Outcomes in Patients with Non-Small-Cell Lung Cancer with Brain Metastases: A Real-World Data Study from a Resource-Limited Country

Academic Editors: Roberto Fabiani and Irene Giacchetta Received: 3 April 2025 Revised: 29 April 2025 Accepted: 7 May 2025 Published: 9 May 2025 Citation: Randjelovic, N.; Petronijevic, M.; Calamac, M.; Peulic, M.; Filipovic, B.; Mutavdzic, V.; Djuric, A.; Rankovic, T.; Bugarcic, M.; Canak, I.; et al. Outcomes in Patients with Non-Small-Cell Lung Cancer with Brain Metastases: A Real-World Data Study from a Resource-Limited Country. Cancers 2025,17, 1603. https://doi.org/10.3390/ cancers17101603 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/). Article Outcomes in Patients with Non-Small-Cell Lung Cancer with Brain Metastases: A Real-World Data Study from a Resource-Limited Country Nevena Randjelovic 1,* , Marina Petronijevic 1, Marina Calamac 2, Marija Peulic 1, Biljana Filipovic 1, Vladan Mutavdzic 1, Aleksandar Djuric 3, Teodora Rankovic 1, Milos Bugarcic 4, Ivana Canak 4, Jelena Mikov 4, Nebojsa Igrutinovic 5, Stela Novak 3, Marko Marjanovic 3, Jelena Perovic 3, Teodora Urosevic 3and Tanja Cufer 6 1Department of Medical Oncology, University Clinical Centre of Kragujevac, 34000 Kragujevac, Serbia; [email protected] (M.P.); [email protected] (M.P.); [email protected] (B.F.); [email protected] (V.M.); [email protected] (T.R.) 2Daily Hospital Care, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; [email protected] 3Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; aleksandar[email protected] (A.D.); [email protected] (S.N.); [email protected] (M.M.); [email protected] (J.P.); [email protected] (T.U.) 4Institute for Pulmonary Diseases of Vojvodina, 21204 Sremska Kamenica, Serbia; [email protected] (M.B.); [email protected] (I.C.); [email protected] (J.M.) 5Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; [email protected] 6Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia; [email protected] *Correspondence: [email protected] Simple Summary: This study addresses the lack of real-world data on life expectancy for metastatic lung cancer patients in Serbia, specifically focusing on NSCLC patients with brain metastases (BMs). Conducted retrospectively at a single academic center, 267 patients diagnosed with BMs from 2018 to 2022 were analyzed. The median overall survival rate (OS) was 5.0 months. Several factors linked to improved survival can affect a person’s outlook including age under 65, female gender, single and asymptomatic BM, good performance status (ECOG 0–1), BM verification at diagnosis and combined systemic and local therapy. Both immunotherapy and targeted therapy were associated with the longest survival (median OS: 13.0 months), while the poorest outcomes (median OS: 2.0 months) were recorded when using best supportive care and local-only therapy. This study highlights the survival gap in NSCLC patients with BMs without novel therapies, emphasizing the urgent need for improved global access to innovative treatments. Abstract: Background: Real-world data provide insights into populations underrepresented in clinical trials such as non-small-cell cancer (NSCLC) patients with brain metastases (BMs). Despite global survival improvement due to novel drug employment, their impact in resource-limited settings like Serbia remains underexplored. This study analyzes the overall survival (OS) of NSCLC patients with BMs treated in routine clinical practice, considering patient-, diseaseand treatment-related factors amid restricted access to novel drugs. Methods: We retrospectively analyzed 267 NSCLC patients diagnosed with BMs from 2018 to 2022 at a single Serbian clinical center. Inclusion required histologically confirmed NSCLC, radiologically verified BMs and complete clinical data. OS was defined as the time from BM verification to death or last follow-up. Kaplan–Meier curves and Cox regression were used for survival analysis. Results: Median OS (mOS) was 5.0 months. Univariate analysis linked age < 65 years, female gender, single BM, asymptomatic BMs, ECOG PS 0–1, BM verification at diagnosis and combined systemic and local therapy to better OS. Cancers 2025,17, 1603 https://doi.org/10.3390/cancers17101603 Cancers 2025,17, 1603 2 of 15 Combined therapy offered the best survival rates (mOS: 9.0 months), while best supportive care and local-only therapy both resulted in a poor mOS of 2.0 months. Immunotherapy and targeted therapy were associated with the highest mOS, outperforming chemotherapy alone (13.0 vs. 7.0 months, p< 0.001). Multivariate analysis confirmed younger age, single BM, early BM verification and combined therapy as independent predictors of improved survival. Conclusions: limited access to novel therapies remains associated with poor patient survival, highlighting the need for better global availability. Keywords: lung cancer; brain metastases; NSCLC 1. Introduction Lung cancer (LC) remains one of the most prevalent cancers globally, with around 2.5 million new cases and the highest mortality, causing approximately 1.8 million deaths annually [ 1 ]. In Serbia, LC ranks first in incidence and mortality rates [ 2 ]. Non-small-cell lung cancer (NSCLC) comprises about 85% of all LC cases [ 3 ], with a 5-year survival rate for distant-stage disease below 10% [ 4 ]. Additionally, brain metastases (BMs) occur in 40–50% of patients with advanced NSCLC [ 5 ], particularly in those with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) oncogene mutations [6]. Sperduto et al. reported a median survival of 7.0 months for NSCLC patients with brain metastases (BMs) diagnosed between 1985 and 2005, influenced by factors such as histology, patients’ age, Karnofsky performance score, presence of extracranial metastases and number of BMs [ 7 , 8 ]. An updated analysis for patients treated from 2006 to 2014, which included EGFR and ALK status, showed improved survival up to 12 months overall with 15.2 months for adenocarcinoma and 9.2 months for non-adenocarcinoma patients [ 9 ]. This improvement was linked to the lack of testing in the non-adenocarcinoma cohort and targeted therapies, as EGFR-mutated patients naive to tyrosine kinase inhibitors (TKIs) at BM diagnosis had a longer survival rate; the median survival rate was 14 months for EGFR/ALK-negative patients, 23 months for EGFR-mutated and 45 months for ALKpositive patients [10]. Programmed death ligand 1 (PD-L1) also emerged as a prognostic factor, with lung adenocarcinoma patients showing higher PD-L1 expression and experiencing an improved median survival rate. As a result, PD-L1, along with EGFR and ALK status, was incorporated into the updated Graded Prognostic Assessment (GPA) score [11]. Survival in NSCLC patients with BMs can be significantly extended, especially in cases of targetable metastatic NSCLC (mNSCLC). EGFR mutations enhance sensitivity to radiation, with preclinical data showing increased cytotoxicity when combined with EGFRTKIs. The third generation of EGFR-TKIs offers strong CNS penetration and efficacy while CNS-active ALK-TKIs show similar benefits for ALK-positive patients [ 12 ]. Osimertinib, a third-generation EGFR-TKI, demonstrated high intracranial efficacy in the FLAURA trial with 20 of 22 EGFR-mutant patients with evaluable BM achieving an intracranial response [ 13 ]. Likewise, lorlatinib, a third-generation ALK-TKI showed an 82% intracranial response rate in treatment-naive ALK-positive NSCLC patients in the CROWN trial [14]. In the context of immunotherapy, a pooled analysis of PD-L1-positive advanced or mNSCLC patients from the KEYNOTE-001, -010, -024, and -042 trials showed that pembrolizumab provided similar progression-free survival benefits in patients with and without baseline BMs. However, BMs remained a negative prognostic factor as overall survival (OS) was lower in patients with baseline BMs compared to those without them [ 15 ]. The ATEZO-BRAIN study demonstrated that atezolizumab combined with chemotherapy Cancers 2025,17, 1603 3 of 15 achieved intracranial responses comparable to systemic responses, potentially delaying the need for local therapy and helping maintain quality of life [16]. Randomized controlled trials (RCTs), while essential for internal validity, often exclude broader patient populations, thus limiting their real-world applicability. Contrary to the above mentioned, real-world data (RWD) offer insights from more diverse clinical settings and help bridge gaps in evidence [ 17 ]. Sperduto et al. have recently reported a median overall survival (mOS) of 17 months for adenocarcinoma and 8 months for nonadenocarcinoma patients with BM [ 11 ]. In patients without targetable mutations, RWD from five European Union countries showed an mOS under one year ranging from 5 months in France to 9 in Germany, with a shorter survival rate seen in non-adenocarcinoma histology (5–6 months) compared to adenocarcinoma (9 months) [ 18 ]. Alarmingly, recent data indicate that mNSCLC patients with BMs not receiving systemic therapy may have an mOS as low as 2 months [19]. Unfortunately, there is a lack of data on the survival of metastatic lung cancer patients in Serbia based on RWD. Additionally, no specific studies have focused on NSCLC patients with BMs in this population. Therefore, this study aims to analyze the characteristics of NSCLC patients with BMs treated in routine clinical settings and to determine overall survival after BMs diagnoses considering patient-, diseaseand treatment-related factors in the era before the introduction of novel targeted therapies in everyday clinical practice in our country. 2. Materials and Methods We retrospectively collected NSCLC patients diagnosed with BMs at any point during their disease course between 1 January 2018 and 31 December 2022. Data were collected from electronic archives at a single academic clinical center in Serbia. The inclusion criteria required histologically confirmed NSCLC, detection of BMs through magnetic resonance imaging (MRI) or computed tomography (CT) at any stage of the disease or treatment from the time of NSCLC diagnosis until death or last follow-up. Additionally, complete clinical data and follow-up information had to be available. Patients without complete electronic and/or physical medical files were excluded, as well as those with the presence of more than one malignancy or radiological suspicion of leptomeningeal metastases (Figure 1). Patient follow-up was finished on the date of 25 May 2024, thus ensuring a minimum 2-year follow-up for all patients included. We extracted socio-demographic patient data, diagnosis details (radiological and pathological), treatment and follow-up information and Eastern Cooperative Oncology Group performance status (ECOG PS) data, which allowed us to track patients from diagnosis to the end of treatment, death or last follow-up. Overall survival was evaluated as the duration of time from the BM radiological verification until death or the last followup. Patients’ personal data were completely anonymized. In Serbia, oncology care is delivered within a universal healthcare system, with patients receiving treatment through mandatory national health insurance. The timing of cranial radiological evaluation was determined by the treating clinician. In the studied group, the type of NSCLC was identified using standard immunohistochemistry (IHC) on biopsy or surgical tissue samples. During the period covered by this study, molecular testing was limited. Since 2020, PD-L1 IHC testing has been available on demand for all mNSCLC patients with an ECOG performance status (PS) of 0–1. EGFR polymerase chain reaction (available throughout the study period) and ALK IHC testing (available since 2020) were performed on demand for patients with unresectable adenocarcinoma, adenosquamous carcinoma, or not-otherwise-specified (NOS) histology. For squamous cell carcinoma, these tests were limited to younger, non-smoking patients. EGFR testing was available for Cancers 2025,17, 1603 4 of 15 patients with ECOG PS 0–1, while ALK testing was permitted for those with ECOG PS 0–2 if brain metastases (BMs) were the cause of the PS decline. Cancers 2025, 17, x FOR PEER REVIEW 4 of 16 Figure 1. Patient collection flow chart. In Serbia, oncology care is delivered within a universal healthcare system, with patients receiving treatment through mandatory national health insurance. The timing of cranial radiological evaluation was determined by the treating clinician. In the studied group, the type of NSCLC was identified using standard immunohistochemistry (IHC) on biopsy or surgical tissue samples. During the period covered by this study, molecular Figure 1. Patient collection flow chart. Cancers 2025,17, 1603 5 of 15 Molecular testing referrals reflected both treatment availability and reimbursement policies. Novel therapies are approved by the national health insurance fund based on indications established by RCTs and eligibility criteria, as specified in national reimbursement guidelines. As a result, patients with poorer PS were not evaluated for actionable mutations but would be reassessed for testing and treatment if their PS improved. Patient treatment followed national health insurance guidelines, which included access to targeted therapy and immunotherapy—available predominantly in the first-line setting for advanced unresectable or metastatic NSCLC, mostly since 2020. More specifically, during the study period, firstand second-generation EGFR-TKIs were available for first-line use, while osimertinib was restricted to second-line treatment for patients with a confirmed T790M mutation. Similarly, only second-generation ALK-TKIs were available for first-line therapy. Immune checkpoint inhibitors were available as first-line treatment exclusively for patients with PD-L1 expression ≥50%. Statistical Analysis The commercial, standard software package SPSS version 20.0 was used for statistical data processing. (The Statistical Package for Social Sciences software (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY, USA: IBM Corp.)). Each of the prognostic variables was evaluated using the long rank method, after which the significant variables were entered into the Cox hazards univariate and multivariate regression model for the assessment of predictive significance. Prognostic overall survival was analyzed using Kaplan–Meier curves. Values of p< 0.05 were considered statistically significant. 3. Results The majority of our sample consisted of male patients (60.7%) of age <65 years (60.3%) and of non-squamous NSCLC histology (81.6%). Detailed samples’ characteristics are presented in Table 1. Representation of molecular testing and applied systemic treatment is shown in Table 2. In our study, 165 patients (61.8%) underwent a CT scan of the brain to assess intracranial disease spread at initial diagnosis and/or at the moment of symptom appearance indicating intracranial disease, while 101 patients (37.8%) had an MRI, and only one patient (0.4%) underwent both. Table 1. Demographic, clinicopathological, and treatment characteristics of the study population. Variable Patients Number Percentage Age <65 161 60.3 ≥65 106 39.7 Gender Male 162 60.7 Female 105 39.3 Smoking status Smokers and ex-smokers 197 73.8 Non-smokers 70 26.2 Histologic type Squamous cell lung cancer 49 18.4 Non-squamous cell lung cancer 218 81.6 ECOG performance status PS 0–1 110 41.2 PS ≥2 157 58.8 Stage IV At first diagnosis 196 73.4 During the disease course 71 26.6 Timing of brain metastases verification At first diagnosis 167 62.5 At later stage IV diagnosis 61 22.8 During the stage IV treatment 39 14.6 Cancers 2025,17, 1603 6 of 15 Table 1. Cont. Variable Patients Number Percentage Number of brain metastases 1 90 33.7 >1 177 66.3 Symptoms Yes 145 54.3 No 122 45.7 Brain metastases treatment BSC 29 10.9 Systemic + local 133 49.4 Local treatment only 105 39.3 Local treatment 1 SBRT 75 28.1 WBRT 112 41.6 Operative 51 19.1 Systemic treatment 2 Immune Checkpoint Inhibitor 39 14.6 Chemotherapy alone 83 31.1 Target therapy 11 4.1 ECOG—Eastern Cooperative Oncology Group; BSC—best supportive care; SBRT—stereotactic body radiation therapy; WBRT—whole brain radiotherapy. 1 Twenty-nine (10.9%) patients were not treated with any local treatment. 2One hundred and thirty-four (50.2%) patients were not treated with any systemic treatment. Table 2. Data on molecular testing and applied systemic treatment. Molecular Test Test Results Patients Systemic Treatment Immune Checkpoint Inhibitor Chemotherapy Alone Target Therapy PD-L1 ≥50% 39 (14.6%) 39 (29.4%) 0 0 1–49% 24 (9.0%) 0 12 (9.0%) 3 (2.3%) <1% 57 (21.3%) 0 28 (21.1%) 2 (1.5%) Not tested 147 (55.1%) 0 43 (32.3%) 6 (4.5%) EGFR Wild-type 132 (49.4%) 30 (22.6%) 54 (40.6%) 0 Mutated 19 (7.1%) 0 4 (3.0%) 11 (8.3%) Not tested 116 (43.4%) 9 (6.8%) 25 (18.8%) 0 ALK Positive 0 0 0 0 Negative 99 (37.1%) 28 (21.1%) 37 (27.8%) 5 (3.8%) Not tested 168 (62.9%) 9 (6.8%) 83 (62.4%) 0 ALK—anaplastic lymphoma kinase; EGFR—epidermal growth factor receptor; PD-L1—programmed death ligand 1. For the total sample, calculated median OS in months is 5.0 (CI 95%, 3.981–6.019) (Figure 2). Median follow-up time for OS in months is 35.0 (CI 95% 19.064–50.936). Univariate analysis showed that statistically significant factors influencing the OS in the studied population were age, gender, ECOG PS, timing of BM verification, number of BMs, symptoms and BM treatment (Table 3). Significantly better survival was recorded in patients with age < 65 years (5.0 vs. 3.0 months, p= 0.029), female patients (6.0 vs. 4.0 months, p= 0.038), patients with ECOG PS 0–1 (9.0 vs. 3.0 months, p< 0.001), patients who were diagnosed with BMs earlier in the disease—at first diagnosis and at later stage IV diagnosis (6.0 and 4.0 vs. 2.0 months, p= 0.002), patients with only one brain metastasis (7.0 vs. 3.0 months, p< 0.001), patients with no symptomatic BMs (8.0 vs. 3.0 months, p< 0.001) and patients treated with combined systemic + local treatment, with mOS being 9.0 months versus patients treated with best supportive care (BSC) and local-only treatment, both amounting to the mOS of only 2.0 months (p< 0.001). Cancers 2025,17, 1603 7 of 15 Table 3. Univariate and multivariate analysis of overall survival. Variable Univariate Analysis Multivariate Analysis mOS in Months (95% CI) HR (95% CI) pHR (95% CI) p Age <65 5.0 (3.537–6.463) 0.752 (0.583–0.971) 0.029 0.760 (0.580–0.994) 0.045 ≥65 3.0 (1.448–4.552) 1 Gender Male 4.0 (3.066–4.934) 0.762 (0.590–0.985) 0.038 1 0.135 Female 6.0 (4.661–7.339) 0.815 (0.623–1.066) Smoking status Smokers and ex-smokers 5.0 (3.791–6.209) 0.859 (0.651–1.134) 0.285 - - Non-smokers 4.0 (2.277–5.723) - Histologic type Squamous cell lung cancer 3.0 (1.753–4.247) 0.814 (0.592–1.120) 0.207 - - Non-squamous cell lung cancer 6.0 (4.807–7.193) - ECOG performance type PS 0–1 9.0 (5.979–12.021) 0.478 (0.368–0.621) <0.001 0.676 (0.418–1.093) 0.110 PS ≥23.0 (2.060–3.940) 1 Stage IV At first diagnosis 5.0 (3.789–6.211) 0.917 (0.691–1.217) 0.548 - - During the disease course 4.0 (2.826–5.174) - Timing of brain metastases verification At first diagnosis 6.0 (4.778–7.222) 0.533 (0.373–0.761) 0.002 0.610 (0.424–0.878) 0.022 1 At later stage IV diagnosis 4.0 (2.729–5.271) 0.614 (0.406–0.927) 0.594 (0.389–0.910) During the stage IV treatment 2.0 (0.980–3.020) 1 1 Number of brain metastases 17.0 (5.366–8.634) 0.569 (0.434–0.745) <0.001 0.576 (0.432–0.769) <0.001 >1 3.0 (2.069–3.931) 1 Symptoms Yes 3.0 (2.351–3.649) 0.511 (0.396–0.659) <0.001 1 0.428 No 8.0 (5.540–10.460) 1.218 (0.748–1.983) Brain metastases treatment BSC 2.0 (1.317–2.683) 1 <0.001 1 <0.001 1 Systemic + local 9.0 (6.828–11.172) 0.237 (0.154–0.366) 0.320 (0.197–0.520) Local treatment only 2.0 (1.352–2.648) 0.610 (0.402–0.928) 0.746 (0.486–1.145) ECOG—Eastern Cooperative Oncology Group; BSC—best supportive care; HR—hazard ratio; CI–confidence interval; mOS—median overall survival. 1 p-value for the whole variable. Bolded p-values indicate statistical significance (p< 0.05). Cancers 2025,17, 1603 8 of 15 Cancers 2025, 17, x FOR PEER REVIEW 7 of 16 Figure 2. Overall survival rates of all patients (n = 267) from the moment of BM diagnosis. Univariate analysis showed that statistically significant factors influencing the OS in the studied population were age, gender, ECOG PS, timing of BM verification, number of BMs, symptoms and BM treatment (Table 3). Significantly better survival was recorded in patients with age < 65 years (5.0 vs. 3.0 months, p = 0.029), female patients (6.0 vs. 4.0 months, p = 0.038), patients with ECOG PS 0–1 (9.0 vs. 3.0 months, p < 0.001), patients who were diagnosed with BMs earlier in the disease—at first diagnosis and at later stage IV diagnosis (6.0 and 4.0 vs. 2.0 months, p = 0.002), patients with only one brain metastasis (7.0 vs. 3.0 months, p < 0.001), patients with no symptomatic BMs (8.0 vs. 3.0 months, p < 0.001) and patients treated with combined systemic + local treatment, with mOS being 9.0 months versus patients treated with best supportive care (BSC) and local-only treatment, both amounting to the mOS of only 2.0 months (p < 0.001). The types of local and systemic treatments were excluded from the regression analysis evaluating the impact of these treatment modalities on OS due to the high proportion of untreated patients (29 patients (10.9%) did not receive any form of local treatment, and 134 patients (50.2%) did not receive any systemic treatment). Following the exclusion of patients with missing data, the log-rank test was performed. In regard to the type of local treatment, statistically significant differences in survival were found (p < 0.001). Patients treated with stereotactic body radiation therapy (SBRT) had an mOS of 7.0 months (95% CI: 4.695–9.305). Whole brain radiotherapy (WBRT)-treated patients yielded an mOS of 3.0 months (95% CI: 1.522–4.478), while operative treatment yielded an mOS of 8.0 months (95% CI: 4.819–11.181) (Figure 3a). In terms of systemic therapy, statistically significant differences in OS were also found (p = 0.003). Immune checkpoint inhibitor (ICI) treatment resulted in an mOS of 13.0 months (95% CI: 6.882–19.118). Chemotherapy alone yielded an mOS of 7.0 months (95% CI: 5.090–8.910), while targeted therapy demonstrated an mOS of 13.0 months (95% CI: 5.232–20.768) (Figure 3b). Figure 2. Overall survival rates of all patients (n = 267) from the moment of BM diagnosis. The types of local and systemic treatments were excluded from the regression analysis evaluating the impact of these treatment modalities on OS due to the high proportion of untreated patients (29 patients (10.9%) did not receive any form of local treatment, and 134 patients (50.2%) did not receive any systemic treatment). Following the exclusion of patients with missing data, the log-rank test was performed. In regard to the type of local treatment, statistically significant differences in survival were found (p< 0.001). Patients treated with stereotactic body radiation therapy (SBRT) had an mOS of 7.0 months (95% CI: 4.695–9.305). Whole brain radiotherapy (WBRT)-treated patients yielded an mOS of 3.0 months (95% CI: 1.522–4.478), while operative treatment yielded an mOS of 8.0 months (95% CI: 4.819–11.181) (Figure 3a). In terms of systemic therapy, statistically significant differences in OS were also found (p= 0.003). Immune checkpoint inhibitor (ICI) treatment resulted in an mOS of 13.0 months (95% CI: 6.882–19.118). Chemotherapy alone yielded an mOS of 7.0 months (95% CI: 5.090–8.910), while targeted therapy demonstrated an mOS of 13.0 months (95% CI: 5.232–20.768) (Figure 3b). Cancers 2025, 17, x FOR PEER REVIEW 8 of 16 (a) (b) Figure 3. Overall survival rates by the type of local and systemic treatment: (a) overall survival rates by the type of local treatment; (b) overall survival rates by the type of systemic treatment. Multivariate Cox regression analysis included statistically significant variables from the univariate analysis as predictors—age, gender, ECOG PS, timing of BM verification, number of BMs, symptoms and BM treatment. An omnibus test showed that the overall model was significant (χ2 = 99.114, p < 0.001). Independent predictive factors of better OS with statistical significance were shown to be age < 65 years (Figure 4a), timing of BM verification at first diagnosis (p = 0.008) and at later stage IV diagnosis (p = 0.017) (Figure 4b), having only one BM (Figure 4c) and treatment of BMs with combined systemic + local treatment (p < 0.001) (Table 2). Only application of local treatment did not show statistical significance in the model (p = 0.180) (Figure 4d). Table 3. Univariate and multivariate analysis of overall survival. Variable Univariate Analysis Multivariate Analysis mOS in Months (95% CI) HR (95% CI) p HR (95% CI) p Age <65 5.0 (3.537–6.463) 0.752 (0.583–0.971) 0.029 0.760 (0.580–0.994) 0.045 ≥65 3.0 (1.448–4.552) 1 Gender Male 4.0 (3.066–4.934) 0.762 (0.590–0.985) 0.038 1 0.135 Female 6.0 (4.661–7.339) 0.815 (0.623–1.066) Smoking status Smokers and ex-smokers 5.0 (3.791–6.209) 0.859 (0.651–1.134) 0.285 - - Non-smokers 4.0 (2.277–5.723) - Histologic type Squamous cell lung cancer 3.0 (1.753–4.247) 0.814 (0.592–1.120) 0.207 - - Non-squamous cell lung cancer 6.0 (4.807–7.193) - ECOG performance type PS 0–1 9.0 (5.979–12.021) 0.478 (0.368–0.621) <0.001 0.676 (0.418–1.093) 0.110 PS ≥2 3.0 (2.060–3.940) 1 Stage IV At first diagnosis 5.0 0.917 0.548 - - Figure 3. Overall survival rates by the type of local and systemic treatment: (a) overall survival rates by the type of local treatment; (b) overall survival rates by the type of systemic treatment. Multivariate Cox regression analysis included statistically significant variables from the univariate analysis as predictors—age, gender, ECOG PS, timing of BM verification, number of BMs, symptoms and BM treatment. An omnibus test showed that the overall model was significant ( χ2 = 99.114, p< 0.001). Independent predictive factors of better Cancers 2025,17, 1603 9 of 15 OS with statistical significance were shown to be age < 65 years (Figure 4a), timing of BM verification at first diagnosis (p= 0.008) and at later stage IV diagnosis (p= 0.017) (Figure 4b), having only one BM (Figure 4c) and treatment of BMs with combined systemic + local treatment (p< 0.001) (Table 2). Only application of local treatment did not show statistical significance in the model (p= 0.180) (Figure 4d). Cancers 2025, 17, x FOR PEER REVIEW 9 of 16 (3.789–6.211) (0.691–1.217) During the disease course 4.0 (2.826–5.174) - Timing of b rain metastases verification At first diagnosis 6.0 (4.778–7.222) 0.533 (0.373–0.761) 0.002 0.610 (0.424–0.878) 0.022 1 At later stage IV diagnosis 4.0 (2.729–5.271) 0.614 (0.406–0.927) 0.594 (0.389–0.910) During the stage IV treatment 2.0 (0.980–3.020) 1 1 Number of b rain metastases 1 7.0 (5.366–8.634) 0.569 (0.434–0.745) <0.001 0.576 (0.432–0.769) <0.001 >1 3.0 (2.069–3.931) 1 Symptoms Yes 3.0 (2.351–3.649) 0.511 (0.396–0.659) <0.001 1 0.428 No 8.0 (5.540–10.460) 1.218 (0.748–1.983) Brain metastases treatment BSC 2.0 (1.317–2.683) 1 <0.001 1 <0.001 1 Systemic + local 9.0 (6.828–11.172) 0.237 (0.154–0.366) 0.320 (0.197–0.520) Local treatment only 2.0 (1.352–2.648) 0.610 (0.402–0.928) 0.746 (0.486–1.145) ECOG—Eastern Cooperative Oncology Group; BSC—best supportive care; HR—hazard ratio; CI– confidence interval; mOS—median overall survival. 1 p-value for the whole variable. Bolded p-values indicate statistical significance (p < 0.05). (a) (b) Cancers 2025, 17, x FOR PEER REVIEW 10 of 16 (c) (d) Figure 4. Overall survival rates by independent prognostic factors: (a) overall survival by age; (b) overall survival by the timing of the brain metastasis verification; (c) overall survival by the number of brain metastases; (d) overall survival by the type of brain metastasis treatment. 4. Discussion Real-world data studies offer valuable insights that complement RCTs, particularly by evaluating current and potentially guiding the implementation of new treatment patterns. This is especially relevant for patients with brain metastases (BMs) who are frequently excluded from RCTs. Despite advances in targeted and immunotherapies that have reshaped the treatment landscape for metastatic mNSCLC, RWD continues to highlight poor outcomes in this group. In populations primarily receiving palliative or local treatment for BMs, mOS remains low—reported as just 2 months in some studies [19]. Hatton et al. further showed that survival outcomes were better in patients with known driver mutations. For instance, EGFR-positive patients had a median survival of 4.8 months compared to 3.0 months for EGFR-negative and 1.8 months for those with unknown status. Similarly, patients with known ALK status—whether positive or negative—fared better than those with unknown expression (mOS 1.8 months) [19]. These findings align with Sperduto et al., who also found that unknown molecular status correlated with poorer survival [11]. These observations underscore the importance of early molecular testing and the integration of targeted therapies to improve outcomes. The REFLECT study also emphasized the need for reflex testing and early identification of actionable mutations at diagnosis to enable timely and effective treatment strategies [20]. The mOS in our cohort was 5.0 months, aligning with some published real-world data [18,19]. However, as OS was calculated from the time of BM confirmation, longer medians might be observed if measured from initial NSCLC diagnosis. Molecular testing in our study was performed selectively—primarily to guide first-line treatment with novel agents per local guidelines, which required ECOG PS 0–1. Consequently, a large proportion of patients were not tested—PD-L1 in 55.1%, EGFR in 43.4%, and ALK in 62.9% of cases. This on-demand testing strategy likely contributed to poor outcomes, as only 14.6% received pembrolizumab and 4.1% received EGFR-TKIs for BMs. This highlights that molecular testing was generally reserved for patients considered eligible for novel therapies based on restrictive guidelines. As a result, the selective testing and treatment approach likely influenced the observed mOS, inherently favoring those with better performance status and treatment potential. We also observed differences in OS based on various clinical factors, providing further insight into our study outcomes. In univariate analysis, better OS was associated Figure 4. Overall survival rates by independent prognostic factors: (a) overall survival by age; (b) overall survival by the timing of the brain metastasis verification; (c) overall survival by the number of brain metastases; (d) overall survival by the type of brain metastasis treatment. 4. Discussion Real-world data studies offer valuable insights that complement RCTs, particularly by evaluating current and potentially guiding the implementation of new treatment patterns. This is especially relevant for patients with brain metastases (BMs) who are frequently excluded from RCTs. Despite advances in targeted and immunotherapies that have reshaped the treatment landscape for metastatic mNSCLC, RWD continues to highlight poor outcomes in this group. In populations primarily receiving palliative or local treatment for BMs, mOS remains low—reported as just 2 months in some studies [ 19 ]. Hatton et al. further showed that survival outcomes were better in patients with known driver mutations. For instance, EGFR-positive patients had a median survival of 4.8 months compared to 3.0 months for EGFR-negative and 1.8 months for those with unknown status. Similarly, patients with known ALK status—whether positive or negative—fared better than those with unknown expression (mOS 1.8 months) [ 19 ]. These findings align with Sperduto et al.,