was administered in 60 patients (47.6%). Baseline characteristics were further compared among subgroups with different intracranial. Significant differences were observed for treatment line and radiotherapy timing. Patients treated with ICIs in the first line had higher intracranial response rates than those treated in later lines (66.7% vs. 27.7%, p \\u0026lt; 0.001), and prior radiotherapy was associated with improved responses compared to no radiotherapy, whereas palliative radiotherapy was linked to inferior responses compared with prior or concurrent radiotherapy. After propensity score matching, baseline characteristics of the matched immunotherapy and chemotherapy cohorts are presented in \\u003cstrong\\u003eSupplementary Table S2\\u003c/strong\\u003e, showing well-balanced covariates between groups. The total chemotherapy cohort is described in \\u003cstrong\\u003eSupplementary Table S3.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eTable 1 Baseline characteristics of immunotherapy cohort\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eCharacteristics\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eLevel\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003eOverall\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 168px;\\\"\\u003e\\n \\u003cp\\u003eIntracranial Response\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003eP value\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eNumber\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e126\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e39 (31.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e65 (51.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eSex (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eFemale\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e34 (27.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e8 (20.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e19 (29.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.453\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eMale\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e92 (73.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e31 (79.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e46 (70.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eAge (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;65\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e70 (55.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e23 (59.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e36 (55.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.878\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026gt;=65\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e56 (44.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e16 (41.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e29 (44.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eSmoking history (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e51 (40.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e12 (30.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e31 (47.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.136\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e75 (59.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e27 (69.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e34 (52.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eECOG (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003e0 or1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e97 (77.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e28 (71.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e48 (73.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026gt;=2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e29 (23.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e11 (28.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e17 (26.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eLiver metastases (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e102 (81.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e33 (84.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e51 (78.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.607\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e24 (19.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e6 (15.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e14 (21.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003ePathological subtype (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNon-squamous\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e103 (81.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e33 (84.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e53 (81.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.894\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eSquamous\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e23 (18.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e6 (15.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e12 (18.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eEGFR mutation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e97 (77.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e32 (82.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e46 (70.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.293\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e29 (23.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e7 (17.9%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e19 (29.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eLine of immunotherapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eFirst\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e59 (46.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e26 (66.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e18 (27.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;0.001\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNon-first\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e67 (53.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e13 (33.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e47 (72.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eCombined chemotherapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e33 (26.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e11 (28.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e20 (30.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.956\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e93 (73.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e28 (71.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e45 (69.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eirAE (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e94 (74.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e26 (66.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e51 (78.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.273\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e32 (25.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e13 (33.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e14 (21.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eNeurological symptom (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e82 (65.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e22 (56.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e42 (64.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.532\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e44 (34.9%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e17 (43.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e23 (35.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eNumber of brain metastases (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eMultiple\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e53 (42.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e14 (35.9%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e34 (52.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.155\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eOligo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e72 (57.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e25 (64.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e31 (47.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eLeptomeningeal metastases (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e121 (96.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e36 (92.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e64 (98.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.292\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e5 (4.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e3 (7.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e1 (1.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eRadiotherapy (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e66 (52.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e15 (38.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e36 (55.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.142\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e60 (47.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e24 (61.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e29 (44.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eRadiotherapy modality (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e66 (52.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e15 (38.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e36 (55.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.104\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eSRT\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e34 (27.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e15 (38.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e13 (20.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eWBRT\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e26 (20.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e9 (23.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e16 (24.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003eRadiotherapy timing (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e66 (52.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e15 (38.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e36 (55.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e0.002\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eBefore\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e23 (18.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e13 (33.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e9 (13.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003eConcurrent\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e18 (14.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e10 (25.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e7 (10.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 130px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 97px;\\\"\\u003e\\n \\u003cp\\u003ePalliative\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e19 (15.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 90px;\\\"\\u003e\\n \\u003cp\\u003e1 (2.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 78px;\\\"\\u003e\\n \\u003cp\\u003e13 (20.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 69px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eECOG, Eastern Cooperative Oncology Group Performance Status; SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eComparison of efficacy and survival outcomes between immunotherapy and chemotherapy in patients with brain metastases\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIn the propensity score\\u0026ndash;matched cohort,\\u0026nbsp;patients treated with immunotherapy had a significantly longer median OS than those receiving chemotherapy\\u0026nbsp;(18.9 vs. 13.3 months, p = 0.001),\\u0026nbsp;as illustrated in \\u003cstrong\\u003eFig. 2\\u003c/strong\\u003e. Intracranial and extracranial PFS were numerically prolonged in the immunotherapy cohort but did not reach statistical significance. The median iPFS was 10.4 months in the immunotherapy group versus 9.6 months in the chemotherapy group (p = 0.09), while the median ePFS was 7.8 versus 7.1 months, respectively (p = 0.06). In terms of intracranial response, the objective response rate was 31.4% (16/51) in the immunotherapy group and 33.9% (19/56) in the chemotherapy group.\\u0026nbsp;No significant difference was observed between ICI monotherapy and chemo-immunotherapy combinations in terms of intracranial response (\\u003cem\\u003ep\\u003c/em\\u003e = 0.374).\\u003c/p\\u003e\\n\\u003cp\\u003eAmong 104 patients who were accessible of intracranial efficacy\\u0026nbsp;the iORR was\\u0026nbsp;37.5% (39/104)\\u0026nbsp;and the eORR was 45.2%\\u0026nbsp;(57/126).\\u0026nbsp;Patients treated with ICI plus chemotherapy and those receiving ICI monotherapy achieved comparable intracranial responses. Patients treated with ICI plus chemotherapy and those receiving ICI monotherapy achieved comparable intracranial responses（38.4 verse 35.5%, p = 0.374). The concordance rate between intracranial and extracranial response was 71.2% (74/104). Among the 30 patients with discordant responses, 20 showed response in extracranial lesions only, while 10 responded intracranially only. Notably, 4 of these 10 patients had not received brain radiotherapy.\\u003c/p\\u003e\\n\\u003cp\\u003eIn the chemotherapy cohort (n = 85), the iORR was 28.8% (23/80), and the eORR was 21.2% (18/85). The concordance rate between intracranial and extracranial responses was 70% (56/80). Among the 24 patients showing discordant responses, 15 showed intracranial response only, of whom 10 had received brain radiotherapy, while 9 showed extracranial response only.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eClinical factors associated with intracranial and extracranial responses\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIn the immunotherapy cohort, several clinical factors were associated with intracranial response\\u0026nbsp;as shown in \\u003cstrong\\u003eFig. 3\\u003c/strong\\u003e. A significantly higher intracranial response rate was observed in patients who received ICI as first-line treatment [Odds Ratio (OR) 5.22, p=0.0002], in those who received stereotactic radiotherapy (SRT) versus no radiotherapy (OR 2.77, p = 0.037), and in those who received radiotherapy prior to (OR 3.47, p = 0.019) or concurrently with (OR 3.43, p = 0.034) ICI compared with no radiotherapy. However, only the line of immunotherapy remained an independent predictive factor in multivariate analysis. \\u003cstrong\\u003eFig. 4\\u0026nbsp;\\u003c/strong\\u003edemonstrated that extracranial response was significantly associated with first-line ICI treatment (OR 2.98, p=0.003) and the occurrence of immune-related adverse events (irAEs) (OR 3.08, p=0.001). Nevertheless, only the line of treatment was retained as an independent influencing factor in multivariate analysis.\\u003c/p\\u003e\\n\\u003cp\\u003eIn the chemotherapy cohort, intracranial response was associated with receipt of SRT\\u0026nbsp;(OR 5.42, p = 0.017) or radiotherapy\\u0026nbsp;administered\\u0026nbsp;prior to chemotherapy (OR 3.87, p = 0.023), compared to those without radiotherapy (\\u003cstrong\\u003eSupplementary Fig. S1\\u003c/strong\\u003e). The presence of neurological symptoms related to brain metastases (OR 0.087, p = 0.021), and receiving chemotherapy as non-first line treatment (OR 0.276, p = 0.027) was associated with a reduced extracranial response (\\u003cstrong\\u003eSupplementary Fig. S2\\u003c/strong\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003ePrognostic factors for progression-free survival and overall survival\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAs displayed in \\u003cstrong\\u003eFig. 5\\u003c/strong\\u003e,\\u0026nbsp;in the immunotherapy cohort, overall survival was significantly prolonged in patients who developed irAEs\\u0026nbsp;[Hazard Ratio (HR) 0.614, p=0.039], received SRT (HR 0.622, p=0.046), or underwent radiotherapy prior to immunotherapy (HR 0.530, p=0.021). Among pairwise comparisons of timing of radiotherapy,\\u0026nbsp;only prior radiotherapy conferred a significant survival advantage compared with no radiotherapy (\\u003cem\\u003ep\\u003c/em\\u003e = 0.014) or palliative radiotherapy (\\u003cem\\u003ep\\u003c/em\\u003e = 0.018). As shown in \\u003cstrong\\u003eFig. 6\\u003c/strong\\u003e, patients who received intracranial radiotherapy prior to immunotherapy achieved a median overall survival of up to 32.3 months, whereas those who underwent concurrent radiotherapy and immunotherapy had a median survival of 19.0 months. As shown in \\u003cstrong\\u003eFig. 7\\u003c/strong\\u003e, administration of whole-brain radiotherapy (WBRT) (HR 2.22, p=0.006) and palliative radiotherapy (HR 4.86, p\\u0026lt;0.001) were significantly associated with shorter iPFS. In contrast, as illustrated in Fig. 8, male sex (HR 0.528, p=0.005), the occurrence of irAEs (HR 0.548, p=0.020), and receipt of SRT (HR 0.54, p=0.029) were significantly associated with prolonged ePFS. \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eIn the chemotherapy-only cohort, patients aged \\u0026ge; 65 years (HR 2.45, \\u003cem\\u003ep\\u003c/em\\u003e \\u0026lt; 0.001) had significantly shorter overall, while patients with an ECOG performance status of 2 or higher (HR 1.96, p=0.083) or with multiple brain metastases (HR 1.46, p=0.100) tended to have shorter survival. (Supplementary Fig. S3). Multiple brain metastases showed a trend toward shorter iPFS (HR 1.54, p=0.084), while palliative radiotherapy was significantly associated with reduced iPFS (HR 2.37, p=0.010) compared to those without radiotherapy (Supplementary Fig. S4). Regarding ePFS, patients aged \\u0026ge; 65 years (HR 1.69, p=0.042) had earlier extracranial progression (\\u003cstrong\\u003eSupplementary Fig. S5\\u003c/strong\\u003e).\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eThis study provides exploratory, real-world insights into the intracranial and extracranial efficacy of immunotherapy in NSCLC patients with brain metastases. Our matched analysis suggested a potential survival advantage with immunotherapy over chemotherapy, although these findings should be interpreted with caution given the retrospective design and limited sample size. Among potential prognostic indicators, the occurrence of immune-related adverse events, and prior brain radiotherapy particularly stereotactic radiotherapy (SRT) appeared most consistently associated with improved survival outcomes in patients receiving immunotherapy.\\u003c/p\\u003e\\u003cp\\u003eIn terms of intracranial efficacy, the iORR of the overall immunotherapy cohort was 37.5%, and 31.4% in the matched immunotherapy cohort, which was comparable to 33.9% in the matched chemotherapy cohort. In real-world settings, the iORR of ICI monotherapy has been reported as 24.2% (n\\u0026thinsp;=\\u0026thinsp;33), regardless of PD-L1 levels [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e], while that of immunotherapy combined with chemotherapy generally ranges from 20% to 40% [\\u003cspan additionalcitationids=\\\"CR9\\\" citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. In our study, approximately 70% of patients demonstrated concordant intracranial and extracranial responses, consistent across treatment groups. While discordant responses were observed in the remainder, including cases with greater intracranial than extracranial responses. Similar discordance has been reported in 21% (n\\u0026thinsp;=\\u0026thinsp;44) of patients receiving ICI monotherapy[\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e] and 26.8% (n\\u0026thinsp;=\\u0026thinsp;41) regardless of combination with chemotherapy. These findings suggest that, beyond immune microenvironmental differences, tumor-intrinsic heterogeneity may also contribute to divergent responses. Recent evidence indicates that increased genomic instability and intratumor heterogeneity in brain metastases facilitate immune remodeling and local immune escape [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e], underscoring the need to tailor immunotherapy strategies to both immune and genomic features of metastatic lesions. The median OS for patients receiving ICIs was 18.9 months, significantly longer than that of patients treated with chemotherapy, and comparable to the 18.8 months reported in the KEYNOTE-189 trial [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eBy analyzing clinical factors related to treatment response and survival, we found that in the chemotherapy cohort, long-term survival was more closely associated with baseline features such as age, ECOG performance status, and the number of intracranial lesions, although some of these associations did not reach statistical significance. In contrast, such baseline factors showed less influence in the immunotherapy cohort, consistent with previous studies suggesting that even elderly or functionally impaired patients may still derive benefit from ICIs [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. These findings though preliminary, support the possibility that immunotherapy could provide a potential survival benefit even in vulnerable patient populations traditionally considered less fit for systemic therapy.\\u003c/p\\u003e\\u003cp\\u003eWe also noted that patients with EGFR mutations who received immunotherapy after tyrosine kinase inhibitor (TKI) progression achieved clinical benefits comparable to those with EGFR wild-type disease, in terms of treatment response and survival outcomes. This aligns with prior reports suggesting that ICIs combined with chemotherapy may retain activity in NSCLC with EGFR-sensitive mutations post-TKI progression [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. In our cohort, the line of immunotherapy administration influenced intracranial and extracranial responses but was not significantly associated with progression-free survival or overall survival likely due to the relatively high proportion (23%) of EGFR-mutant patients receiving ICIs as later-line therapy. Nevertheless, earlier-line administration has been associated with improved survival in pivotal trials and real-world studies[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e], although benefit persists across treatment lines. As unique adverse events of immune checkpoint blockade, the development of irAEs was significantly associated with improved extracranial efficacy and prolonged survival in our cohort, in line with growing evidence that irAEs may serve as a surrogate marker of ICI response [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eWith regard to radiotherapy, we observed that intracranial radiotherapy administered prior to systemic treatment was associated with improved intracranial response in both immunotherapy and chemotherapy cohorts In the immunotherapy cohort, patients who received radiotherapy before ICIs tended to have longer survival, while such an association was not observed in the chemotherapy group. Patients who received intracranial radiotherapy prior to immunotherapy achieved a median overall survival of up to 32.3 months, significantly longer than 19.0 months for those treated concurrently with radiotherapy and immunotherapy. These findings may suggest a potential interaction between radiotherapy and immune checkpoint blockade. Previous studies have indicated that combining radiotherapy with immunotherapy may improve intracranial response [\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e], whereas its effect on long-time survival remains inconclusive [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. Translational data further suggest that radiotherapy delivered during or after ICIs may compromise the immune microenvironment by eliminating infiltrating lymphocytes [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e] and disrupting tertiary lymphoid structures (TLS), which serve as immunological hubs facilitating adaptive immune activation and predict favorable immunotherapy outcomes [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. Remarkably, TLS have also been identified within brain metastases originating from lung cancer, albeit often in an immature form [\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. Clinical trial data also highlight the complex interplay between radiotherapy and immunotherapy: In the original PACIFIC study[\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e], immunotherapy administered sequentially after completion of chemoradiation significantly improved survival, whereas the PACIFIC-2 trial [\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e], which evaluated concurrent delivery of immunotherapy with chemoradiation, did not demonstrate such benefit. These contrasting outcomes suggest that treatment timing may be critical although remains incompletely defined. Similarly, a real-world analysis reported improved survival when radiotherapy was delivered within 14 days before or after programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) inhibition, compared with delayed radiotherapy (\\u0026ge;\\u0026thinsp;14 days after ICI) [\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]. The biological effects of radiotherapy persist long after therapy ends, including ongoing tumor cell apoptosis, vascular injury [\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e], and modulation of the immune landscape - such as antigen release, dendritic cell recruitment, and upregulation of PD-L1 on tumor and myeloid cells [\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e], thereby supporting the rationale for administering immunotherapy sequentially after radiotherapy.\\u003c/p\\u003e\\u003cp\\u003eThis study had several limitations. First, its retrospective and relatively small sample size inherently carries the risk of selection bias and limits the strength of causal inferences, underscoring the need for validation in larger, multi-institutional cohorts. Second, part of the chemotherapy cohort was treated during an earlier period, which may have introduced heterogeneity in molecular testing methods and radiotherapy techniques compared with the immunotherapy group. Third, the frequency of follow-up imaging was not uniform, as intracranial assessments were generally performed at longer intervals than extracranial evaluations, and some patients did not undergo brain MRI strictly at predefined timepoints.\\u003c/p\\u003e\"},{\"header\":\"Conclusions\",\"content\":\"\\u003cp\\u003eThis analysis provides exploratory, real-world insights into the management of NSCLC with brain metastases. Our matched comparisons suggest that immunotherapy may be associated with improved survival outcomes compared with chemotherapy, and that these benefits appear less dependent on baseline characteristics such as age and performance status. Our finding that intracranial radiotherapy administered before immunotherapy was associated with longer survival suggests a sequence-dependent interplay between radiotherapy and immunotherapy. Nevertheless, these results arise from a retrospective analysis with limited sample size and without external validation and should therefore be considered exploratory. Prospective, larger-scale studies will be needed to clarify the clinical relevance of treatment sequencing and to define optimal strategies for NSCLC patients with brain metastases.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eNSCLC: Non-small cell lung cancer\\u003c/p\\u003e\\n\\u003cp\\u003eBMs: Brain metastases\\u003c/p\\u003e\\n\\u003cp\\u003eICIs: Immune checkpoint inhibitors\\u003c/p\\u003e\\n\\u003cp\\u003eOS: Overall survival\\u003c/p\\u003e\\n\\u003cp\\u003eiPFS: Intracranial progression-free survival\\u003c/p\\u003e\\n\\u003cp\\u003eePFS: Extracranial progression-free survival\\u003c/p\\u003e\\n\\u003cp\\u003eORR: Objective response rate\\u003c/p\\u003e\\n\\u003cp\\u003eiORR: Intracranial objective response rate\\u003c/p\\u003e\\n\\u003cp\\u003eeORR: Extracranial objective response rate\\u003c/p\\u003e\\n\\u003cp\\u003ePSM: Propensity score matching\\u003c/p\\u003e\\n\\u003cp\\u003eSMDs: Standardized mean differences\\u003c/p\\u003e\\n\\u003cp\\u003ePD-1: Programmed death-1\\u003c/p\\u003e\\n\\u003cp\\u003ePD-L1: Programmed death-ligand 1\\u003c/p\\u003e\\n\\u003cp\\u003eMRI: Magnetic resonance imaging\\u003c/p\\u003e\\n\\u003cp\\u003eCIs: Confidence intervals\\u003c/p\\u003e\\n\\u003cp\\u003eCR: Complete response\\u003c/p\\u003e\\n\\u003cp\\u003ePR: Partial response\\u003c/p\\u003e\\n\\u003cp\\u003eCT: Computed tomography\\u003c/p\\u003e\\n\\u003cp\\u003eHR: Hazard ratio\\u003c/p\\u003e\\n\\u003cp\\u003eECOG: Eastern Cooperative Oncology Group\\u003c/p\\u003e\\n\\u003cp\\u003eEGFR: Epidermal growth factor receptor\\u003c/p\\u003e\\n\\u003cp\\u003eTKIs: Tyrosine kinase inhibitors\\u003c/p\\u003e\\n\\u003cp\\u003eARMS: Amplification refractory mutation system\\u003c/p\\u003e\\n\\u003cp\\u003eNGS: Next-generation sequencing\\u003c/p\\u003e\\n\\u003cp\\u003eSRT: Stereotactic radiotherapy\\u003c/p\\u003e\\n\\u003cp\\u003eWBRT: Whole-brain radiotherapy\\u003c/p\\u003e\\n\\u003cp\\u003eirAEs: Immune-related adverse events\\u003c/p\\u003e\\n\\u003cp\\u003eRANO-BM: Response Assessment in Neuro-Oncology Brain Metastases\\u003c/p\\u003e\\n\\u003cp\\u003eRECIST: Response Evaluation Criteria in Solid Tumors\\u003c/p\\u003e\\n\\u003cp\\u003eTLS: Tertiary lymphoid structures\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003eEthics approval and consent to participate\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was conducted in accordance with the Helsinki Declaration and was approved by the Institutional Review Board of Peking Union Medical College Hospital. The requirement for informed consent was waived by the Institutional Review Board of Peking Union Medical College Hospital. \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAvailability of data\\u003c/p\\u003e\\n\\u003cp\\u003eThe datasets generated and/or analysed during the current study are provided in the Supplementary Information.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eCompeting interest\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare no conflicts of interest.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eFunding\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eCRediT authorship contribution statement\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eMZW contributed to the conception and design of the study. MJC contributed to the critical review, commentary, or revision of the manuscript. YXW contributed to the drafting of the article. RZL \\u0026nbsp;performed data visualization. XYL, YQS and XYF participated in data analysis and interpretation. YX and JZ provided supervision and guidance throughout the study. All authors reviewed and approved the final manuscript.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAcknowledgements\\u003c/p\\u003e\\n\\u003cp\\u003eWe gratefully acknowledge the technical support provided by Gaohui Bian and his engineering team for database services.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eThe Lancet O. Curbing the climb in cancer incidence. Lancet Oncol. 2024;25(5):529. http://dx.doi.org/10.1016/S1470-2045(24)00217-1\\u003c/li\\u003e\\n\\u003cli\\u003eMolina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584-94. http://dx.doi.org/10.4065/83.5.584\\u003c/li\\u003e\\n\\u003cli\\u003eNaresh G, Malik PS, Khurana S, Pushpam D, Sharma V, Yadav M, et al. Assessment of Brain Metastasis at Diagnosis in Non-Small-Cell Lung Cancer: A Prospective Observational Study From North India. JCO Glob Oncol. 2021;7:593-601. http://dx.doi.org/10.1200/GO.20.00629\\u003c/li\\u003e\\n\\u003cli\\u003eSperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):655-61. http://dx.doi.org/10.1016/j.ijrobp.2009.08.025\\u003c/li\\u003e\\n\\u003cli\\u003eNigen B, Goronflot T, Herbreteau G, Mathiot L, Sagan C, Raimbourg J, et al. Impact of first-line immunotherapy on survival and intracranial outcomes in a cohort of non-small cell lung cancer patients with brain metastases at diagnosis. Lung Cancer (Amsterdam, Netherlands). 2023;184:107321. http://dx.doi.org/10.1016/j.lungcan.2023.107321\\u003c/li\\u003e\\n\\u003cli\\u003eLe Rhun E, Guckenberger M, Smits M, Dummer R, Bachelot T, Sahm F, et al. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol. 2021;32(11):1332-47. http://dx.doi.org/10.1016/j.annonc.2021.07.016\\u003c/li\\u003e\\n\\u003cli\\u003eSkribek M, Rounis K, Makrakis D, Agelaki S, Mavroudis D, De Petris L, et al. Outcome of Patients with NSCLC and Brain Metastases Treated with Immune Checkpoint Inhibitors in a \\u0026apos;Real-Life\\u0026apos; Setting. Cancers (Basel). 2020;12(12). http://dx.doi.org/10.3390/cancers12123707\\u003c/li\\u003e\\n\\u003cli\\u003eKang S, Jeong H, Park JE, Kim HS, Kim YH, Lee DH, et al. Central nervous systemic efficacy of immune checkpoint inhibitors and concordance between intra/extracranial response in non-small cell lung cancer patients with brain metastasis. J Cancer Res Clin Oncol. 2022;10.1007/s00432-022-04251-3. http://dx.doi.org/10.1007/s00432-022-04251-3\\u003c/li\\u003e\\n\\u003cli\\u003eSun C, Zhou F, Li X, Zhao C, Li W, Li J, et al. PD-1/PD-L1 Inhibitor Combined with Chemotherapy Can Improve the Survival of Non-Small Cell Lung Cancer Patients with Brain Metastases. Onco Targets Ther. 2020;13:12777-86. http://dx.doi.org/10.2147/OTT.S286600\\u003c/li\\u003e\\n\\u003cli\\u003eSheng J, Li H, Yu X, Yu S, Chen K, Pan G, et al. Efficacy of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer and brain metastases: A real-world retrospective study in China. Thorac Cancer. 2021;12(22):3019-31. http://dx.doi.org/10.1111/1759-7714.14171\\u003c/li\\u003e\\n\\u003cli\\u003eWang X, Bai H, Zhang J, Wang Z, Duan J, Cai H, et al. Genetic Intratumor Heterogeneity Remodels the Immune Microenvironment and Induces Immune Evasion in Brain Metastasis of Lung Cancer. Journal of Thoracic Oncology : Official Publication of the International Association For the Study of Lung Cancer. 2024;19(2):252-72. http://dx.doi.org/10.1016/j.jtho.2023.09.276\\u003c/li\\u003e\\n\\u003cli\\u003eYang F, Markovic SN, Molina JR, Halfdanarson TR, Pagliaro LC, Chintakuntlawar AV, et al. Association of Sex, Age, and Eastern Cooperative Oncology Group Performance Status With Survival Benefit of Cancer Immunotherapy in Randomized Clinical Trials: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020;3(8):e2012534. http://dx.doi.org/10.1001/jamanetworkopen.2020.12534\\u003c/li\\u003e\\n\\u003cli\\u003eGomes F, Wong M, Battisti NML, Kordbacheh T, Kiderlen M, Greystoke A, et al. Immunotherapy in older patients with non-small cell lung cancer: Young International Society of Geriatric Oncology position paper. Br J Cancer. 2020;123(6):874-84. http://dx.doi.org/10.1038/s41416-020-0986-4\\u003c/li\\u003e\\n\\u003cli\\u003eZhou S, Ren F, Meng X. Efficacy of immune checkpoint inhibitor therapy in EGFR mutation-positive patients with NSCLC and brain metastases who have failed EGFR-TKI therapy. Front Immunol. 2022;13:955944. http://dx.doi.org/10.3389/fimmu.2022.955944\\u003c/li\\u003e\\n\\u003cli\\u003eReck M, Rodr\\u0026iacute;guez-Abreu D, Robinson AG, Hui R, Csőszi T, F\\u0026uuml;l\\u0026ouml;p A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-33. \\u003c/li\\u003e\\n\\u003cli\\u003eBrown LJ, Khou V, Brown C, Alexander M, Jayamanne D, Wei J, et al. First-line chemoimmunotherapy and immunotherapy in patients with non-small cell lung cancer and brain metastases: a registry study. Front Oncol. 2024;14:1305720. http://dx.doi.org/10.3389/fonc.2024.1305720\\u003c/li\\u003e\\n\\u003cli\\u003eHaratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R, et al. Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer. JAMA Oncol. 2018;4(3):374-8. http://dx.doi.org/10.1001/jamaoncol.2017.2925\\u003c/li\\u003e\\n\\u003cli\\u003eShi Y, Fang J, Zhou C, Liu A, Wang Y, Meng Q, et al. Immune checkpoint inhibitor-related adverse events in lung cancer: Real-world incidence and management practices of 1905 patients in China. Thorac Cancer. 2022;13(3):412-22. http://dx.doi.org/10.1111/1759-7714.14274\\u003c/li\\u003e\\n\\u003cli\\u003eKim DY, Kim PH, Suh CH, Kim KW, Kim HS. Immune Checkpoint Inhibitors with or without Radiotherapy in Non-Small Cell Lung Cancer Patients with Brain Metastases: A Systematic Review and Meta-Analysis. Diagnostics (Basel). 2020;10(12). http://dx.doi.org/10.3390/diagnostics10121098\\u003c/li\\u003e\\n\\u003cli\\u003ePorte J, Saint-Martin C, Frederic-Moreau T, Massiani M-A, Bozec L, Cao K, et al. Efficacy and Safety of Combined Brain Stereotactic Radiotherapy and Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer with Brain Metastases. Biomedicines. 2022;10(9). http://dx.doi.org/10.3390/biomedicines10092249\\u003c/li\\u003e\\n\\u003cli\\u003eChu X, Niu L, Xiao G, Peng H, Deng F, Liu Z, et al. The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis. Front Immunol. 2022;13:875488. http://dx.doi.org/10.3389/fimmu.2022.875488\\u003c/li\\u003e\\n\\u003cli\\u003eSaddawi-Konefka R, O\\u0026apos;Farrell A, Faraji F, Clubb L, Allevato MM, Jensen SM, et al. Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC. Nat Commun. 2022;13(1):4298. http://dx.doi.org/10.1038/s41467-022-31941-w\\u003c/li\\u003e\\n\\u003cli\\u003eSaut\\u0026egrave;s-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19(6):307-25. http://dx.doi.org/10.1038/s41568-019-0144-6\\u003c/li\\u003e\\n\\u003cli\\u003eNohira S, Kuramitsu S, Ohno M, Fujita M, Yamashita K, Nagasaka T, et al. Tertiary Lymphoid Structures in Brain Metastases of Lung Cancer: Prognostic Significance and Correlation With Clinical Outcomes. Anticancer Res. 2024;44(8):3615-21. http://dx.doi.org/10.21873/anticanres.17184\\u003c/li\\u003e\\n\\u003cli\\u003eChaft JE, Rimner A, Weder W, Azzoli CG, Kris MG, Cascone T. Evolution of systemic therapy for stages I-III non-metastatic non-small-cell lung cancer. Nat Rev Clin Oncol. 2021;18(9):547-57. http://dx.doi.org/10.1038/s41571-021-00501-4\\u003c/li\\u003e\\n\\u003cli\\u003eSpigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2022;40(12):1301-11. http://dx.doi.org/10.1200/JCO.21.01308\\u003c/li\\u003e\\n\\u003cli\\u003eYu Y, Chen H, Tian Z, Zhang Q, Shui Y, Shen L, et al. Improved survival outcome with not-delayed radiotherapy and immediate PD-1/PD-L1 inhibitor for non-small-cell lung cancer patients with brain metastases. J Neurooncol. 2023;165(1):127-37. http://dx.doi.org/10.1007/s11060-023-04459-4\\u003c/li\\u003e\\n\\u003cli\\u003eCarvalho HdA, Villar RC. Radiotherapy and immune response: the systemic effects of a local treatment. Clinics (Sao Paulo). 2018;73(suppl 1):e557s. http://dx.doi.org/10.6061/clinics/2018/e557s\\u003c/li\\u003e\\n\\u003cli\\u003eGuo S, Yao Y, Tang Y, Xin Z, Wu D, Ni C, et al. Radiation-induced tumor immune microenvironments and potential targets for combination therapy. Signal Transduct Target Ther. 2023;8(1):205. http://dx.doi.org/10.1038/s41392-023-01462-z \\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-cancer\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bcan\",\"sideBox\":\"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bcan/default.aspx\",\"title\":\"BMC Cancer\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"NSCLC, brain metastases, immune checkpoint inhibitors, radiotherapy, intracranial objective response rate, intracranial progression-free survival\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7676603/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7676603/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e\\u003cp\\u003eBrain metastases (BMs) are common in patients with non-small cell lung cancer (NSCLC) and remain a major therapeutic challenge. While immune checkpoint inhibitors (ICIs) have improved systemic outcomes, their Intracranial efficacy and prognostic determinants in patients with BMs, particularly in comparison with chemotherapy, remain insufficiently characterized.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e\\u003cp\\u003eWe conducted a multi-center, retrospective cohort study including NSCLC patients with BMs who received ICIs or chemotherapy alone. Propensity score matching was performed to balance baseline characteristics between treatment groups. Intracranial and extracranial responses, intracranial progression-free survival (iPFS), extracranial PFS (ePFS), and overall survival (OS) were compared. Logistic regression and Cox proportional hazards models were used to identify clinical and treatment-related prognostic factors associated with treatment response and survival.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e\\u003cp\\u003eIn the matched cohort, patients treated with immunotherapy achieved significantly longer median OS than those receiving chemotherapy (18.9 vs. 13.3 months, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.001), while intracranial and extracranial PFS were numerically but not significantly prolonged. The intracranial objective response rate (iORR) was 31.4% in the matched subset of immunotherapy cohort, comparable to 33.9% in the matched chemotherapy cohort. Concordance between intracranial and extracranial responses was about 70% across groups. In the immunotherapy cohort, development of immune-related adverse events (irAEs), receipt of stereotactic radiotherapy (SRT), and prior radiotherapy were associated with improved OS. Patients receiving intracranial radiotherapy before ICIs achieved a median OS of 32.3 months versus 19.0 months with concurrent therapy. In the chemotherapy cohort, age\\u0026thinsp;\\u0026ge;\\u0026thinsp;65 years and multiple brain metastases were associated with inferior survival.\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e\\u003cp\\u003eThis real-world study suggests that immunotherapy may confer a survival advantage over chemotherapy in NSCLC patients with brain metastases, with efficacy less dependent on baseline factors such as age or performance status. Radiotherapy administered before ICIs appeared associated with favorable outcomes, although this observation remains hypothesis-generating given the study limitations.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Clinical outcomes and predictive factors of immunotherapy efficacy in non-small cell lung cancer brain metastases: A comparative study\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-10-15 16:10:37\",\"doi\":\"10.21203/rs.3.rs-7676603/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2025-10-23T04:30:46+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-18T10:33:27+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"19635197792420157643818273842759127651\",\"date\":\"2025-10-16T09:31:54+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-08T13:07:15+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"79929556917756244799883517082122984351\",\"date\":\"2025-10-02T12:03:35+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-10-02T01:09:40+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-09-30T08:36:24+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2025-09-29T07:22:53+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-09-28T00:37:22+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"BMC Cancer\",\"date\":\"2025-09-28T00:33:34+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-cancer\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bcan\",\"sideBox\":\"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bcan/default.aspx\",\"title\":\"BMC Cancer\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"6c0ae0b0-d820-4895-a259-58462c1abbdf\",\"owner\":[],\"postedDate\":\"October 15th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-12-08T16:12:08+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-7676603\",\"link\":\"https://doi.org/10.1186/s12885-025-15327-x\",\"journal\":{\"identity\":\"bmc-cancer\",\"isVorOnly\":false,\"title\":\"BMC Cancer\"},\"publishedOn\":\"2025-12-07 15:58:29\",\"publishedOnDateReadable\":\"December 7th, 2025\"},\"versionCreatedAt\":\"2025-10-15 16:10:37\",\"video\":\"\",\"vorDoi\":\"10.1186/s12885-025-15327-x\",\"vorDoiUrl\":\"https://doi.org/10.1186/s12885-025-15327-x\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7676603\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7676603\",\"identity\":\"rs-7676603\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}