Non-small Cell Lung Cancer Brain Metastases Research Articles

EXTH-45. DEVELOPMENT OF COMBINATION THERAPIES OF KRASG12C INHIBITOR ADAGRASIB IN PRECLINICAL MODELS OF BRAIN METASTASIS

Abstract BACKGROUND The highly selective KRASG12C inhibitor adagrasib (MRTX849) is FDA-approved for KRASG12C+ advanced non-small cell lung cancer (NSCLC). We recently provided preclinical evidence of MRTX849 brain penetration and activity, allowing MRTX849 inclusion in a national genomically-guided multicenter clinical trial (NCT03994796) for patients with brain metastasis (BM). However, multiple genetic alterations such as CDKN2A/B deletions, a common driver of NSCLC BM, can limit MRTX849 efficacy. Furthermore, although MRTX849 can sensitize extracranial tumors to immune checkpoint inhibitors (ICI), its intracranial immune benefit is unknown. Our objective was to improve MRTX849 monotherapy, evaluating combination therapies with CDK4/6 inhibitor abemaciclib or anti-PD-1 in preclinical models of BM. METHODS We tested in vitro sensitivity of MRTX849 and abemaciclib, using KRASG12C+, CDKN2A-deleted human lung cancer cell lines SW1573 and H2122. The efficacy of a 5-week treatment of MRTX849 and abemaciclib was evaluated in an intracranial NSCLC BM model in nude mice. Additionally, we utilized a syngeneic murine KrasG12C colorectal cancer BM model (CT26G12C) to test different MRTX849 dosages and assess its therapeutic effects in combination with anti-PD-1 antibody. RESULTS MRTX849 and abemaciclib demonstrated mild synergy in reducing cell viability in vitro. Combination treatment of MRTX849 and abemaciclib significantly improved both survival and intracranial tumor control relative to controls in SW1573 NSCLC BM model. In a syngeneic colorectal BM model, we identified benefit of a 2-week MRTX849 single treatment at 100 mg/kg (BID) in controlling brain tumor growth. In a dual subcutaneous intracranial BM model with CT26G12C, MRTX849 alone and combination therapy mediated complete regression of extracranial tumors. Although monotherapies reduced intracranial tumor growth, MRTX849 combination with anti-PD-1 resulted in a greater benefit. Both MRTX849 monotherapy and the combination therapy extended animal survival. CONCLUSIONS MRTX849 combination therapies with abemaciclib or anti-PD-1 demonstrate intracranial activity, inhibiting BM progression and prolonging survival, in preclinical models of KRASG12C+ BM.

The value of EGFR in individualized treatment for brain metastases in non-small cell lung cancer

The prognosis of brain metastases in non-small cell lung cancer (NSCLC) is poor, and patients with EGFR mutations are more likely to have brain metastases. The epidermal growth factor receptor (EGFR) gene status has changed the direction of treatment for NSCLC patients with brain metastases. The development of EGFR tyrosine kinase inhibitors (EGFR-TKI) has prolonged the survival time of NSCLC patients with brain metastases. The treatment of patients with NSCLC brain metastases should be individualized according to the clinical symptoms, tumor stage, and different gene mutation status. As cancer is heterogeneous at the molecular level, related biomarker studies looking for individualized characteristics are recommended.

Intracranial Control with Combined Dual Immune-Checkpoint Blockade and SRS for Melanoma and NSCLC Brain Metastases

It is unknown whether the use of dual immune-checkpoint inhibition (D-ICI) combined with stereotactic radiosurgery (SRS) affects local control of brain metastases (BMs). We sought to characterize the efficacy of SRS and D-ICI in patients with BMs in a large, single-institution cohort. Patients with melanoma and non-small cell lung cancer (NSCLC) BMs treated with SRS from January 1, 2016 to August 1, 2022 were evaluated. Patients were stratified by treatment with D-ICI versus single ICI (S-ICI). Concurrent ICI was defined as ICI given within four weeks of SRS. Local recurrence (LR), intracranial progression (IP), and overall survival (OS) were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. One thousand seven hundred four SRS-treated BMs from 288 patients met inclusion criteria. 55% of patients were symptomatic from their BMs at presentation. Median age, KPS, number of lesions, and SRS courses were 64 (Q1Q3:56-70.5), 90 (80-90), 2 (1-4), and 1 (1-2), respectively. One hundred twenty-eight (44%) melanoma and 160 (56%) NSCLC patients were included. 82 (28.5%), 129 (44.8%), and 77 (26.7%) patients were treated with D-ICI, S-ICI, or SRS alone. Median SRS dose, fractions, and PTV were 20 (Q1Q3:20-25), 1 (1-5), and 0.3cc3 (0.1-1.2). The median follow-up was 14.3 months. One hundred twenty-seven (7.45%) BMs recurred post-SRS and the median time to LR was 4.8 months (Q1Q3:3.0-9.2). On competing risk analysis, LR was significantly reduced with D-ICI (HR: 0.452, p = 0.0024), but not with S-ICI (HR: 0.693, p = 0.0596) compared to SRS alone. The 1-year LR was 3.77% (95% CI = 2.19-6.00), 6.8% (5.19-8.70), and 8.96% (6.48-11.93) with D-ICI, S-ICI, and SRS alone. The median time to IP was 4.1 months (Q1Q3 = 2.9-9.5). On competing risk analysis, IP was significantly reduced with D-ICI (HR = 0.638, p = 0.031), but not with S-ICI (HR = 0.756, p = 0.106) compared to SRS alone. 1-year IP was 40.05% (95% CI = 29.14-50.70), 51.86% (42.78-60.19), and 58.49% (46.30-68.84) with D-ICI, S-ICI, and SRS alone. Concurrent delivery of D-ICI and SRS significantly reduced IP (HR = 0.463, p = 0.0071), whereas other combinations of timing and ICI did not reach significance. Median OS was 11.9 months after SRS. On Kaplan Meier analysis, OS was significantly improved with D-ICI (HR = 0.616, 95% CI = 0.412-0.923, p = 0.019), but not with S-ICI (HR = 0.877, 95% CI = 0.633-1.217, p = 0.433) compared to SRS alone. Hospitalizations (p = 0.021) and immune-related adverse events (irAEs) (p<0.001) were increased with D-ICI. Any grade radiation necrosis (RN) was also increased with D-ICI (p = 0.013), but neurologic adverse events were comparable across cohorts (p = 0.572). D-ICI combined with SRS was associated with improved local control, intracranial control, and overall survival compared to SRS alone, whereas S-ICI was not associated with an improvement in these outcomes. However, D-ICI was also associated with increased risks of irAEs and RN.

Incidence and Risk Factors for Brain Metastases in Patients with Lung Cancer: A Systematic Review and Meta-Analysis

Brain metastases (BM) are a very common metastatic site in lung cancer, but the exact rate of metastasis is still controversial. Risk factors for BM development are also largely lacking, hampering personalized treatment strategies. This study aimed to identify the incidence and possible risk factors for BM in lung cancer. A systematic review, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guide-lines, was conducted using PubMed, Medline databases and Cochrane Library databases from inception until February 2023. Two investigators independently searched and selected literature, included in randomized controlled trials and cohort studies. Heterogeneity was assessed using the χ2 test and the I2 statistic. Significant heterogeneity was indicated by P <0.05 in Cochrane Q tests and a ratio greater than 40% in I2 statistics. The review is registered on PROSPERO, number: CRD42022370173. Forty-nine studies were included in the meta-analysis. The results showed that the incidence rate of BM in non-small cell lung cancer (NSCLC) was 0.24 (95% confidence interval [CI]: 0.23-0.25; I2 = 97.1%). The incidence rate in early NSCLC was 0.11 (95% CI: 0.10-0.13), locally advanced NSCLC was 0.32 (95% CI: 0.29-0.34), and advanced NSCLC was 0.37 (95% CI: 0.35-0.38). Lung adenocarcinoma was more prone to BM in NSCLC (risk ratio [RR] = 3.59, 95% CI: 1.97-6.54; P<0.001). The BM rate of NSCLC with EGFR mutation was also higher (hazard ratio [HR] = 1.49, 95% CI: 1.14-1.94; P = 0.004). Sex and smoking had no significant effect on the incidence of BM in NSCLC. Prophylactic Cranial Irradiation (PCI) could significantly reduce BM in NSCLC (HR = 0.36, 95% CI: 0.23-0.56; P<0.001), but chemotherapy had no obvious effect on decreasing the rate of BM (HR = 0.91, 95% CI: 0.54-1.54; P = 0.73). The incidence rate of BM in small cell lung cancer (SCLC) was 0.28 (95% CI: 0.27-0.30; I2 = 95.9%), and 0.23 (95% CI: 0.20-0.25) in the limited-stage SCLC. Older age (≥65) (HR = 0.70, 95% CI: 0.54-0.92; P = 0.01) were associated with less BM in SCLC. A higher T stage (≥T3) (HR = 1.72, 95% CI: 1.16-2.56; P = 0.007) was a significant risk factor for BM, while sex, smoking dose were not. PCI could also significantly decreased BM in SCLC (HR = 0.47, 95% CI: 0.38-0.58; P<0.001). This study is the first meta-analysis of BM incidence rate in lung cancer, and further explores the factors affecting BM, providing some suggestions for clinical decision-making of BM prevention in patients with lung cancer.

Stereotactic Radiosurgery (SRS) for Brain Metastasis in the Era of Evolving Systemic Treatment (Immunotherapy or Targeted Therapy) in Patients with Non-Small Cell Lung Cancer (NSCLC)

With evolving role for targeted and immunomodulatory agents, the survival rate of NSCLC has been improved even with brain metastasis. This study analyzed the outcome of brain metastasis treated with SRS in conjunction with immunotherapy and target therapy as well as chemotherapy. After obtaining institutional review board (IRB) approval, 229 patients with NSCLC with brain metastasis treated with SRS at our institution were retrospectively reviewed from 2008-2021. Demographic information (e.g., age, sex, race), performance status (PS), extracranial metastasis (ECM), sequence of systemic therapy (SST) and surgery for BM (SBM) were reviewed and collected. Overall survival (OS) and intracranial recurrence free survival (ICRFS) were analyzed using the Kaplan-Meier method/Cox regression, and time to each event were measured from the date of the first SRS treatment. All statistical analyses were performed using SAS version 9.4 (Carey, NC). Of the 229 pts, the median age of pts at first SRS was 64.1 (range, 34.8- 83.0 years). 38.6% were biomarker (EGFR/ALK/ROS/PDL1) positive, and 30% were PDL1 positive. 28.8 % had surgery before SRS. The median number of SRS was 1 (range, 1 - 6), and 10 patients received salvage whole brain radiation therapy (WBRT) after SRS. With a median follow-up of 9.6 months (mo), median OS and ICRFS were 14.0 mo and 8.1 mo respectively. On univariate outcome analysis, PS, ECM, SBM and PDL1 were associated with OS while biomarker, SBM and SST were closely related to ICRFS. Pts with poor PS had worse median OS of 8.3 mo compared to 29.1 mo with good PS (p = 0.001). Median OS for no ECM vs. ECM were 20.7 mo vs. 9.6 mo respectively (p = 0.002). Patients who underwent SBM initially had better median OS of 28.7 mo compared to 9.9 mo without SBM (p<0.001). There was a trend of significant impact of positive PDL1 on median OS (21.1 mo vs. 11.7 mo, p = 0.06). Similarly, SBM was found closely related to ICRFS with median ICRFS of 8.1 mo vs. 4.9 mo for those with and without SBM respectively. Both positive biomarker (13.1 mo vs. 6.4 mo, P = 0.17) and SRS first SST (8.1 mo vs. 4.9 mo, p = 0.11) demonstrated a trend of increased median ICRFS. On multivariable analyses, no SBM was linked with worse OS (HR: 1.85; 95% CI:1.15 - 2.97; p = 0.01) and decreased ICRFS (HR: 1.65; 95% CI: 1.09 - 2.51; p = 0.02). Of 31 pts with information on cause of death, 3.2% died from brain metastasis related cause. This study demonstrated effective treatment of brain metastasis in NSCLC with multiple SRSs, especially for patients with favorable prognosis. Of noticed there was only a small number of patients received salvage WBRT and most patients didn't die from brain metastasis related progression.

Efficacy and Safety of PD-1/PD-L1 Inhibitors Combined with Radiotherapy in Patients with Brain Metastases Caused by Non-Small Cell Lung Cancer: A Multi-Center Retrospective Analysis

To investigate efficacy and safety of PD-1/PD-L1 inhibitors plus radiotherapy in patients that brain metastases (BMs) from non-small cell lung cancer (NSCLC). All 234 eligible patients were divided into PD-1/PD-L1 inhibitors plus intracranial radiotherapy (BM-RT) group and immunotherapy (non-BM-RT) group. 144 patients in BM-RT group were divided into patients received extracranial radiotherapy for NSCLC (extra-RT) group and had not (non-extra-RT) group. According to the Lung Immune Prognostic Index (LIPI), patients were stratified into good, intermediate, and poor groups. The toxicity was assessed with Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Kaplan-Meier method and Log-rank test were used to analyze intracranial progression-free survival (iPFS) and overall survival (OS). The median iPFS (11.6 months vs. 9.9 months, P = 0.001) and median OS (17.3 months vs. 14.6 months, P = 0.029) had a significant difference in BM-RT group and non-BM-RT group. Meanwhile, median iPFS (15.7 months vs. 10.5 months, P<0.001) and median OS (20.2 months vs. 15.1 months, P = 0.024) in extra-RT group were longer than non-extra-RT group. The median iPFS (12.9 months vs. 10.4 vs. 8.4 months, P = 0.001) and median OS (20.1 months vs. 16.7 months vs. 12.6 months, P = 0.025) were longer in good group than intermediate group and poor group in LIPI. Our data suggested there was a significant difference in iPFS and OS with or without radiotherapy in patients of BMs from NSCLC, and with safety profiles. LIPI helped predict prognosis of BMs in NSCLC.

Long noncoding RNA LGALS8-AS1 promotes angiogenesis and brain metastases in non-small cell lung cancer.

Brain metastases (BM) are associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). Considering that, LGAS8-AS1-mediated progression of BM was probed in NSCLC. The clinical characteristics of 60 NSCLC patients (30 without BM and 30 with BM) were analyzed. NSCLC patients with BM had higher levels of LGALS8-AS1 than NSCLC patients without BM. Depleting LGALS8-AS1 prevented NSCLC cell proliferation, migration, invasion, and angiogenesis in vitro, and NSCLC tumorigenesis and BM in vivo. LGALS8-AS1 targeted miR-885-3p to mediate Fascin actin-bundling protein 1 (FSCN1) expression. Restoring miR-885-3p inhibited NSCLC growth, angiogenesis, and BM, and FSCN1 induction rescued the performance of LGALS8-AS1 depletion on NSCLC cells. Our results provide new insights into LGALS8-AS1-mediated NSCLC metastasis and suggest that LGALS8-AS1 may be a useful biomarker for identifying NSCLC with metastatic potential.

DO GENOMIC ALTERATIONS INflUENCE THE DEVELOPMENT OF BRAIN METASTASES IN ADVANCED AND METASTATIC NON-SMALL CELL LUNG CANCER? A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract AIMS Establish prevalence at diagnosis, and incidence of BM in patients with advanced and metastatic non-small cell lung cancer (NSCLC), stratified by genomic alterations. METHOD A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines (PROSPERO ID CRD42022315915). Three databases were searched (Search date 30th April 2022). Prevalence at diagnosis, and per-patient year incidence of brain metastases were obtained, including patients with EGFR, ALK, KRAS, ROS1, RET, and other genomic alterations. Pooled incidence rates were calculated using random effects models. RESULTS Of 960 articles identified, 65 were included (24,784 patients). The combined BM prevalence at diagnosis was 28.6% (45 studies, 95% Confidence Interval [CI] 26.1-31.0). Median follow-up was 24 months (Interquartile range [IQR] 16-36 months). The combined incidence of BM development was 10.8% per year (40 studies, 95% CI 9.2- 12.6). The per-year incidence of new BM was 15.6%/year in the EGFR +ve group (16 studies, 95% CI 11.4-21.2), 17.0% in the ALK+ve group (7 studies, 95% CI 11.3-25.8), 9.8% in the KRAS +ve group (4 studies, 95% CI 5.5-17.5), 12.5% in the ROS1 +ve group (3 studies, 95% CI 5.7-27.6), and 11.8% in the RET +ve group (2 studies, 95% CI 8.0-17.5). Combined overall prevalence was 55.0% (21 studies, IQR 44.2-67.8). CONCLUSIONS This systematic review indicates a high rate of brain metastases in NSCLC and is the first and only study to describe incidence, stratified by genomic alterations. This will have a major clinical impact by stratifying brain imaging at staging and follow-up by patient subgroup, particularly in ALK and EGFR mutations.

P07.13.B A RANDOMIZED STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER (LIMITLESS)

Abstract BACKGROUND The blood-brain barrier (BBB) limits the efficacy of systemic therapies for brain metastases (BM), for which non-small cell lung cancer (NSCLC) is the most common etiology. BBB disruption (BBBD) has been demonstrated, in preclinical models, to improve systemic drug delivery for BM. Low-intensity focused ultrasound (LIFU) results in non-invasive BBBD synergistically with intravenously (IV) administered microbubble oscillators. This randomized controlled trial (RCT) aims to determine the safety and efficacy of LIFU-mediated BBBD for NSCLC BM with immunotherapy. METHODS LIMITLESS is an ongoing prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in 2:1 ratio. Included patients have age ≥18 years, normal organ function, Karnofsky Performance Status ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting measurable disease criteria as per response assessment in neuro-oncology for BM (RANO-BM). Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). These patients undergo pre-treatment MRI brain, followed by IV administration of oscillating microbubbles for enhanced sonication. MR-guided BBBD is then performed using a 220 kHz LIFU device with real-time acoustic feedback for maintaining effective cavitation. Pembrolizumab is infused immediately thereafter, and a repeat MRI is done 24-48 hours later to confirm the closure of BBB each cycle. The primary study endpoint is the overall objective response rate (ORR) at 6 months, as assessed using RANO-BM criteria. Using a Bayesian design for power analysis, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for a total sample size of N=96, 64 subjects in LIFU and 32 in the control arm, for 80% power using a two-sided chi-square test with an alpha of 0.05. For the upper-bound estimate ORR of 45% in the LIFU arm and 30% in the control arm, the study needs N=369 subjects; 246 in the LIFU arm and 123 in the control arm. The secondary outcomes are the best objective response rate and median time-to-response per treatment arm. The exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life. RESULTS Patient enrollment commenced in 2022. CONCLUSION Findings from this trial will be critical to liquid biopsy in brain metastases (Clinical trial information: NCT05317858).

A meta-analysis for the efficacy and safety of icotinib combined with radiotherapy in treating brain metastases of non-small cell lung cancer.

Currently, the therapies for brain metastases of non-small cell lung cancer (NSCLC) mainly include whole brain radiotherapy and icotinib. For exploring the efficacy and safety of radiotherapy and icotinib, a meta-analysis was performed based on a series of data. A systematic search was performed on PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure and Wanfang Database. The search time was set from the database establishment to December, 2022. All randomized controlled trials evaluating the efficacy and safety of whole brain radiotherapy alone or in combination with icotinib for whole brain metastases of NSCLC were included in our meta-analysis. Clinical outcomes and adverse reactions were analyzed using Stata17.0 software. Finally, 10 clinical studies were enrolled in this meta-analysis, including 717 patients. Briefly, compared with radiotherapy alone, icotinib combined with radiotherapy increased response rate [relative ratio (RR) = 1.240; 95% confidence interval (CI) (1.141, 1.348); P < .001] and disease control rate (RR = 1.240, 95% CI [1.141,1.348], P < .001). Besides, according to the outcomes of adverse reaction assessment exhibited, there were no significant differences between the 2 group patients in the incidence of rash (RR = 1.536, 95% CI [0.694, 3.402], P = .290), adverse reaction in gastrointestinal tract (RR = 1.060, 95% CI [0.792, 1.419], P = 1.419), hepatic injury (RR = 1.541, 95% CI [0.798,2.975], P = .198) and leukopenia (RR = 1.182, 95% CI [0.787, 1.777], P = .421). However, the patients receiving combination treatment showed much longer progression free survival than those receiving radiotherapy alone (standardized mean difference = 1.559; 95% CI [0.699, 2.419]; P < .001). Icotinib combined with radiotherapy can significantly short-term and long-term efficacy of NSCLC patients with brain metastases but not increase adverse reactions.

Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis

Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we show CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations are noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression.

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.

BSBM-09 IN VIVO CRISPR ACTIVATION SCREEN IDENTIFIES ß-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 (BACE1) AS A DRIVER OF NON-SMALL CELL LUNG CANCER BRAIN METASTASIS

Abstract Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumour and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome wide CRISPR activation (CRISPRa) screen to identify molecular drivers of brain metastasis from a NSCLC patient-derived xenograft model. We identified activation of the Alzheimer’s disease associated ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) led to a significant increase in brain metastasis. BACE1 is highly expressed in NSCLC and patients with BACE1 expressed in their metastatic brain tumour survived for shorter periods. Genetic loss with CRISPR-Cas9 or pharmacological inhibition of BACE1 with MK-8931 decreased cell proliferation and sphere forming capacity in vitro. Furthermore, BACE1 knockout and MK-8931 treatment blocked brain metastasis in vivo. Mechanistically, we identified BACE1 activation lead to downstream signalling through MEK and ERK. Together our data highlights the power of in vivo CRISPR screening to identify novel molecular drivers and potential therapeutic targets of NSCLC brain metastasis.

Immune checkpoint inhibitors for the treatment of non-small cell lung cancer brain metastases.

Lung cancer has the highest risk of brain metastasis (BM) among all solid carcinomas. The emergence of BM has a significant impact on the selection of oncologic treatment for patients. Immune checkpoint inhibitors (ICIs) are the most promising treatment option for patients without druggable mutations and have been shown to improve survival in patients with non-small cell lung cancer (NSCLC) BM in clinical trials with good safety. Moreover, ICI has shown certain effects in NSCLC BM, and the overall intracranial efficacy is comparable to extracranial efficacy. However, a proportion of patients showed discordant responses in primary and metastatic lesions, suggesting that multiple mechanisms may exist underlying ICI activity in BM. According to studies pertaining to tumor immune microenvironments, ICIs may be capable of provoking immunity in situ. Meanwhile, systematic immune cells activated by ICIs can migrate into the central nervous system and exert antitumor effects. This review summarizes the present evidence for ICI treatment efficacy in NSCLC BM and proposes the possible mechanisms of ICI treatment for NSCLC BMs based on existing evidence.

Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer: analysis of the safety cohort for non-randomized, open-label, phase I/II trial

BackgroundUp to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There...

Genetic profiling of circulating cell-free DNA from cerebrospinal fluid and paired plasma in ALK-positive lung cancer with brain metastases.

This study used next-generation sequencing (NGS) to investigate the genetic profiles in cerebrospinal fluid (CSF), plasma, and tumor tissue to explore alternative detection methods for anaplastic lymphoma kinase (ALK) rearrangement status and potential resistance mechanisms to ALK inhibitors. From January 2016 to January 2021, 19 non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) and ALK-positive primary tumors were enrolled at Beijing Chest Hospital. CSF, plasma, and primary tumor samples from patients with BMs of NSCLC were tested using NGS with a 168-gene panel. The intracranial response and prognosis were also investigated. The study included 19 patients, seven females and 12 males, aged between 29 and 68 (median age 44). CSF cytology was negative in all cases. NGS results showed ALK fusion genes detected in 26.3% (5/19) of CSF cfDNA samples, 78.9% (15/19) of plasma samples, and 89.5% (17/19) of tumor samples from ALK-positive patients. ALK-positive CSF samples had significantly higher allele fractions in CSF cfDNA compared with the other two sample types. In five patients with ALK-positive in CSF, after receiving ALK inhibitors ± local treatment, one case achieved an intracranial complete response, and two had an intracranial partial response. In CSF samples, the intracranial median progression-free survival was 8.0 and 18.0 months for ALK-positive (n = 5) and ALK-negative (n = 14), respectively (p = 0.077). CSF may serve as a liquid biopsy for ALK-positive lung cancer with BMs by detecting cfDNA within CSF to characterize driver and resistant genes.

Prediction of brain metastases progression and overall survival in patients with metastatic non-small cell lung cancer treated by immune checkpoint inhibitors using a radiomic model.

e21169 Background: Brain metastases (BMs) incidence is high in patients with metastatic non-small cell lung cancer (NSCLC). Immune Checkpoints Inhibitors (ICIs) are now standard of care for metastatic NSCLC in the first-line or beyond settings. However, less than half of patients will have a tumor response, and the determinants of BMs response to ICIs remain unknown. This study aims to evaluate the value of radiomics to predict control/progression of BMs at a lesion level, and outcomes at a patient level in the BM+ NSCLC population treated by ICIs. Methods: We conducted a retrospective multicenter (5 European centers) study including consecutive patients with NSCLC BMs and available baseline MRI before ICIs (evaluation cohort) or chemotherapy (control cohort) with a 2:1 ratio, between 2011 and 2021. After modified RANO (Response Assessment in Neuro-Oncology) assessment of individual BMs, we developed a radiomic model to predict BMs control/progression to ICIs at the first brain follow-up imaging. The ICIs cohort was split into two datasets used for (i) model training with 5-fold cross-validation and (ii) model testing. The Chemotherapy cohort was used to ensure the specificity of our model to ICIs-treated patients. Results: Ninety-four and 49 patients were included in the ICIs and Chemotherapy cohorts respectively, of which 56 (59.6%, N = 227 BMs) and 39 (79.6%, N = 192 BMs) patients had available brain follow-up imaging. The ICIs cohort was specifically enriched in radiomic features which were significantly associated to BMs progression. Our final model, based on extreme gradient boosting (xgboost) on BMs &gt; 10mm from the training set (N = 39 BMs), could predict individual BMs progression to ICIs with an area under curve (AUC) of 0.77 (p-value = 0.029, 95% CI [0.56-0.98]) in the test set (N = 20 BMs). We further generated a radiomic score to stratify BM+ NSCLC ICIs-treated patients between High-Risk or Low-Risk groups according to the predicted individual BMs progression. High-risk patients were associated with worse overall survival (OS) (median OS of 6.3 months, 95% CI [3.02-10.49]) compared to Low-risk patients (median OS of 11.87 months, 95% CI [7.02-21.90], p = 0.042). The prognostic value of the radiomic score on OS was validated in a multivariate analysis in the ICIs cohort (Table). Conclusions: To our knowledge, this is the first study to explore the value of radiomics in the prediction of BMs response to immunotherapy. Prospective evaluation will confirm the generalizability of our model in clinical practice.[Table: see text]

Efficacy of PD-1 Inhibitors Combined with Anti-Angiogenic Therapy in Driver Gene Mutation Negative Non-Small-Cell Lung Cancer with Brain Metastases.

Anti-angiogenic therapy has proven effective in non-small-cell lung cancer (NSCLC) patients. The purpose of this study was to evaluate the efficacy of programmed cell death protein 1 (PD-1) inhibitors combined with anti-angiogenic therapy in patients with driver gene mutation negative NSCLC and brain metastases (BMs). A retrospective analysis was performed on NSCLC BMs in patients without driver gene mutations who received PD-1 inhibitors. Two groups, receiving either PD-1 inhibitor monotherapy or PD-1 inhibitor plus anti-angiogenesis therapy, were identified. The primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS). The secondary endpoints were safety, intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). 113 NSCLC patients were included, 51 (45.1%) in the PD-1 inhibitor monotherapy group and 62 (54.9%) in the PD-1 inhibitor plus anti-angiogenesis therapy group. The median follow-up time was 26.2 months. OS was higher in the combination therapy cohort than in the monotherapy cohort (OS: 21.4 vs. 11.8 months; p = 0.004), with no significant difference in iPFS (p = 0.088). Moreover, the PD-1 inhibitor + anti-angiogenic therapeutic regimen exhibited the preferred iDCR (p = 0.005) but not the iORR (p = 0.121). There was no significant difference in the incidence of grade 3-4 adverse events between the two groups. In multivariate Cox regression analysis, PD-1 inhibitor therapy combined with anti-angiogenic treatment (p = 0.003) was an independent prognostic indicator of OS. Combining PD-1 inhibitor therapy with anti-angiogenic treatment significantly improves the OS of driver gene mutation negative NSCLC patients with BMs.

Metabolic and textural changes in the brain of non‐small cell lung cancer patients: A total‐body positron emission tomography/computed tomography study

AbstractBackgroundBrain metastases are frequent complications for lung cancer patients. However, changes in the brain of lung cancer patients have received little attention. We aimed to explore whether alterations in brain glucose uptake and brain texture occur in non‐small cell lung cancer (NSCLC) patients and to investigate associations between brain alterations and NSCLC via the uEXPLORER positron emission tomography/computed tomography (PET/CT) system.MethodsIn total, 105 participants were enrolled, including 55 healthy controls and 50 NSCLC patients. Images were acquired using the PET/CT system. Standardized uptake values normalized by lean body mass were calculated as indicators of glucose uptake. Correlation analysis was conducted between aberrant brain glucose uptake, glucose uptake of cancer lesions, and concentrations of serum lung cancer markers. Radiomics was used to investigate whether features extracted from regions with altered brain glucose uptake could serve as biomarkers of lung cancer progression.ResultsCompared with healthy controls, NSCLC patients showed decreased standardized uptake values normalized by lean body mass in the left insula, medial frontal gyrus, and anterior cingulate. Correlation analysis demonstrated that glucose uptake of the anterior cingulate was negatively correlated with serum lung cancer marker concentrations. Radiomic features on PET/CT images of the above brain regions could classify NSCLC patients and healthy controls with an accuracy of 79%.ConclusionsNSCLC patients exhibited altered brain glucose uptake and changes in brain textures. These alterations may reflect alterations in behavioral domains in NSCLC and may be related to altered lung‐brain interactions and potential brain metastasis of NSCLC.

The abscopal effect: inducing immunogenicity in the treatment of brain metastases secondary to lung cancer and melanoma.

The phenomenon of radiation therapy (RT) causing regression of targeted lesions as well as lesions outside of the radiation field is known as the abscopal effect and is thought to be mediated by immunologic causes. This phenomena has been described following whole brain radiation (WBRT) and stereotactic radiosurgery (SRS) of brain metastasis (BM) in advanced melanoma and non-small-cell lung cancer (NSCLC). We systematically reviewed the available literature to identify which radiation modality and immunotherapy (IT) combination may elicit the abscopal effect, the optimal timing of RT and IT, and potential adverse effects inherent to the combination of RT and IT. Using PRISMA guidelines, a search of PubMed, Medline, and Web of Science was conducted to identify studies demonstrating the abscopal effect during treatment of NSCLC or melanoma with BM. 598 cases of irradiated BM of melanoma or NSCLC in 18 studies met inclusion criteria. The most commonly administered ITsincluded PD-1 or CTLA-4 immune checkpoint inhibitors (ICI), with RT most commonly administered within 3 months of ICI. Synergy between ICI and RT was described in 16 studies including evidence of higher tumor response within and outside of the irradiated field. In the 12 papers (n = 232 patients) that reported objective response rate (ORR) in patients with BM treated with RT and concurrent systemic IT, the non-weighted mean ORR was 49.4%; in the 5 papers (n = 110 patients) that reported ORR for treatment with RT or IT alone, the non-weighted mean ORR was 27.8%. No studies found evidence ofsignificantly increased toxicity in patients receiving RT and ICI. The combination of RT and ICIs may enhance ICI efficacy and induce more durable responses via the abscopal effect in patients with brain metastases of melanoma or NSCLC.