Cell Lung Cancer Brain Metastases Research Articles

Immunotherapy in association with stereotactic radiotherapy for non-small cell lung cancer brain metastases: results from a multicentric retrospective study on behalf of AIRO.

To define efficacy and toxicity of Immunotherapy (IT) with stereotactic radiotherapy (SRT) including radiosurgery (RS) or hypofractionated SRT (HFSRT) for brain metastases (BM) from non-small cell lung cancer (NSCLC) in a multicentric retrospective study from AIRO (Italian Association of Radiotherapy and Clinical Oncology). NSCLC patients with BM receiving SRT + IT and treated in 19 Italian centers were analyzed and compared with a control group of patients treated with exclusive SRT. One hundred patients treated with SRT + IT and 50 patients treated with SRT-alone were included. Patients receiving SRT + IT had a longer intracranial Local Progression-Free Survival (iLPFS) (propensity score-adjusted P = .007). Among patients who, at the diagnosis of BM, received IT and had also extracranial progression (n = 24), IT administration after SRT was shown to be related to a better overall survival (OS) (P = .037). A multivariate analysis, non-adenocarcinoma histology, KPS = 70 and use of HFSRT were associated with a significantly worse survival (P = .019, P = .017 and P = .007 respectively). Time interval between SRT and IT ≤7 days (n = 90) was shown to be related to a longer OS if compared to SRT-IT interval >7 days (n = 10) (propensity score-adjusted P = .008). The combined treatment was well tolerated. No significant difference in terms of radionecrosis between SRT + IT patients and SRT-alone patients was observed. The time interval between SRT and IT had no impact on the toxicity rate. Combined SRT + IT was a safe approach, associated with a better iLPFS if compared to exclusive SRT.

Phase 1, 2 trial of concurrent anti-PD1 and stereotactic radiosurgery for melanoma and non-small cell lung cancer brain metastases (NCT02858869).

2022 Background: The safety and efficacy of concurrent pembrolizumab (anti-PD1) and stereotactic radiosurgery (SRS) for brain metastases (BM) is unknown. Methods: Patients with melanoma or NSCLC, 1-10 brain metastases, ≥ 1 extra-cranial lesion, age ≥ 18, and ECOG 0-1 were treated with anti-PD1 every 3 weeks. SRS was administered 1-2 days after starting anti-PD1. SRS used three different radiation arms: Arm A used 6 Gray (Gy) in 5 fractions (fx), Arm B used 9 Gy in 3 fx, and Arm C used 18-21 Gy in single fx. Primary endpoint was grade 3 CNS toxicity at 3 months (CTCAE v 4.0). Secondary endpoints were overall survival (OS), local control (LC) within the SRS field, intra-cranial progression free survival (IC-PFS), extra-cranial progression free survival (EC-PFS), rate of extra-cranial clinical benefit, and immunological changes. OS, LC, IC-PFS, and EC-PFS were estimated using the Kaplan-Meier method, and covariates were compared using log-rank tests. 95% confidence intervals for 6-month and 12-month were estimated using Greenwood’s formula. Results: 25 patients were treated from 2016 until 2020. The mean age was 61. The mean number of CNS lesions was 2.7. The mean number of extra-cranial lesions was 2.5. Six were enrolled on Arm A, 12 on Arm B, and 7 on Arm C. 21 had melanoma. 4 had NSCLC. Of the melanoma, 8 were BRAF-, 10 were BRAF+, and 3 had unknown mutation status. 12 patients (48%) had progressed on prior immunotherapy and/or other oncological therapies. The trial met its primary endpoint, with no grade 3 CNS toxicity at 3 months. Two patients (8%) experienced ≥ Grade 3 anti-PD1 related toxicity, and no grade 5 toxicity was noted. The median OS was 32.8 months. The 6 and 12 month OS were 79.1% (56.5-90.8%) and 67.8% (43.3-83.5%), respectively. The 1 year OS was similar between previously treated and treatment naïve patients (71.8% vs. 65.6%), suggesting some role for SRS in overcoming therapy resistance. However, with longer follow-up, the OS trended worse (p=0.07) for previously treated patients. LC was 95.7% (72.9-99.4%) at 6 and 12 months. IC-PFS at 6 months was 69.1% (45.8-83.9%), and at 12 months was 57.5% (33.7-75.5%). The EC-PFS at 6 and 12 month was 54.5% (32.1-72.4%) and 43.6% (22.3-63.2%), respectively. Clinical benefit, which was defined as a best overall response of stable disease or better according to RECIST 1.1, occurred in 12 patients (48%). No outcome differences were noted amongst the three different SRS arms. 70% of the patients demonstrating early activation (within 3 weeks of starting SRS/anti-PD1) of CD8+PD1+Ki67+ T cells demonstrated a clinical benefit. 100% of patients that failed to show early activation of CD8+PD1+Ki67+ T cells progressed. Conclusions: Concurrent pembrolizumab (Anti-PD-1) and SRS is safe and effective. Early activation of CD8+PD1+Ki67+ T cells correlates with improved outcome. Further trials testing pembrolizumab and SRS are justified. Clinical trial information: NCT02858869.

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]

Outcomes of KRAS mutated, EGFR mutated, ALK mutated and wildtype patients in non-small cell lung cancer brain metastases.

e21028 Background: Non-small cell lung cancer (NSCLC) is the most common primary tumor leading to brain metastases. Multiple genetic markers have been profiled in NSCLC patients for potential targeted therapies. EGFR is mutated in up 50% of NSCLCs, while ALK is mutated in around 4-7%. KRAS is the most commonly overexpressed marker, seen in up to 85% of all lung cancers. In this retrospective study, we evaluated the overall survival (OS) and progression-free survival (PFS) between NSCLCBM patients with KRAS mutations, ALK mutations, EGFR mutations, and wildtype. Methods: NSCLCBM patients diagnosed between 2010 and 2019 were analyzed. We collected information regarding molecular marker status, systemic therapies, and date of progression. We defined OS as the date of diagnosis of brain metastases to the date of last follow-up or death. OS and PFS were estimated by the Cox proportional model. Results: We found a total of 2989 NCSLCBM patients, 184 were KRAS mutated, 68 had an ALK gene rearrangement, 184 were EGFR mutated, and 1469 were wildtype. The respective median age was 64.3 years, 64.5 years, 58.2 years, and 64.2 years. Females made up 61.8% of KRAS-positive, 51.8% of ALK-positive, 63% of EGFR-positive, and 46.4% of wildtype patients. The median OS (mOS) in patients who were KRAS-positive, ALK-positive, EGFR-positive, and wildtype were 43.3 months, 119.2 months, 57.9 months, and 33.1 months, respectively. The median PFS (mPFS) for the same cohort was 38.0 months, 112.4 months, 55.3 months, and 30.5 months, respectively. ALK-positive patients showed statistically significant mOS (p-value (p) < 0.001) and mPFS (p = 0.002) when compared to EGFR-positive, KRAS-positive, and wildtype patients. Conclusions: Molecular mutations serve as both prognostic predictors and alternative targeted therapies for NSCLCBM treatment. Our retrospective study showed improved mOS and mPFS in NSCLCBM patients with ALK rearrangements when compared to patients with EGFR mutations, KRAS mutations, and the wildtype. While these results looked at patient outcomes with specific tumor markers, further investigation needs to be done regarding outcomes of specific therapies in each cohort, as well as, intracranial lesion response.

Abstract PO-041: An immunologic niche of antigen presenting cells and stem-like CD8+ T-cells is present in non-small cell lung cancer brain metastases

Abstract Background: Non-small cell lung cancer (NSCLC) patients with brain metastases have a very poor prognosis. The first line treatments for NSCLC brain metastases are typically surgery and pre- or post-operative stereotactic radiosurgery (SRS) or SRS alone. However, subsequent intra-cranial failure and death is common. Importantly, we have previously shown that a unique immune niche in genitourinary malignancies correlates with the risk for disease recurrence. Accordingly, here we investigated whether this immune niche was present in brain metastases, whether it correlated with patient outcomes, and whether it was modulated by SRS. Methods: Formalin fixed paraffin embedded brain metastases were stained by immunofluorescence for CD8, PD-1, TCF-1, MHC-II and DAPI. Following successful image acquisition using fluorescent whole slide scanning, we used a custom quantitative analysis pipeline to measure the cellularity, relative cellular locations, local cellular density, and marker staining intensity. Results: We identified immune niches consisting of both stem-like TCF-1+ CD8+ T-cells and antigen presenting cells (MHC-II+) in brain metastases. TCF-1+ CD8+ T-cells were found at in areas of higher MHC-II+ cell density than the TCF-1 CD8+negative T-cells. The amount of tumor issue occupied by immune niches correlated with TCF1+ CD8+ T-cell infiltration, as well as with total CD8+ T-cell and MHC-II+ cell infiltration. Importantly, we found that higher MHC-II+ cell density correlated with longer overall survival in this cohort of patients. Additionally, we found this immune niche is preserved following pre-operative SRS. Conclusions: Our study is the first to demonstrate stem-like CD8+ T-cells in brain metastases and that these cells form an immune niche similar to those described extra-cranial tumor sites. Additionally, we report that the immune niche is preserved following SRS, which is highly clinically relevant to the use of combinatorial strategies between SRS and checkpoint blockade. Citation Format: Caroline S. Jansen, Luke del Balzo, Roshan Prabhu, Suzanna Logan, Prasanthi Chappa, Kirtesh Patel, Scott Wilkinson, Ross Lake, Hui-Kuo G. Shu, Jim Zhong, Vishal Dhere, Jeffrey Olson, Adam G. Sowalsky, Mohammad K. Khan, Haydn T. Kissick, Zachary S. Buchwald. An immunologic niche of antigen presenting cells and stem-like CD8+ T-cells is present in non-small cell lung cancer brain metastases [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-041.

Neutrophil to lymphocyte ratio influences impact of steroids on efficacy of immune checkpoint inhibitors in lung cancer brain metastases

Steroids are often utilized to manage patients with non-small cell lung cancer brain metastases (NSCLCBM). Steroids and elevated neutrophil-to-lymphocyte ratio (NLR) have been associated with decreased overall survival (OS) in patients treated with immune checkpoint inhibitors (ICI). We retrospectively investigated patients treated with ICI after the diagnosis of NSCLCBM at a single tertiary care institution examing the impact of steroids and NLR. Overall survival (OS) and intracranial progression-free survival (PFS) were analyzed. 171 patients treated with ICI for NSCLCBM were included. Thirty-six received steroids within 30 days of the start of ICI, and 53 patients had an NLR ≥ 5 before the start of ICI. Upfront steroids was associated with decreased OS on multivariable analysis (median OS 10.5 vs. 17.9 months, p = .03) and intracranial PFS (5.0 vs. 8.7 months, p = .045). NLR ≥ 5 was indicative of worse OS (10.5 vs. 18.4 months, p = .04) but not intracranial PFS (7.2 vs. 7.7 months, p = .61). When NLR and upfront steroids are modeled together, there is a strong interaction (p = .0008) indicating that the impact of steroids depended on the patient’s NLR. In a subgroup analysis, only in patients with NLR < 4 was there a significant difference in OS with upfront steroids (26.1 vs. 15.6 months, p = .032). The impact of steroids on the efficacy of ICI in patients with NSCLCBM is dependent on the patient's NLR underscoring its importance in these patients. Patients with a low NLR, steroid use decreases the efficacy of ICI. These results can inform clinicians about the impact of steroids in patients treated with ICI.

Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases

Non-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible. Herein we report on a direct-from patient-derived xenograft (PDX) model system of NSCLC brain metastases with genomic annotation useful for translational and mechanistic studies. Both heterotopic and orthotopic intracranial xenografts were established and RNA and DNA sequencing was performed on patient and matching tumors. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples with more than more than 95% of variants detected being retained in the matched PDXs. PDXs demonstrated response to radiation, response to selumetinib in tumors harboring KRAS G12C mutations and response to savolitinib in a tumor with MET exon 14 skipping mutation. Savolitinib also demonstrated in vivo radiation enhancement in our MET exon 14 mutated PDX. Early passage cell strains showed high consistency between patient and PDX tumors. Together, these data describe a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.

RO01.01 Prospective Evaluation of Ipilimumab and Nivolumab in Patients with Non-Small Cell Lung Cancer Brain Metastasis

RO01.01 Prospective Evaluation of Ipilimumab and Nivolumab in Patients with Non-Small Cell Lung Cancer Brain Metastasis

Pre-radiosurgery leucocyte ratios and modified glasgow prognostic score predict survival in non-small cell lung cancer brain metastases patients

Pre-radiosurgery leucocyte ratios and modified glasgow prognostic score predict survival in non-small cell lung cancer brain metastases patients

Neutrophil-to-lymphocyte ratio is superior as a prognostic predictor in radiosurgically treated non-small cell lung cancer brain metastases patients under immunotherapy or targeted therapy

Neutrophil-to-lymphocyte ratio is superior as a prognostic predictor in radiosurgically treated non-small cell lung cancer brain metastases patients under immunotherapy or targeted therapy

Pre-radiosurgery leucocyte ratios and modified glasgow prognostic score predict survival in non-small cell lung cancer brain metastases patients

IntroductionThe predictive value of the pre-radiosurgery Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR) and the modified Glasgow Prognostic Score (mGPS) was assessed for the first time in a homogenous group of NSCLC brain metastaes (BM) patients.MethodsWe retrospectively evaluated 185 NSCLC-BM patients, who were treated with Gamma Knife Radiosurgery (GKRS). Patients with immunotherapy or targeted therapy were excluded. Routine laboratory parameters were reviewed within 14 days before GKRS1.ResultsMedian survival after GKRS1 was significantly longer in patients with NLR < 5 (p < 0.001), PLR < 180 (p = 0.003) and LMR ≥ 4 (p = 0.023). The Cox regression model for the continuous metric values revealed that each increase in the NLR of 1 equaled an increase of 4.3% in risk of death (HR: 1.043; 95%CI = 1.020–1.067, p < 0.001); each increase in the PLR of 10 caused an increase of 1.3% in risk of death (HR: 1.013; 95%CI = 1.004–1.021; p = 0.003) and each increase in the LMR of 1 equaled a decrease of 20.5% in risk of death (HR: 0.795; 95%CI = 0.697–0.907; p = 0.001). Moreover, the mGPS group was a highly significant predictor for survival after GKRS1 (p < 0.001) with a HR of 2.501 (95%CI = 1.582–3.954; p < 0.001). NLR, PLR, LMR values and mGPS groups were validated as independent prognostic factors for risk of death after adjusting for sex, KPS, age and presence of extracranial metastases.ConclusionNLR, PLR, LMR and mGPS represent effective and simple tools to predict survival in NSCLC patients prior to radiosurgery for brain metastases.

Neurological symptom burden impacts survival prognosis in patients with newly diagnosed non-small cell lung cancer brain metastases.

BackgroundBrain metastases (BM) are a frequent complication of advanced cancer and are characterized by a variety of neurological symptoms. Although the presence of neurological symptoms is included in the response assessment in patients with primary brain tumors, to the authors' knowledge little is known regarding the prognostic impact of neurological symptoms in patients with BM.MethodsPatients with newly diagnosed BM from non–small cell lung cancer were identified from the Vienna Brain Metastasis Registry and were evaluated according to the incidence, distribution, and prognostic impact of neurological symptoms at the time of diagnosis of BM.ResultsA total of 1608 patients (57.3% male and 42.7% female; median age, 62 years) were available for further analyses. Neurological symptoms including focal deficits (985 patients; 61.3%), signs of increased intracranial pressure (483 patients; 30.0%), epileptic seizures (224 patients; 13.9%), and neuropsychological symptoms (233 patients; 14.5%) were documented in 1186 of the 1608 patients (73.8%). Patients with asymptomatic BM presented with a longer median overall survival after the diagnosis of BM compared with patients with symptomatic BM (11 months vs 7 months; P < .001). In multivariate analysis with a diagnosis‐specific graded prognostic assessment (hazard ratio, 1.41; 95% CI, 1.33‐1.50 [P < .001]), the presence of neurological symptoms (hazard ratio, 1.39; 95% CI, 1.23‐1.57 [P < .001]) was found to be independently associated with survival prognosis from the time of diagnosis of BM.ConclusionsNeurological symptoms at the time of BM diagnosis demonstrated a strong and independent association with survival prognosis. The results of the current study have highlighted the need for the integration of the presence of neurological symptoms into the prognostic assessment of patients with BM from non–small cell lung cancer.Lay Summary Neurological symptom evaluation is included regularly in the assessment of patients with primary brain tumors. However, to the authors' knowledge, little is known regarding the prognostic impact in patients with newly diagnosed brain metastases (BM).The current study has provided a detailed clinical characterization of the incidence, distribution, and prognostic impact of neurological symptoms in a large, real‐life cohort of patients with BM from non–small cell lung cancer.In this cohort, neurological symptoms at the time of diagnosis of BM demonstrated a strong, independent prognostic impact on the survival prognosis.The results of the current study have highlighted the need for the integration of neurological symptom burden into the prognostic assessment of patients with BM from non–small cell lung cancer.

Stereotactic irradiation of non-small cell lung cancer brain metastases: evaluation of local and cerebral control in a large series

Stereotactic radiotherapy (SRT) of brain metastases (BM) results are often reported in the heterogeneous primitive population. Here, we report our experience in consecutively treated patients who underwent SRT alone for BM from non-small cell lung cancer (NSCLC). This retrospective analysis included consecutive patients with no history of cerebral treatment who underwent Cyberknife™ SRT for BM from NSCLC in our institution from 2007 to 2016. One hundred patients were included in the study, with a median follow-up of 33 months (20–64). Mean age was 63 years (SD ± 10); 88% had Karnofsky Performance Status (KPS) > 70; 67% had unique BM; 18 patients received single-fraction SRT (20–25 Gy), and 82 received hypo-fractionated SRT (HSRT) (24–36 Gy in 3–5 fractions). We reported a complication rate of 17% (2% of G3-4). Median survival was 10.1 months [95% confidence interval (CI) 7.8–13.9]. At 1 year, local and cerebral control rates were respectively 78.7% (95% CI 70–86.5%) and 43% (95% CI 33.5–53%). Thirty patients underwent salvage treatment (whole brain radiation therapy, n = 13; SRT, n = 14; surgery, n = 3). Cyberknife™-based SRT is an effective treatment associated with high local control rate with low morbidity for patients with NSCLC’s BM. Close follow-up is necessary to perform salvage treatment.

Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases

Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited. To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT. FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019. SRS and WBRT for small cell lung cancer brain metastases. Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses. In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results. Results of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.

Computational Modeling of Interstitial Fluid Pressure and Velocity in Non-small Cell Lung Cancer Brain Metastases Treated With Stereotactic Radiosurgery.

Background: Early imaging-based treatment response assessment of brain metastases following stereotactic radiosurgery (SRS) remains challenging. The aim of this study is to determine whether early (within 12 weeks) intratumoral changes in interstitial fluid pressure (IFP) and velocity (IFV) estimated from computational fluid modeling (CFM) using dynamic contrast-enhanced (DCE) MRI can predict long-term outcomes of lung cancer brain metastases (LCBMs) treated with SRS.Methods: Pre- and post-treatment T1-weighted DCE-MRI data were obtained in 41 patients treated with SRS for intact LCBMs. The imaging response was assessed using RANO-BM criteria. For each lesion, extravasation of contrast agent measured from Extended Tofts pharmacokinetic Model (volume transfer constant, Ktrans) was incorporated into a computational fluid model to estimate tumor IFP and IFV. Estimates of mean IFP and IFV and heterogeneity (skewness and kurtosis) were calculated for each lesion from pre- and post-SRS imaging. The Wilcoxon rank-sum test was utilized to assess for significant differences in IFP, IFV, and IFP/IFV change (Δ) between response groups.Results: Fifty-three lesions from 41 patients were included. Median follow-up time after SRS was 11 months. The objective response (OR) rate (partial or complete response) was 79%, with 21% demonstrating stable disease (SD) or progressive disease (PD). There were significant response group differences for multiple posttreatment and Δ CFM parameters: post-SRS IFP skewness (mean −0.405 vs. −0.691, p = 0.022), IFP kurtosis (mean 2.88 vs. 3.51, p = 0.024), and IFV mean (5.75e-09 vs. 4.19e-09 m/s, p = 0.027); and Δ IFP kurtosis (mean −2.26 vs. −0.0156, p = 0.017) and IFV mean (1.91e-09 vs. 2.38e-10 m/s, p = 0.013). Posttreatment and Δ thresholds predicted non-OR with high sensitivity (sens): post-SRS IFP skewness (−0.432, sens 84%), kurtosis (2.89, sens 84%), and IFV mean (4.93e-09 m/s, sens 79%); and Δ IFP kurtosis (−0.469, sens 74%) and IFV mean (9.90e-10 m/s, sens 74%).Conclusions: Objective response was associated with lower post-treatment tumor heterogeneity, as represented by reductions in IFP skewness and kurtosis. These results suggest that early post-treatment assessment of IFP and IFV can be used to predict long-term response of lung cancer brain metastases to SRS, allowing a timelier treatment modification.

Detection of circulating tumor DNA from non-small cell lung cancer brain metastasis in cerebrospinal fluid samples.

BackgroundEvaluating the molecular characteristics of brain metastases is limited by difficult access and by the blood–brain barrier, which prevents circulating tumor DNA (ctDNA) from entering the blood. In this study, we aimed to compare the sequencing results from cerebrospinal fluid (CSF) ctDNA versus plasma ctDNA, plasma circulating tumor cells (CTCs), and brain tissue specimens from patients with brain metastasis from non‐small cell lung cancer (NSCLC).MethodsThis was a prospective study of 21 consecutive patients with NSCLC and brain metastasis diagnosed between April 2018 and January 2019. Samples of CSF and peripheral blood were obtained from all 21 patients. Brain tissues were obtained from five patients after surgical resection. Next‐generation sequencing was performed using the Ion system. Single nucleotide variants (SNVs) and small insertions or deletions (indels) were searched.ResultsMutations were detected in the CSF ctDNA of 20 (95.2%) patients. The detection rate of epidermal growth factor receptor (EGFR) mutations in CSF ctDNA was 57.1% (12/21) whereas this rate was only 23.8% (5/21) in peripheral blood ctDNA and in CTCs. EGFR mutations were found in the CSF of 9 of 11 (81.8%) patients with leptomeningeal metastases, as compared with three of 10 (30%) patients with brain parenchymal metastases. Mutations were also detected in KIT, PIK3CA, TP53, SMAD4, ATM, SMARCB1, PTEN, FLT3, GNAS, STK11, MET, CTNNB1, APC, FBXW7, ERBB4, and KDR (all >10%). The status of EGFR and TP53 mutations was consistent between CSF ctDNA and brain lesion tissue in all five patients.ConclusionSequencing of CSF ctDNA revealed specific mutation patterns in driver genes among patients with NSCLC and brain metastasis.Key pointsIn some small‐sample studies, the importance of cerebrospinal fluid in guiding the treatment of cancerous brain lesions has been verified in that it may reflect genomic mutations of brain tumors relatively accurately.Cerebrospinal fluid is a new form of liquid biopsy that can be helpful in improving the management of patients with brain metastasis from non‐small cell lung cancer by detecting genetic abnormalities specific to brain metastases.

CMET-18. IMPACT OF KRAS MUTATION STATUS ON THE EFFICACY OF IMMUNOTHERAPY IN LUNG CANCER BRAIN METASTASES

Abstract BACKGROUND Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.

Dynamic transition of the blood-brain barrier in the development of non-small cell lung cancer brain metastases.

Invasion of the brain by non-small cell lung cancer (NSCLC) results in a shift of the blood-brain barrier (BBB) to the insufficiently characterized blood-tumor barrier (BTB). Effective drug delivery through the BTB is one of the greatest therapeutic obstacles in treating brain metastases. Using an experimental model, we defined key changes within the BTB and the BBB in the brain around the tumor (BAT) region over time. Brain-seeking NSCLC cells were delivered into the circulation of athymic-nude mice via intracardiac injection and developing brain metastases were evaluated over six-weeks. Components of the BBB and BTB were analyzed using immunofluorescence microscopy and compared using a mixed model of regression. Our results demonstrate a dynamic time-dependent BTB phenotype. Capillaries of the BAT and BTB were dilated with increased CD31 expression compared to controls. Expression of collagen IV, a pan-basement membrane component, was significantly decreased in the BTB compared to the BBB. There was also a significant increase in the desmin-positive pericyte subpopulation in the BTB compared to the BBB. The most striking changes were identified in astrocyte water channels with a 12.18-fold (p < 0.001) decrease in aquaporin-4 in the BTB; the BAT was unchanged. Analysis of NSCLC brain metastases from patient samples similarly demonstrated dilated capillaries and loss of both collagen IV and aquaporin-4. These data provide a comprehensive analysis of the BTB in NSCLC brain metastasis. Astrocytic endfeet, pericytes, and the basement membrane are potential therapeutic targets to improve efficacy of chemotherapeutic delivery into NSCLC brain metastases.

402PD - Impact of neurological symptom burden on the survival prognosis in a real-life cohort of patients with non-small cell lung cancer brain metastases

BackgroundThe high efficacy of targeted treatments in a- to oligosymptomatic non-small cell lung cancer (NSCLC) brain metastases (BM) revived the long discussion on BM screening. Therefore, we aimed to investigate the prognostic impact of symptomatic burden in patients with newly NSCLC BM in a large real-life cohort. MethodsPatients with newly diagnosed NSCLC BM were identified from the Vienna Brain Metastasis Registry. Results1531 patients (male 57.4%, female 42.3%; median age 62 years) were available for further analysis. Neurological symptoms including neurological deficits (952/153; 62.2%), symptoms of increased intracranial pressure (456/153; 29.8%) and epileptic seizures (199/1531; 13.0%) were evident in 1125/1531 (73.5%) patients. Oligo-to asymptomatic BM were significantly more frequently observed in patients with synchronous diagnosis of BM and NSCLC (p<0.001). Patients with oligo- to asymptomatic BM presented with a longer median overall survival after diagnosis of BM compared to patients with symptomatic BM (11 vs. 7 months; p<0.001). In detail, presence of increased intracranial pressure and seizures showed no impact on survival prognosis (p>0.05), while the median overall survival was significantly longer in patients without neurological deficits (11 vs. 7 months; p<0.001): memory disorders (6 vs. 8 months; p>0.05), ataxia (7 vs. 8; p=0.041) and vertigo (6 vs. 9; p=0.007). In multivariate analysis with DS-GPA (HR 1.41; 95% CI 1.33-1.50; p<0.001), the presence of neurological symptoms was independently associated with survival prognosis from diagnosis of BM (HR 1.19; 95% CI 1.05-1.36; p=0.007). Interestingly, the prognostic impact of neurological symptoms was more pronounced in patients with lower DS-GPA class II-IV (class II: 15 vs. 11; p=0.002, class III: 10 vs. 6; p<0.001, class IV: 6 vs. 3; p=0.018) compared to patients with DS-GPA class I (19 vs. 14; p=0.230). ConclusionsPresence of neurological symptoms presented with a strong and independent association with survival prognosis from diagnosis of BM especially in patients with lower DS-GPA and should be further evaluated for inclusion in the prognostic assessment of patients with newly diagnosed NSCLC BM. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureM. Preusser: Research grant / Funding (self): Böhringer-Ingelheim; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck Sharp & Dome; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Gerson Lehrman Group; Honoraria (self), Advisory / Consultancy: CMC Contrast; Honoraria (self), Advisory / Consultancy: Mundipharma; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Medahead; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo. A.S. Berghoff: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Bristol-Meyers Squibb; Honoraria (self), Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: AbbVie. All other authors have declared no conflicts of interest.

Prognostic assessment in patients with newly diagnosed small cell lung cancer brain metastases: results from a real-life cohort

PurposesBrain metastases (BM) are a frequent complication in small cell lung cancer (SCLC), resulting in a reduced survival prognosis. Precise prognostic assessment is an important foundation for treatment decisions and clinical trial planning.MethodsPatients with newly diagnosed SCLC BM were identified from the Vienna Brain Metastasis Registry and evaluated concerning prognostic factors.Results489 patients (male 62.2%, female 37.8%; median age 61 years) were included. Neurological symptoms were present in 297/489 (60.7%) patients. A- to oligosymptomatic patients (5 vs. 9 months, p = 0.030) as well as patients with synchronous diagnosis of BM and primary tumor (5 vs. 9 months, p = 0.008) presented with improved overall survival (OS) prognosis. RPA (HR 1.66; 95% CI 1.44–1.91; p < 0.001), GPA (HR 1.65; p < 0.001), DS-GPA (HR 1.60; p < 0.001) and LabBM score (HR 1.69; p < 0.001) were statistically significantly associated with OS. In multivariate analysis, DS-GPA (HR 1.59; p < 0.001), neurological deficits (HR 1.26; p = 0.021) and LabBM score (HR 1.57; p < 0.001) presented with statistical independent association with OS.ConclusionA- to oligosymptomatic BM as well as synchronous diagnosis of SCLC and BM were associated with improved OS. Established prognostic scores could be validated in this large SCLC BM real-life cohort.