NSCLC Brain Metastases Research Articles

114 - Real-world data on management of brain metastases in non-small cell lung cancer, Queen Elizabeth Hospital, Birmingham: a retrospective study on progression free survival, overall survival of different treatment modalities for brain metastases and prevalence of brain metastases in NSCLC receiving immunotherapy

114 - Real-world data on management of brain metastases in non-small cell lung cancer, Queen Elizabeth Hospital, Birmingham: a retrospective study on progression free survival, overall survival of different treatment modalities for brain metastases and prevalence of brain metastases in NSCLC receiving immunotherapy

EXTH-31. COMBINATION OF TUMOR TREATING FIELDS (TTFIELDS) AND PACLITAXEL PRODUCES ADDITIVE REDUCTIONS IN PROLIFERATION AND CLONOGENICITY IN PATIENT-DERIVED METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) CELLS

Abstract Clinical trials are underway to test the efficacy of TTFields in patients with progressive NSCLC or NSCLC brain metastases following standard-of-care or radiosurgery, respectively. Our study utilized patient-derived cells isolated from NSCLC brain metastases from a patient previously treated with standard-of-care chemo-radiation prior to progression to brain metastasis. These patient-derived cells underwent TTFields application in vitro with and without paclitaxel to determine if the response to the combination of TTFields with paclitaxel would be different from either treatment alone. Use of patient tissues was approved by the Institutional Review Board. Written informed consent was obtained from the patient, who was 60 years-old and female. She received concurrent carboplatin/paclitaxel and radiotherapy to the upper lobe of her left lung prior to discovery and resection of a solitary brain lesion. Cells isolated from the metastatic brain tumor were cultured for 3 passages prior to plating on coverslips (4×104 each) in DMEM/F12 media with 10% fetal bovine serum. TTFields were applied at ~1.6 V/cm at 150 kHz. Paclitaxel was added to the media to a final concentration of 5 nM. After 14 days, cell lysates were assayed for lactase dehydrogenase (LDH) to represent cell number (n=5) or were harvested and replated in triplicate for the clonogenic assay (n=3). Groups were compared with one-way ANOVA. Mean ± SD of LDH for the control, TTFields-alone, paclitaxel-alone, and the combination were 1.83 ± 0.09, 1.34 ± 0.15, 0.81 ± 0.04, and 0.46 ± 0.21, respectively (ANOVA p< 0.0001). Clonogenic assay counts for the same groups were 26641 ± 4625, 17399 ± 5998, 8697 ± 1617, and 1598 ± 598 (ANOVA p= 0.0003). The additive effects of TTFields and paclitaxel suggest that they target different cell populations within a heterogeneous tumor, and that patients previously treated with standard-of-care may benefit from TTFields therapy.

P2.08-01 Outcomes Following Gamma Knife Radiosurgery for Oligometastatic Brain Metastases in Patients with NSCLC at Leeds Cancer Centre

Gamma knife (GK) radiosurgery has increasingly been used for brain metastases from NSCLC in the oligometastatic setting. This study reports outcome results for patients with synchronous brain and new brain metastases from NSCLC at Leeds Cancer Centre (LCC). 251 patients, who were treated with GK at LCC from 2009 until 2018 were analysed. Retrospective analysis of notes was performed using electronic patient records. Statistical analysis was performed using SPSS. Kaplan-Meier curves were performed to estimate time to intracranial progression, survival from diagnosis of brain metastases, and overall survival. Median age was 65 years (range 33 – 90 years). For patients with new brain metastasis (147 patients), TNM stage at diagnosis was stage I (14 patients), stage II (42 patients), stage IIIA (26 patients) or stage IIIB/IV (65 patients). Histology was majority adenocarcinoma (59%), squamous cell carcinoma (16%) or NSCLC NOS (13%). Radical thoracic treatment (surgery, chemoradiotherapy or stereotactic ablative radiotherapy) was undertaken for 158 patients. 92% completed radical thoracic treatment. Median survival from diagnosis of brain metastases was 382 days (446 days for those with synchronous brain metastases (48 patients), and 325 days for those with new brain metastases (110 patients)). For all patients, median time to intracranial progression after GK was 242 days and overall survival after GK was 293 days. For patients with synchronous brain metastases at presentation (104 patients), median time for overall survival from date of diagnosis was 435 days. For all patients without brain metastases at presentation, median time to intracranial progression from date of diagnosis was 305 days and overall survival was 693 days. In conclusion, GK radiosurgery is an effective treatment for brain metastases in NSCLC, providing high rates of local control and improved survival. Beneficial effects are seen in patients with synchronous and new brain metastases, demonstrating its role in a wide subset of patients with advanced NSCLC. Use of GK, in combination with radical thoracic therapy, therefore has the potential to dramatically improve survival in patients who may not have previously been suitable for radical treatment.

EP1.08-01 Whole-Brain Radiotherapy Plus Sequential or Simultaneous Integrated Boost for the Treatment of Limited Number of Brain Metastases in NSCLC

EP1.08-01 Whole-Brain Radiotherapy Plus Sequential or Simultaneous Integrated Boost for the Treatment of Limited Number of Brain Metastases in NSCLC

P2.01-34 Endostar Combined with Whole Brain Radiotherapy in Patients with NSCLC Brain Metastases

P2.01-34 Endostar Combined with Whole Brain Radiotherapy in Patients with NSCLC Brain Metastases

P095 MicroRNA-330-3p Promotes Brain Metastasis of Non-Small Cell Lung Cancer by Activating MAPK/MEK/ERK Signaling Through GRIA3

Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with NSCLC. Discovery and development of biomarkers and elucidation of the mechanism underlying BM in NSCLC is critical for effective prophylactic interventions. MicroRNAs (miRNAs) play an essential role in the development of NSCLC. We investigated miRNAs that serve as biomarkers to differentiate NSCLC patients with and without BM, and explored the underlying mechanism. Logistic regression was conducted in 122 NSCLC patients (60 without BM, 62 with BM) to examine the association between miRNAs and BM. Stable over-expression and knock-down of miR-330-3p in NSCLC cells was constructed with lentivirus. Expression levels of miR-330-3p in NSCLC cells were quantified by quantitive real-time PCR (qRT-PCR). The effects of miR-330-3p on NSCLC cells were investigated using assays of cell viability, migration, invasion, cell cycle, apoptosis, western blotting, immunohistochemical and immunofluorescence staining. A xenograft nude mouse model and in situ brain metastasis model were used to observe tumor growth and brain metastasis. The potential target of miR-330-3p in NSCLC cells was explored using the luciferase reporter assay, qRT-PCR, and western blotting. The miR-330-3p targets were identified using bioinformatics analysis and verified by luciferase reporter assay. High serum miR-330-3p was an independent risk for BM. Tissue miR-330-3p was also higher in subjects with BM (P=0.003). Migration and invasiveness were increased by over-expressing miR-330-3p using a lentivirus, and decreased by miR-330-3p knockdown in both cell lines. In nude mice receiving NSCLC cells, either subcutaneously or into the brain, tumor growth was faster in mice receiving cells permanently expressing exogenous miR-330-3p, and slower in cells expressing the anti-miR-330-3p sequence. Bioinformatics analysis, followed by microarray analysis of A549 cells over-expressing miR-330-3p and luciferase reporter assay suggested the glutamate receptor GRIA3 as a target of miR-330-3p. Experiments using selective kinase inhibitors suggested that GRIA3 is regulated by miR-330-3p via MAPK/MEK/ERK signaling pathway. miR-330-3p promotes NSCLC brain metastasis possibly in part via the MAPK/MEK/ERK pathway and GRIA3, and might be a potential target for the further research of NSCLC brain metastasis.

P097 ctDNA Changes and TCR Diversity Associated with Clinical Outcomes Following Brain Therapy in NSCLC Brain Metastases

P097 ctDNA Changes and TCR Diversity Associated with Clinical Outcomes Following Brain Therapy in NSCLC Brain Metastases

The Expressional Pattern of Invasion-Related Extracellular Matrix Molecules in CNS Tumors

abstractAim of the study: Astrocytomas are primary CNS malignancies which infiltrate the peritumoral tissue, even when they are low-grade. Schwannomas are also primary CNS tumors, however, they do not show peritumoral infiltration similarly to brain metastases which almost never invade the neighboring parts of brain. Extracellular matrix is altered in composition in various cancer types and is proposed to play an important role in the development of invasiveness of astrocytic tumors. This study aims to identify differences in the ECM composition of CNS tumors with different invasiveness.Materials and methods: The mRNA and protein levels of ECM components were measured by QRT-PCR and mass-spectrometry, respectively, in grade II astrocytoma, NSCLC brain metastasis, schwannomas, and non-tumor brain control samples. Expressional data was analyzed statistically with ANOVA and nearest neighbor search.Results: There is a significant difference in the expressional pattern of invasion-related ECM components among various CNS tumors, especially among those of different embryonic origin. Non-invasive tumors show only slight differences in the expressional pattern of ECM molecules. Tumor samples can be separated based on their expressional pattern using statistical classifiers, therefore the ECM composition seems to be typical of various cancer types.Conclusions: Differences in the expressional pattern of the ECM could be responsible for the different invasiveness of various CNS tumors.

Synchronous Oligometastatic Lung Cancer Deserves a Dedicated Management

Oligometastatic stage IV non-small lung cancer (NSCLC) patients have a 5-year overall survival of 30% versus 4% to 6% in historical cohorts of stage IV NSCLC patients. We reviewed data and patterns of care of patients affected by oligometastatic NSCLC in our center between 2001 and2017. We retrospectively reviewed clinical and pathological files of all patients with lung cancer and synchronous isolated adrenal or brain metastases, or both, treated by locally ablative treatments (surgery or radiotherapy, or both) of both primary cancer and distant metastasis. Statistical analysis was performed to assess the effect on overall survival of patient- and tumor-related characteristics and therapeutic approaches. Overall survival was assessed by the Kaplan-Meier method. Survival rates were compared by log-rank test. Significance was accepted at a level of p of less than 0.05. Our department treated 51 patients affected by NSCLC and synchronous brain metastasis (n= 41), adrenal metastasis (n= 9), or both (n= 1). Median survival was 42 months (95% confidence interval, 22.3 to 63.7). Overall survival was 62% at 2 years and 34.4% at 5 years. A univariate and multivariate analysis the positive prognostic factors for survival was cessation of smoking (p= 0.006) and lymphovascular and perineural spreading in the tissues (p= 0.024). In selected oligometastatic synchronous NSCLC patients, a multimodality approach encompassing radical treatment of the primary tumor and ablative treatment of concurrent metastases is recommended, with encouraging results. Smoking cessation is a part of the treatment sequence.

Survival Effect Difference of Whole-Brain Radiation Therapy and TKIs in Patients with Brain Metastases from Non-Small Cell Lung Cancer Stratified by EGFR Mutation Status

To compare overall (OS) and intracranial progression-free survival (iPFS) effects of whole-brain radiotherapy (WBRT) and tyrosine kinase inhibitors (TKIs) in NSCLC patients with brain metastases (BM) stratified by EGFR mutation status (positive+, negative-, unknown). We performed a retrospective analysis of 595 NSCLC BM patients diagnosed in 2013-2015 and followed-up to December 1 2016. The stratified K-M curves and multivariate Cox models were used to evaluate effects of WBRT (defined as ≥30Gy, ' W ') and TKIs application (after BM, ' T ') on OS and iPFS independently and jointly. Covariates includes sex, age, KPS,CVD,NSCLC history length, resection of primary tumor, number of BM lesions, brain/brainstem/meningeal involvement status, BM resection, BM chemotherapy after screening. two-sided p>0.05 as ns. BM age mean (range) was 59 (22 - 87) and female 44%. Overall MTS of OS and iPFS were 9.3 and 8.9 months respectively. EGFR+ (114 pts, 53% of mutation tests), W+31% and T+76%. Multivariate HR(p) of W+ and T+ were OS - 0.768 (ns), 0.180 (0.00), iPFS - 1.057(ns) and 0.255 (0.00). Compared with W-T- (14 pts), multivariate HR(p) of W+T+(22 pts),W-T+(65) and W+T- (13) were OS - 0.196 (0.00), 0.114 (0.00), 0.434 (ns) and iPFS - 0.272 (0.01), 0.200 (0.00), 0.622 (ns). W+T+ vs. W-T+ had OS 1.717(ns) and iPFS 1.361 (ns). EGFR- (101 pts), W+43%. Multivariate HR(p) of W+ vs. W- were OS - 0.539 (0.11), iPFS - 0.485(0.05). EGFR unknown (380 pts), W+38%, T+17%. Compared with W-T- (202 pts), multivariate HR(p) of W+T+(30 pts),W-T+(35) and W+T- (113) were OS-0.304 (0.00), 0.370 (0.00), 0.465 (ns) and iPFS - 0.365(0.00), 0.556 (0.01), 0.562 (ns). W+T+ vs. W-T+ had OS 0.821(ns) and iPFS 0.657 (ns). Compared with EGFR-, TKIs use in EGFR+ or EGFR-unknown patients reduces the survival effect of WBRT on OS and iPFS in patients with NSCLC brain metastases. Whether to delay WBRT in TKIs users for EGFR+ BM patients for better survival or QOL benefit deserves RCTs.

P2.01-01 The Impact of Anlotinib on Brain Metastases of NSCLC: Post-Hoc Analysis of a Phase III Randomized Control Trial (ALTER0303)

P2.01-01 The Impact of Anlotinib on Brain Metastases of NSCLC: Post-Hoc Analysis of a Phase III Randomized Control Trial (ALTER0303)

P2.01-127 Efficacy of Endostar Combined with Whole Brain Radiotherapy in Patients with NSCLC Brain Metastases

P2.01-127 Efficacy of Endostar Combined with Whole Brain Radiotherapy in Patients with NSCLC Brain Metastases

Research Progress of Immunotherapy for Brain Metastases in Patients with Drive Gene Negative NSCLC

脑转移是非小细胞肺癌（non-small cell lung cancer, NSCLC）常见的转移部位和导致死亡的主要原因。酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）改善了驱动基因阳性NSCLC患者的生存，同时也为驱动基因阳性NSCLC脑转移患者带来了福音，然而对于驱动基因阴性脑转移NSCLC仍然缺少有效的治疗手段。近年来，免疫靶向治疗取得突破性进展，成为晚期NSCLC，尤其是驱动基因阴性患者一、二线治疗选择。免疫靶向治疗在NSCLC的特殊人群——脑转移患者尤其是驱动基因阴性患者中发挥怎样的作用已经成为研究者关注的焦点。本文将总结免疫靶向治疗在NSCLC脑转移尤其是驱动基因阴性患者中的研究进展，分析现有研究的局限和未来面临的挑战。

Abstract 4786: WSD0922: A novel, oral bioavailable, brain penetrable and reversible EGFRm+ inhibitor for the treatment of primary and metastatic brain tumors

Abstract Epidermal growth factor receptor (EGFR) is a cell surface protein that regulates normal cellular growth in tissues of epithelial origin. Des-regulated EGFR signaling (caused by mechanisms of overexpression, mutation, autocrine activation) contributes for oncogenesis by inducing cells proliferation and resisting apoptosis. In patients with NSCLC, activating mutants (EGFRm+) occur within exon 18-21 with increased EGFR activity. About 90% of these mutations (G719x, exon 19 deletions and exon 21 mutation) are sensitizing EGFRm+. EGFR TKIs have shown good performance in clinic for systemic NSCLC anchoring EGFRm+. However, up to 65% of NSCLC patients will develop brain metastasis (BM) ultimately. Current approved EGFR TKIs are not so effective for BM due to limited brain penetration as they are substrates of P-gp or BCRP, two main efflux transporters expressed on human BBB. In patients with GBM, the most common mutation is EGFRvIII (exon2-7 deletion) with an overall frequency of 25–64%. Current EGFR TKIs are ineffective in GBM treatment probably due to resistance caused by EGFRvIII as well as limited brain penetration. One-year survival of GBM patients is approximate 43%. Herein, we report a discovery of brain penetrable EGFR inhibitor WSD0922 for NSCLC BM and GBM with IC50 against EGFRm is <10nM. The ex-vivo antiproliferative GI50 in GBM tissues with EGFRvIII amplification is <100nM. WSD0922 is highly selective over other kinases. In-vitro MDCKII transfected cells and Caco-2 assays showed that WSD0922 is highly permeable and not a substrate of P-gp or BCRP. Preclinical CNS PK studies confirmed good brain penetration of WSD0922 with Kp,uu,brain close to unity. Treatment of mice bearing PC-9 (exon 19 del of NSCLC) in both subcutaneous (SC) and intracranial models with WSD0922 at 1-10mpk BID via PO resulted in dose dependent tumor growth inhibition (TGI) or regression with statistically significant survival benefit. Moreover, significant TGI for mice bearing GBM PDX model was achieved by treatment with WSD0922. No toxicity was observed in the animals during the treatment. Predicted human PK properties are very promising to offer sufficient target engagement in clinic. Taken together, our data provide a good rationale for WSD0922 to be developed toward clinic for the treatment of patients with BM of NSCLC or GBM harboring EGFRm+. Citation Format: Wei Zhong, Jinqiang Zhang, Zhihua Mu, Claire Sun. WSD0922: A novel, oral bioavailable, brain penetrable and reversible EGFRm+ inhibitor for the treatment of primary and metastatic brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4786.

Safety and efficacy of combining pembrolizmumab and dose escalation/fraction de-escalation SRS for melanoma and NSCLC brain metastasis: Preliminary results from arm a of a prospective pilot trial.

e21542Background: Brain metastases occur in 15–40% of patients (pts) with systemic cancers, such as lung and melanoma. The standard of care for brain metastases is radiation therapy. Methods to min...

Isolated metastasis of an EGFR-L858R-mutated NSCLC of the meninges: the potential impact of CXCL12/CXCR4 axis in EGFRmut NSCLC in diagnosis, follow-up and treatment.

Brain and leptomeningeal metastasis (LMM) of non-small cell lung cancer is still associated with poor prognosis. Moreover, the current diagnostic standard for LMM often yields false negative results and the scientific progress in this field is still unsatisfying.We present a case of a 71-year old patient with an isolated LMM. While standard diagnostics could only diagnose a cancer of unknown primary, the use of [68Ga]-Pentixafor-PET/CT (CXCR4-PET/CT, a radiotracer targeting CXCR4) and a liquid biopsy of the cerebrospinal fluid revealed the primary NSCLC. The detection of L858R-EGFR, a common driver mutation in NSCLC, enabled us to treat the patient with Afatinib and monitor treatment using [68Ga]-Pentixafor PET/CT. To estimate the impact of CXCR4 signaling and its ligands in NSCLC brain metastasis we looked at their expression and correlation with EGFR mutations in a primary and brain metastasis data set and investigated the previously described binding of extracellular ubiquitin to CXCR4.In conclusion, we describe a novel approach to improve diagnostics towards LMM and underline the impact of the CXCL12/CXCR4 axis in brain metastasis in a subset of NSCLC patients. We cannot confirm a correlation of CXCR4 expression with EGFR mutations or the binding of extracellular ubiquitin as previously reported.

OC-0495: Early PD-1 blockade improves disease control for NSCLC brain metastases treated with radiosurgery

OC-0495: Early PD-1 blockade improves disease control for NSCLC brain metastases treated with radiosurgery

PO-0722: Radiosurgery in association with immunotherapy for NSCLC brain metastases: feasibility and results

PO-0722: Radiosurgery in association with immunotherapy for NSCLC brain metastases: feasibility and results

Prognostic factors affecting survival after whole brain radiotherapy in patients with brain metastasized lung cancer

Background: Whole-brain radiotherapy (WBRT) has been the standard of care for multiple NSCLC brain metastases but due to its toxicity and lack of survival benefit, its use in the palliative setting is being questioned.Patient and methods: This was a single institution cohort study including brain metastasized lung cancer patients who received WBRT at Karolinska University Hospital. Information about Recursive Partitioning Analysis (RPA) and Graded Prognostic Assessment (GPA) scores, demographics, histopathological results and received oncological therapy were collected. Predictors of overall survival (OS) from the time of received WBRT were identified by Cox regression analyses. OS between GPA and RPA classes were compared by pairwise log rank test. A subgroup OS analysis was performed stratified by RPA class.Results: The cohort consisted of 280 patients. RPA 1 and 2 classes had better OS compared to class 3, patients with GPA <1.5 points had better OS compared to GPA≥ 1.5 points and age >70 years was associated with worse OS (p< .0001 for all comparisons). In RPA class 2 subgroup analysis GPA ≥1.5 points, age ≤70 years and CNS surgery before salvage WBRT were independent positive prognostic factors.Conclusions: RPA class 3 patients should not receive WBRT, whereas RPA class 1 patients should receive WBRT if clinically indicated. RPA class 2 patients with age ≤70 years and GPA ≥1.5 points should be treated as RPA 1. WBRT should be omitted in RPA 2 patients with age >70. In RPA 2 patients with age ≤70 years and GPA <1.5 points WBRT could be a reasonable option.

Individualized early death and long-term survival prediction after stereotactic radiosurgery for brain metastases of non-small cell lung cancer: Two externally validated nomograms

IntroductionCommonly used clinical models for survival prediction after stereotactic radiosurgery (SRS) for brain metastases (BMs) are limited by the lack of individual risk scores and disproportionate prognostic groups. In this study, two nomograms were developed to overcome these limitations. Methods495 patients with BMs of NSCLC treated with SRS for a limited number of BMs in four Dutch radiation oncology centers were identified and divided in a training cohort (n=214, patients treated in one hospital) and an external validation cohort n=281, patients treated in three other hospitals). Using the training cohort, nomograms were developed for prediction of early death (<3months) and long-term survival (>12months) with prognostic factors for survival. Accuracy of prediction was defined as the area under the curve (AUC) by receiver operating characteristics analysis for prediction of early death and long term survival. The accuracy of the nomograms was also tested in the external validation cohort. ResultsPrognostic factors for survival were: WHO performance status, presence of extracranial metastases, age, GTV largest BM, and gender. Number of brain metastases and primary tumor control were not prognostic factors for survival. In the external validation cohort, the nomogram predicted early death statistically significantly better (p<0.05) than the unfavorable groups of the RPA, DS-GPA, GGS, SIR, and Rades 2015 (AUC=0.70 versus range AUCs=0.51–0.60 respectively). With an AUC of 0.67, the other nomogram predicted 1year survival statistically significantly better (p<0.05) than the favorable groups of four models (range AUCs=0.57–0.61), except for the SIR (AUC=0.64, p=0.34). The models are available on www.predictcancer.org. ConclusionThe nomograms predicted early death and long-term survival more accurately than commonly used prognostic scores after SRS for a limited number of BMs of NSCLC. Moreover these nomograms enable individualized probability assessment and are easy into use in routine clinical practice.