Brain Metastases In Non-small Cell Lung Cancer Patients Research Articles

Abstract 703: GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiosensitize primary and metastatic lung adenocarcinoma tumors

Abstract In non-small cell lung cancer (NSCLC) treatment, targeted therapies help a subset of patients, and radiotherapy responses are not durable and toxicity limits therapy. Most advanced-stage NSCLC patients have brain metastases that render an abysmal prognosis. Standard-of-care radiation therapy for NSCLC brain metastasis includes stereotactic radiosurgery (SRS) if the number of lesions is less than ten, otherwise whole brain radiation therapy (WBRT) is administered. Challenges in applying radiotherapy include overcoming radiation resistance and reducing significant associated co-morbidities. Cancer neuroscience is an evolving area, and the purpose of this study is to determine if activation of GABA(A) receptors intrinsic to NSCLC cells can improve radiation efficacy in primary NSCLC and its brain metastasis. We find that a GABA(A) receptor activator, AM-101, impairs the viability and clonogenicity of NSCLC primary and brain metastatic cells. Employing a human-relevant ex vivo ‘chip’, AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via multimerization of GABA(A) Receptor-Associated Protein (GABARAP), stabilization of mitochondrial receptor Nix, utilization of ubiquitin-binding protein p62, and upregulation of Beclin-1. A high-affinity peptide disrupting Nix binding to GABARAP inhibits the cytotoxicity of AM-101. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis that triggers autophagy. In NSCLC brain metastases patients, GABA(A) receptor activation may improve radiation efficacy and tumor control while allowing radiation dose de-intensification to reduce toxicity. Citation Format: Debanjan Bhattacharya, Riccardo Barrile, Donatien Kamdem Toukam, Vaibhavkumar S. Gawali, Laura Kallay, Taukir Ahmed, Hawley Brown, Sepideh Rezvanian, Aniruddha Karve, Pankaj B. Desai, Mario Medvedovic, Kyle Wang, Dan Ionascu, Nusrat Harun, Chenran Wang, Andrew M. Baschnagel, Joshua A. Kritzer, James Cook, Daniel A. Pomeranz Krummel, Soma Sengupta. GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiosensitize primary and metastatic lung adenocarcinoma tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 703.

Use of comprehensive genomic profiling for biomarker discovery for the management of non-small cell lung cancer brain metastases.

Clinical biomarkers for brain metastases remain elusive. Increased availability of genomic profiling has brought discovery of these biomarkers to the forefront of research interests. In this single institution retrospective series, 130 patients presenting with brain metastasis secondary to Non-Small Cell Lung Cancer (NSCLC) underwent comprehensive genomic profiling conducted using next generation circulating tumor deoxyribonucleic acid (DNA) (Guardant Health, Redwood City, CA). A total of 77 genetic mutation identified and correlated with nine clinical outcomes using appropriate statistical tests (general linear models, Mantel-Haenzel Chi Square test, and Cox proportional hazard regression models). For each outcome, a genetic signature composite score was created by summing the total genes wherein genes predictive of a clinically unfavorable outcome assigned a positive score, and genes with favorable clinical outcome assigned negative score. Seventy-two genes appeared in at least one gene signature including: 14 genes had only unfavorable associations, 36 genes had only favorable associations, and 22 genes had mixed effects. Statistically significant associated signatures were found for the clinical endpoints of brain metastasis velocity, time to distant brain failure, lowest radiosurgery dose, extent of extracranial metastatic disease, concurrent diagnosis of brain metastasis and NSCLC, number of brain metastases at diagnosis as well as distant brain failure. Some genes were solely associated with multiple favorable or unfavorable outcomes. Genetic signatures were derived that showed strong associations with different clinical outcomes in NSCLC brain metastases patients. While these data remain to be validated, they may have prognostic and/or therapeutic impact in the future. Using Liquid biopsy in NSCLC brain metastases patients, the genetic signatures identified in this series are associated with multiple clinical outcomes particularly these ones that lead to early or more numerous metastases. These findings can be reverse-translated in laboratory studies to determine if they are part of the genetic pathway leading to brain metastasis formation.

SDPS-39 AN UPDATED VALIDATION OF PREDICTIVE ALGORITHMS FOR BRAIN METASTASES IN NON-SMALL CELL LUNG CANCER: SYSTEMATIC REVIEW AND INDEPENDENT COHORTVALIDATION ANALYSIS

Abstract INTRODUCTION Many non-small cell lung cancer (NSCLC) patients eventually develop brain metastases (BM). Reliable risk stratification with predictive algorithms can lead to early intervention. Here, we evaluated the performance of published BM risk-stratification algorithms using an independent cohort of NSCLC patients. METHODS We evaluated statistical models predicting BM in NSCLC by systematically reviewing relevant studies and testing them on an independent cohort of NSCLC patients in electronic medical records (2011-2020) from Penn State Health. Patient data was randomly split into 70% training and 30% testing for modeling using L1-regularized logistic regression, and we assessed the models' performance using ROC analyses. RESULTS Out of 1,643 publications, 22 met our criteria, and 12 of those studies (527,258 patients) included variables consistently available in patient charts. Our validation cohort included 1,699 NSCLC patients, with a median age at diagnosis of 68 and 20.4% developing BM. Among feasible models, Zhang 2021 had the highest performance in our cohort (AUROC [95% CI]: 0.89 [0.85-0.93]) and was comprised of the following predictors: age at diagnosis; surgical, chemotherapy, and radiation status; T and N stage; histological grade; and number of organs with metastases. Within our independent cohort, logistic regression revealed that the most informative predictors were the number of organs with metastases (OR [95% CI]: 3.25 [2.70, 3.92]), age at NSCLC diagnosis (OR [95% CI]: 0.98 [0.96, 0.99]), N-stage 1 at diagnosis (OR [95% CI]: 1.83 [1.08, 3.11]), and non-carcinoid or -carcinoma histology (OR [95% CI]: 0.29 [0.10, 0.84]). CONCLUSION Our robust approach, including systematic review and one of the largest-to-date independent institutional datasets, proposes a clinically feasible, novel algorithm for stratifying NSCLC patients based on risk of developing BM. This work can inform pragmatic screening and surveillance guidelines to facilitate early detection of BM in NSCLC patients.

18F-FDG PET/CT radiomics predicts brain metastasis in I-IIIA resected Non-Small cell lung cancer

ObjectiveTo establish 18F-FDG PET/CT radiomics model for predicting brain metastasis in non-small cell lung cancer (NSCLC) patients. MethodsThis research comprised 203 NSCLC patients who had received surgical therapy at two institutions. To identify independent predictive factors of brain metastasis, metabolic indicators, CT features, and clinical features were investigated. A prediction model was established by incorporating radiomics signature and clinicopathological risk variables. The suggested model’s performance was assessed from the perspective of discrimination, calibration, and clinical application. ResultsThe C-indices of the PET/CT radiomics model in the training, internal validation, and external validation cohorts were 0.911, 0.825 and 0.800, respectively. According to the multivariate analysis, neuron-specific enolase (NSE) and air bronchogram were independent risk factors for brain metastasis (BM). Furthermore, the combined model integrating radiomics and clinicopathological characteristics related to brain metastasis performed better in terms of prediction, with C-indices of 0.927, 0.861, and 0.860 in the training, internal validation, and external validation cohorts, respectively. The decision curve analysis (DCA) suggested that the PET/CT nomogram was clinically beneficial. ConclusionsA predictive algorithm based on PET/CT imaging information and clinicopathological features may accurately predict the probability of brain metastasis in NSCLC patients following surgery. This presented doctors with a unique technique for screening NSCLC patients at high risk of brain metastasis.

CNS efficacy of afatinib as first-line treatment in advanced non-small cell lung cancer patients with EGFR mutations.

Afatinib is a potent, irreversible second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor which has demonstrated efficacy in advanced non-small cell lung cancer (NSCLC) patients harboring either common or uncommon EGFR mutations. However, data on its activity against brain metastases are limited. This study aimed to retrospectively evaluate the efficacy and safety of afatinib as first-line treatment for EGFR-mutant NSCLC patients with brain metastases. Treatment-naive advanced NSCLC patients harboring EGFR mutations and brain metastases treated with afatinib were retrospectively reviewed to assess the central nervous system (CNS) efficacy and also the systematic benefits. Totally 43 patients with measurable or non-measurable brain metastases were enrolled in the CNS full analysis (cFAS) set. Among them, 23 patients with measurable brain metastases were included in the CNS evaluable for response (cEFR) set. The CNS ORR was 48.8% (95% CI, 33.3 - 64.5%) in the cFAS set and 82.6% (95% CI, 61.2 - 95.0%) in the cEFR set, respectively. CNS mDoR was 8.9 months (95% CI, 4.7 - 13.1 months) and CNS mPFS was 12.7 months (95% CI, 6.9 - 18.5 months) in the cFAS set. In the subgroup analysis stratified by EGFR mutation types, CNS ORR of cEFR set in the common mutation cohort was 100% (95% CI, 75.3 - 100%) and 60% (95% CI, 26.2 - 87.8%) in the uncommon mutation cohort (p = 0.024); CNS ORR of cFAS set was 57.7% (95% CI, 36.9 - 76.6%) and 35.3% (95% CI, 14.2 - 61.7%), respectively (p = 0.151). CNS mPFS was 14.4 months in patients with common mutations and 6.1 months in patients with uncommon mutations (hazard ratio, 0.47; 95% CI, 0.22 - 1.00; p = 0.045). Patients with common mutations showed a significantly lower cumulative incidence of CNS failure than uncommon mutation cohort (p = 0.0026). Most of patients experienced grade 1/2 treatment-related adverse events. First-line afatinib demonstrated encouraging efficacy on brain metastases in NSCLC patients harboring either common or major uncommon EGFR mutations in a real-world setting, with manageable toxicities. Patients with common mutations showed better CNS outcomes than those with uncommon mutations.

Experimental study of EGFR-TKI aumolertinib combined with ionizing radiation in EGFR mutated NSCLC brain metastases tumor

Aumolertinib is an irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), although it has been administered for the treatment of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). However, it is unclear whether aumolertinib combined with ionizing radiation (IR) has potential therapeutic effects in treating brain metastases (BM) tumors from NSCLC. This study explored the anti-tumor effects of aumolertinib combined with IR in epidermal growth factor receptor mutated (EGFRm) NSCLC BM tumors. First, we established a xenograft model of NSCLC BM tumors in BALB/c nude mice and assessed the anti-tumor effects of this combination. Furthermore, we examined the concentrations of aumolertinib in brain tissue and blood using liquid chromatography-mass spectrometry (LC-MS); after that, we used CCK-8, colony formation, flow cytometry assay, and immunofluorescence staining to detect the effects of aumolertinib combined with IR upon PC-9 and NCI–H1975 cells, such as cell proliferation, survival, apoptosis, cycle distribution, the situation of DNA damage, and the expression levels of relevant proteins which were detected via western blotting; finally, we chose a clinical case with which to explore the clinical benefits to the EGFRm NSCLC BM patient after the treatment of the aforementioned combination. The experiments of NSCLC BM tumor animal models demonstrated that the combination enhanced the therapeutic effects and increased the intracranial accumulation of aumolertinib; the combination can inhibit cell proliferation and survival, delay the repair of DNA damage, and increase the rates of cell apoptosis and aumolertinib abrogated G2/M phase arrest, which the IR induced; the clinical study verified that the combination demonstrated better patient benefits. In conclusion, our study demonstrated that combining aumolertinib and IR has promising anti-tumor effects in EGFR-mutant NSCLC and that this combined treatment modality may be employed as a potential therapeutic strategy for EGFR-mutant NSCLC BM patients clinically.

Clinical outcomes of non-small cell lung cancer brain metastases treated with stereotactic radiosurgery and immune checkpoint inhibitors, EGFR tyrosine kinase inhibitors, chemotherapy and immune checkpoint inhibitors, or chemotherapy alone.

Immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used in the systemic management of non-small cell lung cancer (NSCLC) brain metastases (BMs). However, optimizing control of NSCLC BM with stereotactic radiosurgery (SRS) and various systemic therapies remains an area of investigation. Between 2016 and 2019, the authors identified 171 NSCLC BM patients with 646 BMs treated with single-fraction SRS within 3 months of receiving treatment with ICIs (n = 56; 33%), EGFR-TKI (n = 30; 18%), chemotherapy and ICIs (n = 23; 14%), or standard chemotherapy alone (n = 62; 36%). Time-to-event analysis was conducted, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival from SRS. The median follow-up from BM diagnosis was 8.9 months (range 0.3-127 months). The 12-month Kaplan-Meier DIC rates were 37%, 53%, 41%, and 21% (p = 0.047) for the ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy-alone groups, respectively. On multivariate analysis, DIC was improved with EGFR-TKI (HR 0.4, 95% CI 0.3-0.8, p = 0.005) compared with conventional chemotherapy and treatment with SRS before systemic therapy (HR 0.5, 95% CI 0.3-0.9, p = 0.03) compared with after; and LC was improved with SRS before (HR 0.4, 95% CI 0.2-0.9, p = 0.03) or concurrently (HR 0.3, 95% CI 0.1-0.6, p = 0.003) compared with after. No differences in radionecrosis were noted by timing or type of systemic therapy. The authors' analysis showed significant differences in DIC based on receipt of systemic therapy and treatment with SRS before systemic therapy improved DIC. Prospective evaluation of the potential synergism between systemic therapy and SRS in NSCLC BM management is warranted.

Clinical determinants impacting overall survival of patients with operable brain metastases from non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is currently the leading cause of cancer-related death worldwide, and the incidence of brain metastases (BM) in NSCLC patients is continuously increasing. The recent improvements of systemic treatment in NSCLC necessitate continuous updates on prognostic subgroups and factors determining overall survival (OS). In order to improve clinical decision-making in tumor boards, we investigated the clinical determinants affecting survival in patients with resectable NSCLC BM. A retrospective analysis was conducted of NSCLC patients with surgically resectable BM treated in our institution between 01/2015 and 12/2020. The relevant clinical factors affecting survival identified by univariate analysis were included in a multivariate logistic regression model. Overall, 264 patients were identified, with a mean age of 62.39 ± 9.98 years at the initial diagnosis of NSCLC BM and OS of 23.22 ± 1.71 months. The factors that significantly affected OS from the time of primary tumor diagnosis included the systemic metastatic load (median: 28.40 ± 4.82 vs. 40.93 ± 11.18 months, p = 0.021) as well as a number of BM <2 (median: 17.20 ± 2.52 vs. 32.53 ± 3.35 months, p = 0.014). When adjusted for survival time after neurosurgical intervention, a significant survival benefit was found in patients <60 years (median 16.13 ± 3.85 vs. 9.20 ± 1.39 months, p = 0.011) and, among others, patients without any concurrent systemic metastases at time of NSCLC BM diagnosis. Our data shows that the number of BM (singular/solitary), the Karnofsky Performance Status, gender, and age but not localization (infra-/supratentorial), mass-edema index or time to BM occurrence impact OS, and postsurgical survival in NSCLC BM patients. Additionally, our study shows that patients in prognostically favorable clinical subgroups an OS, which differs significantly from current statements in literature. The described clinically relevant factors may improve the understanding of the risks and the course of this disease and Faid future clinical decision making in tumor boards.

A Novel Score Combining Magnetic Resonance Spectroscopy Parameters and Systemic Immune-Inflammation Index Improves Prognosis Prediction in Non-Small Cell Lung Cancer Patients With Brain Metastases After Stereotactic Radiotherapy.

ObjectiveThe aim of this study was to evaluate the prognostic significance of the combination of the magnetic resonance spectroscopy (MRS) parameters and systemic immune-inflammation index (SII) in patients with brain metastases (BMs) from non-small cell lung cancer (NSCLC) treated with stereotactic radiotherapy.MethodsA total of 118 NSCLC patients with BM who were treated with stereotactic radiotherapy were retrospectively enrolled in this study. All patients underwent MRS and blood samples test for SII analysis before the initiation of stereotactic radiotherapy. The correlation between the parameters of MRS and SII level was assessed using Spearman’s correlation coefficient. The cutoff values for the parameters of MRS, SII, and clinical laboratory variables were defined by the receiver operating characteristic (ROC) curve analysis to quantify these predictive values. The prognostic factors of overall survival (OS) and progression-free survival (PFS) curves were assessed using the Kaplan–Meier and Cox proportional hazards models.ResultsThe median follow-up time was 25 months (range, 12–49 months). The optimal cutoff point for the choline/creatine (Cho/Cr) ratio and SII were 1.50 and 480, respectively. The Cho/Cr ratio was negatively correlated with SII (rs = 0.164, p = 0.075), but there was a trend. The C-SII score was established by combining the Cho/Cr ratio and SII. Patients with both an elevated Cho/Cr ratio (>1.50) and an elevated SII (>480) were given a C-SII score of 2, and patients with one or neither were given a C-SII score of 1 or 0, respectively. The Kaplan–Meier analysis showed that a C-SII score of 2 was significantly linked with poor OS and PFS (p < 0.001 and p < 0.001, respectively). In the Cox proportional hazards model, the C-SII score independently predicted OS [hazard ratio (HR), 1.749; 95% CI, 1.176–2.601; p = 0.006] and PFS (HR, 2.472; 95% CI, 1.624–3.763; p < 0.001).ConclusionThe C-SII score was more accurate for predicting the clinical outcomes of NSCLC patients with BM who underwent stereotactic radiotherapy. The C-SII score, which was superior to either score alone, could be used to identify BM in NSCLC patients with poor outcomes.

Targeting polarized phenotype of microglia via IL6/JAK2/STAT3 signaling to reduce NSCLC brain metastasis

Tumor-associated macrophages have emerged as crucial factors for metastases. Microglia are indispensable components of the brain microenvironment and play vital roles in brain metastasis (BM). However, the underlying mechanism of how activated microglia promote brain metastasis of non-small cell lung cancer (NSCLC) remains elusive. Here, we purified cell lines with brain-metastatic tropism and employed a co-culture system to reveal their communication with microglia. By single-cell RNA-sequencing and transcriptome difference analysis, we identified IL6 as the key regulator in brain-metastatic cells (A549-F3) to induce anti-inflammatory microglia via JAK2/STAT3 signaling, which in turn promoted the colonization process in metastatic A549-F3 cells. In our clinical samples, patients with higher levels of IL6 in serum showed higher propensity for brain metastasis. Additionally, the TCGA (The Cancer Genome Atlas) data revealed that NSCLC patients with a lower level of IL6 had a longer overall survival time compared to those with a higher level of IL6. Overall, our data indicate that the targeting of IL6/JAK2/STAT3 signaling in activated microglia may be a promising new approach for inhibiting brain metastasis in NSCLC patients.

Efficacy and safety of WBRT+EGFR‐TKI versus WBRT only in the treatment of NSCLC patients with brain metastasis: An updated meta‐analysis

BackgroundTo investigate the efficacy and safety of whole brain radiotherapy (WBRT) combined with epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) versus WBRT only in the treatment of brain metastasis in non‐small cell lung cancer (NSCLC) patients by pooling open published data.MethodsProspective clinical studies relevant to WBRT+EGFR‐TKI versus WBRT only in the treatment of NSCLC brain metastasis were electronically searched in the Pubmed, EMbase, Cochrane, Wangfang, CNKI and Google scholar databases. The treatment response, 1‐year survival and treatment‐associated toxicity were pooled and expressed by odds ratio (OR) under a fixed or random effect model. The publication bias was evaluated by Begg's funnel plot and Egger's line regression test.ResultsEighteen prospective clinical studies were included in the study. The combined results indicated that the objective response rate (ORR) in the WBRT+TKI group was superior to WBRT only with a statistical difference (OR = 2.67, 95% CI: 2.10–3.38, p < 0.05) under a fixed effect model. Ten studies reported the 1‐year survival rate between the WBRT+TKI and WBRT only groups. The combined results showed that 1‐year survival rate in the WBRT+TKI group was higher than that of the WBRT only group with a statistical difference (OR = 2.70, 95% CI: 1.95–3.74, p < 0.05). For treatment‐associated toxicity, the combined data indicated that the treatment‐related rash in the WBRT+TKI group was significantly higher than that of the WBRT only group with a statistical difference (OR = 2.72, 95% CI: 1.53–4.84, p < 0.05). However, the incidence of nausea/vomiting (OR = 0.84, 95% CI: 0.60–1.17, p > 0.05), diarrhea (OR = 1.31, 95% CI: 0.83–2.07, p > 0.05), fatigue (OR = 1.40, 95% CI: 0.70–2.81, p > 0.05) and myelosuppression (OR = 0.86, 95% CI: 0.56–1.32, p > 0.05) were not statistically different between the two groups.ConclusionsBased on the current publications, WBRT+EGFR‐TKI can improve the treatment response and 1‐year survival rate but not increase the toxicity except for rash compared to WBRT alone in the treatment of brain metastasis in NSCLC patients.

Anti-PD1 Therapy Plus Whole-Brain Radiation Therapy May Prolong PFS in Selected Non-Small Cell Lung Cancer Patients with Brain Metastases: A Retrospective Study.

BackgroundWhole-brain radiotherapy (WBRT) remains an essential modality of treatment for brain metastases (BMs) derived from non-small cell lung cancer (NSCLC) patients and anti-PD-1 therapy has demonstrated intracranial responses in these patients. We aimed to evaluate if the combination of the two treatments could yield additive efficacy.MethodsA retrospective review of our institution’s database was carried out to identify NSCLC patients with BMs who had been treated with anti-PD1 therapy and/or WBRT between 2015 and 2020. Patient characteristics, main outcomes, including progression-free survival (PFS) and overall survival (OS), and factors affecting these outcomes were analyzed. SPSS 24 was used for statistical analysis. Appropriate statistical tests were employed according to the type of data.ResultsOverall, 21 NSCLC BM patients were identified that had received WBRT. Of these, ten had been additionally treated with anti-PD1 therapy within 30 days of WBRT initiation. Median PFS was 3 (95% CI 0.8–5.1) months with WBRT alone versus 11 (95% CI 6.3–15.6) months with combined treatment. Risk of disease progression was 71% lower with the combined approach (HR 0.29, 95% CI 0.11–0.80; p=0.016). A trend toward improved OS was also observed with the combined approach (HR 0.33, 95% CI 0.08–1.12; p=0.107). Concurrent treatment (p=0.028) and male sex (p=0.052) were associated with improved PFS, while OS was associated only with age (p=0.02).ConclusionConcurrent WBRT and anti-PD1 therapy may delay progression and improve survival in BM patients with confirmed EGFR- and ALK-negative NSCLC histology. Prospective studies are warranted to validate and elucidate on the additive effect of the two modalities.

Outcomes of Immune-Checkpoint Inhibitors (ICIs) and Stereotactic Radiosurgery (SRS) in Non-Small Cell Lung Cancer Brain Metastases (NSCLCBM) Patients

<h3>Purpose/Objective(s)</h3> Non-small cell lung cancer (NSCLC) is the leading cause of brain metastases. Systemic therapies and radiation therapy are both potential treatment options for NSCLCBM patients. ICIs have been designated as a promising alternative in patients without targetable molecular alterations, while SRS has also grown into favor, as it is non-invasive and irradiates only the lesion. In our retrospective study, we evaluated overall survival (OS) and progression-free survival (PFS) between NSCLCBM patients who received ICIs, SRS, and a combination of both treatments. We hypothesize that the combination of ICIs and SRS will be associated with improved OS and PFS when compared to either treatment alone. <h3>Materials/Methods</h3> We investigated all NSCLCBM patients diagnosed between 2010 and 2019. Molecular marker status, types of therapies used, and dates of progression were collected. OS was defined as the start date of either type of therapy to the date of last follow-up or death. Most NSCLCBM patients who received SRS or ICIs therapies also received standard chemotherapy. The Cox proportional model was used to estimate OS and PFS. <h3>Results</h3> A total of 2989 NSCLCBM patients were analyzed. 286 patients received only ICIs, 916 received only SRS, and 469 were treated with both SRS and ICIs. The median OS (mOS) in patients treated with ICI was 17.2 months, while the mOS in patients treated with SRS or both ICI and SRS were 23.2 months (hazard ratio (HR) = 0.79 (95% confidence interval (CI) = 0.68, 0.92), <i>P</i>-value (<i>P</i>) < 0.002) and 48.2 months (HR = 0.45) (95% CI = 0.38, 0.54), <i>P</i> < 0.001), respectively. The median PFS (mPFS) in patients treated with ICIs, SRS, and both SRS and ICIs was 9.92 months, 23.25 months (HR = 0.56 (95% CI = 0.48, 0.64), <i>P</i> < 0.001), and 29.33 months (HR = 0.45 (95% CI = 0.39, 0.53), <i>P</i> < 0.001), respectively. <h3>Conclusion</h3> ICIs and SRS are both common therapies in the field of NSCLCBM. Our retrospective study data showed improved mOS and mPFS in patients who received SRS or the combination of SRS and ICIs when compared to those who received ICIs. Though there was longer mOS and mPFS in the combination group compared to the SRS group, the statistical significance has yet to be analyzed. However, our data is encouraging that there may be a synergistic survival benefit in the combination of SRS and ICIs cohort, which could be especially beneficial in patients with strong PDL1 expression.

Clinical Outcomes of Non-Small Cell Lung Cancer Brain Metastases Treated With Stereotactic Radiosurgery and Immune Checkpoint Inhibitors, EGFR Tyrosine Kinase Inhibitors, Chemotherapy and Immune Checkpoint Inhibitors, or Chemotherapy Alone

Immune checkpoint inhibitors (ICI) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have shown responses in the management of non-small cell lung cancer (NSCLC) brain metastases (BM). However, optimizing control with stereotactic radiosurgery (SRS) and various systemic therapies in the management of NSCLC BM remains an area of investigation. We evaluated clinical outcomes in NSCLC BM treated with SRS and ICI, EGFR-TKI, ICI and chemotherapy, compared to conventional chemotherapy.A total of 174 NSCLC BM patients, treated between 2015 and 2019, to a total of 660 intact (non-operative) BM over 239 single-fraction SRS sessions within 3 months of receiving ICI (n = 58; 33%), EGFR-TKI (n = 30; 17%), chemotherapy and ICI (n = 22; 13%) or standard chemotherapy (n = 64; 37%) were identified. Time-to-event analysis was conducted with the Kaplan-Meier method, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival (OS) from SRS. Cox proportional hazards model was utilized for multivariate analysis (MVA) to identify correlations of clinical variables with outcomes.Median follow-up from BM diagnosis was 8.9 months (0.26-126.5 months) and 7.3 months from SRS (2.5-17.6 months). No significant differences in age (P = 0.55), gender (P = 0.49), treated gross tumor volume (P = 0.31), presence of systemic metastasis (P = 0.1), SRS dose (P = 0.61), or KPS (0.35) were noted between treatment groups. The 12-month DIC was 35%, 53%, 41%, and 20% (P = 0.02) for ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy alone groups, respectively. No differences were noted in LC (P = 0.1) and OS (P = 0.5) between treatment groups. Upon MVA, factors found to be significant for improved DIC included treatment with EGFR-TKI therapy compared to conventional chemotherapy (HR 0.4; 95% CI 0.25-0.76; P = 0.04) and treatment with SRS before systemic therapy (HR 0.6; 95% CI 0.3-0.9; P = 0.03). Factors found to be significant for improved LC on MVA included treatment with SRS before (HR 0.4; 95% CI 0.2-0.9; P = 0.03) or concurrent (HR 0.3; 95% CI 0.1-0.6; P = 0.003) compared to following receipt of systemic therapy. Rates of radiation necrosis (RN) did not differ between treatment groups and were 6% (n = 12), 5% (n = 12), 3% (n = 3), 3% (n = 3), for ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy alone groups, respectively, P = 0.43. In addition, no differences were noted in RN between timing of SRS and receipt of systemic therapy, (P = 0.81).In our analysis of NSCLC BM patients treated with single session SRS alongside systemic therapy, we found significant differences in DIC based on receipt of systemic therapy. In addition, treatment with SRS before or concurrent with systemic therapy improved control rates. No differences in RN were noted between treatment groups or by timing of SRS and systemic therapy. Prospective evaluation of the potential synergistic effect between systemic therapy and SRS in NSCLC BM management is warranted.A.E. Dohm: None. J. Tang: None. M.N. Mills: None. B.A. Perez: Research Grant; BMS.T.J. Robinson: None. B. Creelan: Research Grant; NGenomics Laboratories, Adaptive Biotechnologies Corp. Consultant; Xilio Inc, E.R. Squibb LLC, F. Hoffmann-La Roche AG, AstraZeneca plc, AbbVie, KSQ Therapeutics Inc, GlaxoSmithKline plc, Gilead Sciences Inc, Celgene corp. Speaker's Bureau; AstraZeneca plc, ARIAD Pharmaceuticals, Hoffmann-La Roche AG.J. Gray: None. A.B. Etame: None. M. Vogelbaum: Honoraria; Celgene, Tocagen. Stock Options; Infuseon Therapeutics. Royalty; Infuseon Therapeutics. P. Forsyth: Research Grant; Pfizer, Celgene. Advisory Board; Novocure, BTG, Inovio, AbbVie, Ziopharm, Tocagen, Pfizer. H.M. Yu: Honoraria; UpToDate. Speaker's Bureau; BrainLab. Advisory Board; Novocure, AbbVie. D.E. Oliver: None. K.A. Ahmed: Research Grant; Bristol-Myers Squibb, Genentech.

Identification of a high-risk group for brain metastases in non-small cell lung cancer patients.

Identification of a high-risk group of brain metastases (BM) in patients with non-small cell lung cancer (NSCLC) could lead to early interventions and probably better prognosis. The objective of the study was to identify this group by generating a multivariable model with recognized and accessible risk factors. A retrospective cohort from patients seen at a single center during 2010-2020, was divided into a training (TD) and validation (VD) datasets, associations with BM were measured in the TD with logit, variables significantly associated were used to generate a multivariate model. Model´s performance was measured with the AUC/C-statistic, Akaike information criterion, and Brier score. From 570 patients with NSCLC who met the strict eligibility criteria a TD and VD were randomly assembled, no significant differences were found amid both datasets. Variables associated with BM in the multivariate logit analyses were age [P 0.001, OR 0.96 (95% CI 0.93-0.98)]; mutational status positive [P 0.027, OR 1.96 (95% CI 1.07-3.56); and carcinoembryonic antigen levels [P 0.016, OR 1.001 (95% CI 1.000-1.003). BM were diagnosed in 24% of the whole cohort. Stratification into a high-risk group after simplification of the model, displayed a frequency of BM of 63% (P < 0.001). A multivariate model comprising age, carcinoembryonic antigen levels, and mutation status allowed the identification of a truly high-risk group of BM in NSCLC patients.

Role of stereotactic radiosurgery for the treatment of brain metastasis in the era of immunotherapy: A systematic review on current evidences and predicting factors.

Stereotactic radiosurgery (SRS) in combination with immunotherapy (IT) is increasingly used in the setting of melanoma and non-small cell lung cancer (NSCLC) brain metastases (BM). The synergistic properties of this treatment combination are still not deeply understood. IT-SRS appropriate combination has been envisioned as a strategic point in patients' management. Authors performed a systematic review on current evidences up to December 2020. The impact of SRS-IT and different IT schedules on survival, local/distant intracranial control and toxicity, as well as predictive factors for relevant oncological and radiological outcomes has been analyzed. Authors retrieved 23 pertinent studies. Combining SRS with IT resulted in a significant improvement in OS and lesion response with no increase in radionecrosis, hemorrhage or other complications. The present review suggests that combining IT to SRS is safe and effective in providing a significant improvement in relevant clinical and radiological outcomes in melanoma and NSCLC BMs patients.

Immune checkpoint inhibitors for brain metastases in non-small-cell lung cancer: from rationale to clinical application.

Brain metastases (BM) is common in non-small-cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors (ICIs)have gradually become a routine treatment for NSCLC BM patients. Currently, three PD-1 inhibitors (pembrolizumab, nivolumab and cemiplimab), one PD-L1 inhibitor (atezolizumab) and one CTLA-4 inhibitor (ipilimumab) have been approved for the first-line treatment of metastatic NSCLC. It is still controversial whether PD-L1, tumor infiltrating lymphocytes, and tumor mutation burden can be used as predictive biomarkers for immune checkpoint inhibitorsin NSCLC patients with BM. In addition, clinical data on NSCLC BM were inadequate. Here, we review the theoretical basis and clinical data for the application of ICIsin the therapy of NSCLC BM.

Outcomes of first, second, and third-generation anaplastic lymphoma kinase (ALK) inhibitors in non-small cell lung cancer brain metastases (NSCLCBM).

2034 Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases. ALK, which codes for tyrosine kinase receptors, is rearranged in 4-7% of NSCLC. First-generation ALK inhibitors have restricted efficacy due to poor blood-brain barrier (BBB) penetration and ALK-resistant tumor mutations. Second-generation ALK inhibitors have shown better BBB penetration, while third-generation ALK inhibitors were efficacious even against ALK-resistant mutations. In this retrospective study, we investigated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first, second, and third-generation ALK inhibitors. Methods: NSCLCBM patients between 2010 and 2019 were evaluated. We analyzed data regarding molecular marker status, systemic therapies, and date of progression. OS was defined as the start date of systemic therapy to the date of last follow-up or death. The Cox proportional model was used to estimate OS and PFS. Results: A total of 90 patients had ALK gene rearrangement. 16 ALK positive patients received first-generation ALK inhibitor (crizotinib), with a median age of 59.2 years, 50% of the cohort being female and 83.3% being white. Another 17 patients received second-generation (alectinib, ceritinib, brigatinib) and third-generation ALK inhibitors (lorlatinib), with a combined median age of 52.2 years and a cohort of 52.6% females and 72.2% white patients. The 5-year OS rate was 49% (95% confidence interval (CI) = 24%, 71%) for first-generation ALK inhibitors and 76% (95% CI = 40%, 92%) for second and third-generation ALK inhibitors (p-value (p) = 0.019). The median PFS (mPFS) for patients who received first-generation ALK inhibitors was 45.3 months and for those who received second or third-generation ALK inhibitors was 180.1 months. The respective 5-year PFS rate was 43% (95% CI = 19%, 65%) and 72% (95% CI = 42%, 89%). Conclusions: Newer generations of targeted therapies in NSCLCBM have improved BBB penetration and effectiveness against resistant mutations. We determined that there was a significant 5-year OS benefit in patients who received second and third-generation ALK inhibitors compared to first-generation ALK inhibitors, and a respective trend towards significant PFS benefit in newer-generation ALK inhibitors when compared to first-generation. These results are encouraging, but the effect on intracranial lesion size and response rates should be examined in the future.[Table: see text]

Risk factors for brain metastases in patients with non-small cell lung cancer: a meta-analysis of 43 studies.

Lung cancer is a leading cause of cancer-related mortality worldwide. The purpose of our meta-analysis was to assess the risk factors for brain metastases (BM) in patients with non-small cell lung cancer (NSCLC). Multiple databases, including PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang, were systematically searched to recruit relevant studies investigating the risk factors for BM in NSCLC patients. The Newcastle-Ottawa Scale was used to evaluate literature quality, and the meta-analysis was performed using the Review Manager 5.3. Evidence quality evaluation was carried out according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) standard. The estimated odds ratio (OR) and 95% confidence intervals (CIs) were set as effect measures. Funnel plots and sensitivity analyses were used to assess publication bias and the robustness and reliability of the combined results, respectively. A total of 43 studies with 11,415 participants were included in this meta-analysis. The results indicated that the following factors were significantly associated with an increased risk of BM in NSCLC patients (P<0.05): (I) gender (female) (OR =1.32, 95% CI: 1.17-1.49, P<0.00001); (II) adenocarcinoma (OR =2.34, 95% CI: 1.76-3.11, P<0.00001) or non-squamous cell carcinoma (OR =0.63, 95% CI: 0.42-0.94, P=0.02); (III) advanced tumor stage (OR =1.48, 95% CI: 1.01-2.17, P=0.04); (IV) node stage (OR =2.19, 95% CI: 1.39-3.45, P=0.0007); (V) lymphatic metastasis (OR =2.43, 95% CI: 1.76-3.36, P<0.00001); (VI) epidermal growth factor receptor (EGFR) gene mutation (OR =1.88, 95% CI: 1.26-2.80, P=0.002); (VII) kirsten rat sarcoma viral oncogene (KRAS) gene mutation (OR =2.99, 95% CI: 1.82-4.91, P<0.00001); (VIII) higher levels of carcinoembryonic antigen (P<0.00001), carbohydrate antigen 199 (P<0.0001), cytokeratin-19 fragment (P=0.04), neuron-specific enolase (P<0.00001), and carbohydrate antigen 125 (P=0.0005). This meta-analysis demonstrated that NSCLC patients with BM have more aggressive clinical features.

Risk factors for brain metastases from non-small-cell lung cancer: A protocol for observational study.

Brain metastasis is a common site of distant metastasis of non-small-cell lung cancer (NSCLC) that greatly reduces the prognosis of patients. In this study, we explored the correlation between different clinical factors and secondary brain metastases in NSCLC in an attempt to identify NSCLC patient populations at high risk of metastasis to the central nervous system.We collected data for 350 NSCLC patients from the medical record system of the First Affiliated Hospital of Nanchang University from June 2015 to June 2019, and these patients had pathologically verified diagnoses. The correlations between age at the time of diagnosis, sex, histological type, calcium concentration, hemoglobin (HB), fibrinogen (Fbg), activated partial thromboplastin time (APTT), alkaline phosphatase (ALP), carcinoembryonic antigen (CEA), CA125, and CA199 levels and brain metastasis were analyzed. Multivariate logistic regression analysis was used to identify risk factors for NSCLC brain metastasis. A receiver operating characteristic (ROC) curve was used to calculate the cutoff, sensitivity, and specificity of the independent related factors.Of the 350 patients, 57 were diagnosed with brain metastases. Univariate and multivariate logistic regression analysis indicated that lesion diameter, calcium concentration, and CEA level were independent risk factors correlated with brain metastasis (P < .05). There were no significant differences in age, sex, type of histopathology, presence or absence of mediastinal lymph node metastasis, HB, Fbg, APTT, ALP, cancer antigen 125 (CA-125), or cancer antigen 199 (CA-199) levels between patients with brain metastases and patients without brain metastases (P > .05, respectively). ROC curves demonstrated that these factors had comparable accuracy in predicting brain metastasis (area under the curve [AUCs] were 0.620, 0.661, and 0.729, respectively). The cutoff values for lesion diameter, calcium, and CEA were 5.050 cm, 2.295 mmol/L, and 11.160 ng/mL, respectively. The sensitivities for prediction brain metastasis were 59.6%, 64.9%, and 73.3%, with specificities of 63.1%, 59.2%, and 70.3%, respectively.According to our study, lesion diameter, calcium concentration, and CEA level are independent risk factors for brain metastases in NSCLC patients. Thus, we can strengthen the regular follow-up of NSCLC patients with tumor diameter > 5.050 cm, calcium > 2.295 mmol/L, CEA > 11.160 ng/mL, and use these factors as a reference for preventive treatments.