Intracranial Progression Research Articles

Dose escalation of osimertinib for intracranial progression in EGFR mutated non-small-cell lung cancer with brain metastases.

BackgroundOsimertinib is a selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with increased penetration across the blood–brain barrier compared with previous EGFR-TKIs, and thus, a 52% reduction in the risk of intracranial disease progression is seen when it is used as a first line of therapy compared with gefitinib and erlotinib. It is also efficient as second-line therapy for patients who developed the T790M resistance mutation following treatment with previous generation TKIs. Here, we report 11 patients who were treated by an increasing dose of osimertinib from 80 mg to 160 mg QD orally following intracranial progression in either first- or second-line setting.MethodsThis is a subcohort analysis from a larger nonrandomized, phase 2, open-label trial, evaluating the efficacy of osimertinib dose escalation from 80 mg to 160 mg in EGFR-mutated advanced non-small-cell lung cancer (NSCLC) patients with intracranial progression in either first- (arm A) or second-line setting (arm B for T790M+ and C for T790M−).ResultsEleven patients, 5 in arm A, 4 in arm B, and 2 in arm C were reported in this study. The mPFS of osimertinib before dose escalation was 11.4 ± 8.9 (6.6–30.7) months for arm A, 8.7 ± 1.8 (6.3–11.2) for arm B, and 14.5 ± 7.8 (6.7–22.3) for arm C. Intracranial response rate to dose escalation was 54% (6 of 11) with 2 of 11 having intracranial stability. Median iPFS was 4.3 ± 7.4 (0.7–25.5) months; 3.8 ± 6.4 (1.8–18.9), 5.6 ± 9.7 (0.7–25.5), and 7.0 ± 2.7 (4.3–9.6) for arms A/B/C, respectively. Dose escalation was well tolerated with diarrhea and paronychia as the main dose-limiting symptoms.ConclusionsOsimertinib 160 mg is feasible and may offer a therapeutic alternative for patients with isolated intracranial progression on osimertinib standard (80 mg) dose. Further studies on CNS osimertinib pharmacokinetics are needed to test this hypothesis.

Local and systemic treatment for HER2-positive breast cancer with brain metastases: a comprehensive review.

The management of human epidermal growth factor receptor (HER2)-positive breast cancer has improved over the past decade. However, despite improvements in systemic control, a substantial proportion of patients with advanced HER2-positive breast cancer suffer from central nervous system metastases and even intracranial progression after aggressive local treatment. There is paucity of data and no consensus on the systemic therapies for patients with intracranial progression. This review discusses both local and systemic treatments for HER2-positive breast cancer with brain metastases with a special focus on the response of central nervous system metastases. A recommended practical treatment algorithm to guide physicians in selecting the most appropriate anti-HER2 therapy for their patients is suggested.

Metachronous Brain Metastasis in patients with EGFR-mutant NSCLC indicates a worse prognosis

Purpose: NSCLC patients with EGFR mutation were associated with high incidence of brain metastasis (BM). BM could be grouped by the time of occurrence, including synchronous BM at initial diagnosis and metachronous BM during disease course. The primary aim of the study was to investigate the survival of patients with metachronous BM.Methods: A total of 99 EGFR-mutant advanced NSCLC patients in our institute between 2012 and 2018 were grouped into synchronous BM and metachronous BM. Comparisons of OS were performed based on BM status. The independent prognostic factors of OS were investigated, and extracranial and intracranial PFS were further analyzed.Results: Patients with metachronous BM (mOS: 22.1 months) had poorer outcomes than synchronous BM (mOS: 30.3 months) (P=0.016). Moreover, multivariate analysis indicated that BM status (P=0.015), local therapy for BM (P=0.013) and subsequent treatment of Osimertinib (P=0.008) impact significantly on OS. Significantly, the proportion of local therapy for BM had no difference between patients with synchronous and metachronous BM. And patients with metachronous BM harbored a more favorable prognostic factor (higher proportion of subsequent Osimertinib treatment), but also harbored a poorer prognostic factor (metachronous BM), which confirmed BM status was the most significant prognostic factor of OS. At last, results of extracranial and intracranial PFS indicated that patients with metachronous BM tended to have a higher risk of intracranial disease progression.Conclusions: Patients developing metachronous BM during EGFR-TKIs treatment have worse outcomes than synchronous BM. Our findings suggested that the patients with metachronous BM should receive more aggressive treatments.

Relationship Between Measures of Cerebrovascular Reactivity and Intracranial Lesion Progression in Acute TBI Patients: an Exploratory Analysis

BackgroundFailure of cerebral autoregulation and progression of intracranial lesion have both been shown to contribute to poor outcome in patients with acute traumatic brain injury (TBI), but the interplay between the two phenomena has not been investigated. Preliminary evidence leads us to hypothesize that brain tissue adjacent to primary injury foci may be more vulnerable to large fluctuations in blood flow in the absence of intact autoregulatory mechanisms. The goal of this study was therefore to assess the influence of cerebrovascular reactivity measures on radiological lesion expansion in a cohort of patients with acute TBI.MethodsWe conducted a retrospective cohort analysis on 50 TBI patients who had undergone high-frequency multimodal intracranial monitoring and for which at least two brain computed tomography (CT) scans had been performed in the acute phase of injury. We first performed univariate analyses on the full cohort to identify non-neurophysiological factors (i.e., initial lesion volume, timing of scan, coagulopathy) associated with traumatic lesion growth in this population. In a subset analysis of 23 patients who had intracranial recording data covering the period between the initial and repeat CT scan, we then correlated changes in serial volumetric lesion measurements with cerebrovascular reactivity metrics derived from the pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC (correlation coefficient between the pulse amplitude of intracranial pressure and cerebral perfusion pressure). Using multivariate methods, these results were subsequently adjusted for the non-neurophysiological confounders identified in the univariate analyses.ResultsWe observed significant positive linear associations between the degree of cerebrovascular reactivity impairment and progression of pericontusional edema. The strongest correlations were observed between edema progression and the following indices of cerebrovascular reactivity between sequential scans: % time PRx > 0.25 (r = 0.69, p = 0.002) and % time PAx > 0.25 (r = 0.64, p = 0.006). These associations remained significant after adjusting for initial lesion volume and mean cerebral perfusion pressure. In contrast, progression of the hemorrhagic core and extra-axial hemorrhage volume did not appear to be strongly influenced by autoregulatory status.ConclusionsOur preliminary findings suggest a possible link between autoregulatory failure and traumatic edema progression, which warrants re-evaluation in larger-scale prospective studies.

RBTT-02. RADIOSURGERY FOLLOWED BY TUMOR TREATING FIELDS FOR BRAIN METASTASES (1–10) FROM NSCLC IN THE PHASE 3 METIS TRIAL

Abstract BACKGROUND: Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The METIS study [NCT02831959] investigates the efficacy and safety of TTFields in NSCLC patients with brain metastases. Study Design: NSCLC patients (N=270) with 1–10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, > 18 hours/day) within 7 days of SRS or supportive care. The portable device delivers TTFields to the brain using 4 transducer arrays, while patients receive the best standard-of-care for systemic disease. Patients are followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at two sided alpha of 0.05 to detect a hazard ratio of 0.57. In August 2018, an independent Data Monitoring Committee (DMC) performed a review of the METIS trial data collected to that point. The DMC concluded that no unexpected safety issues had emerged and recommended continuation of the METIS study as planned.

CMET-41. OUTCOMES FOLLOWING STEREOTACTIC RADIOSURGERY (SRS) FOR LIMITED BRAIN METASTASES - AN AUSTRALIAN SINGLE INSTITUTIONAL EXPERIENCE

Abstract INTRODUCTION Despite increasing use of stereotactic radiosurgery (SRS) for management of brain metastases (BM), published Australian data is scarce. We aim to report on the outcomes following SRS for limited BM in a single Australian institution. METHODS This is a retrospective cohort of patients with limited BM treated with SRS between August 2015 and March 2019. A dose of 24Gy/3# were prescribed to intact lesion, and 21Gy/3# to surgical cavity post-surgical resection. All patients were followed with 3-monthly surveillance MRI brain. Primary outcomes were: local failure (LF: increased in size of SRS-treated BM lesion/ recurrence in surgical cavity), distant failure (DF: intracranial progression outside of the SRS-treated lesion/ cavity), and overall survival (OS). LF, DF and OS were estimated using the Kaplan-Meier method. Multivariate Cox regressions were used to evaluate factors associated with outcomes of interest, with death as competing-risk events for LF and DF. RESULTS 76 courses of SRS were delivered in 65 patients (54 unresected BM lesions, and 22 surgical cavities). 43 (66%) patients were ECOG 0–1. 35 (54%) patients had solitary BM. 41 (63%) had symptomatic BM. Half of the patients had primary lung cancer. Median follow-up was 4.8 months (range:0.1–39 months). 10 LF were observed at a median of 3.5 month post-SRS, with 6- and 12-month LF cumulative incidence of 14% and 24% respectively. 30 DF were observed at a median of 3.3 months, with 6- and 12-month DF cumulative incidence of 38% and 63% respectively. The 12- and 24-month OS were 39% and 26% respectively. In multivariate analyses, better ECOG status, solitary BM lesion, resection of BM pre-SRS, and use of subsequent systemic therapy were independently associated with improved OS. CONCLUSION This is one of the few Australian series reporting on outcomes following SRS for limited BM, with comparable outcomes to published international series.

SURG-09. CHANGING PARADIGMS IN THE MANAGEMENT OF CEREBRAL METASTASES

Abstract INTRODUCTION Paradigms in the management of cerebral metastases (CM) are evolving, in part due to the expanded use of laser interstitial thermal therapy or LITT in lesion ablation, with treatment of CM comprising up to 34% of all LITT cases. Currently, CM are treated with LITT largely in the setting of disease progression after initial therapy with focused radiation with no standard for performing biopsy prior to LITT. In this study we aim to assess the significance of the pathology of the lesion at the time of LITT on survival. METHODS We conducted a retrospective review of our institution’s LITT/brain tumor database and identified patients who underwent LITT with concurrent biopsy. For deceased patients, we identified cause of death if secondary to neurologic causes defined as death either due to direct intracranial disease progression leading to rapid neurologic decline or due to progressive neurologic decline without significant extracranial disease burden. RESULTS We identified 16 progressive CM lesions in 15 adults treated with LITT with concurrent biopsy, predominantly with non-small cell lung cancer. The mean age at LITT was 62, median follow-up was 8.5 months and thirteen of fifteen patients had previous focused radiation therapy. Eleven of sixteen lesions demonstrated radiation necrosis(RN) without tumor and 5 with tumor progression(TP). The mean survival in patients with RN was 548 days compared with 285 days in patients with TP (p=0.15). Of the 9 deceased, 2 of 5 patients with RN and 3 of 4 patients with TP died of neurologic causes. CONCLUSIONS Although statistically not significant due to the small sample size, this preliminary analysis suggests that clinically significant differences in survival and cause of death may exist between patients with RN and TP. Further evaluation with implications for treatment, prognosis and the expectant management of the patient with CM is warranted.

CMET-11. RESPONSE TO STEREOTACTIC RADIOSURGERY FOR MULTIPLE BRAIN METASTASES BASED ON HISTOLOGY-SPECIFIC SUBTYPE STATUS

Abstract BACKGROUND This retrospective study evaluated the relationship between histologic subtype and treatment outcomes following SRS for the treatment of multiple brain metastases (MBM). METHODS We analyzed patients with MBM, defined here as >= 3 lesions, treated with SRS at our institution. Primary histologies examined were NSCLC, breast, and melanoma. Patients were categorized according to histology-specific subtypes (NSCLC-EGFR, ALK, KRAS, PD-L1%; breast-HER2, ER, PR; melanoma-BRAF). The primary outcome was local control (defined by RANO-BM) and secondary outcomes included intracranial progression-free survival (iPFS) and overall survival (OS). RESULTS 141 patients met inclusion criteria (66 NSCLC, 61 breast, and 14 melanoma). HER2+ and BRAF V600E+ lesions had increased rates of local control following SRS (P=0.0048 and P=0.0256, respectively) compared to other breast/melanoma subtypes. EGFR mutation was not associated with increased local control with SRS (71 vs 74%), but increased iPFS (P=0.0031). On multivariable analysis, EGFR+ was independently associated with a decreased time-dependent risk of death (P=0.011). The use of progressively newer generations of EGFR-directed therapies was associated with stepwise decreasing risk of intracranial progression and death. HER2+ disease had improved iPFS and OS (P=0.0058 and P< 0.0001, respectively; it was not an independent risk factor for progression or death; however, the use of HER2-directed antibodies was associated with decreased risk of death (p=0.036). The use of tyrosine kinase inhibitors (i.e. lapatanib) was not associated with improvements, although this was a small subset. CONCLUSIONS Some histologic subtypes appear to have better control with SRS, with HER2+ breast cancer and BRAF V600E+ melanoma associated with improved outcomes – this requires further validation; a volumetric analysis is pending. This the protective effect of EGFR mutation appears to be partly related to use of EGFR inhibitors, with the use of newer-generation therapies leading to improved outcomes; although local control with SRS remains excellent regardless of the mutation.

491P - Clinical outcomes of leptomeningeal metastases in EGFR-mutant lung adenocarcinoma

BackgroundLeptomeningeal metastases (LM) remain challenging for patients with non-small cell lung cancer. EGFR mutation shows a higher incidence rate of LM with poor prognosis. 3rd generation TKI has better cerebral-spinal fluid(CSF) penetration and may be a promising treatment. Here we collected LM clinical features and outcome in EGFR-mutant lung adenocarcinoma in high EGFR mutation prevalence area. MethodsThis is a retrospective observational cohort study, conducted in a tertiary medical center in Taiwan. Patients with newly diagnosed advanced lung adenocarcinoma with common EGFR mutation were enrolled. LM were diagnosed by brain imaging study or cytology study of CSF analysis. Patients without initial brain MRI imaging or patients who underwent CNS surgery initially were excluded. All the data is valid up to Dec 31, 2017. ResultsFrom 2013 to 2015, a total of 283 patients was included. All patients were treated with first-line TKIs as systemic treatment initially. Thirty-four patients had LM, accounting for 12.0% (34/283) of this cohort. Only four patients in the LM group (11.7%) received CSF study, and three of them showed malignant cells in their CSF. Patients with LM had median overall survival(OS) 26.2 months, whereas patients with brain tumor progression had median OS 42.3 months. (p = 0.002) For patients with LM, the median OS after LM is 5.1 months. Patients with younger age(HR0.63[0.45-0.90], p = 0.01) and initial M1b(HR 2.86[1.81-4.53], p < 0.001) were associated with higher risk or intracranial progression. Among 34 patients, 6 patients received 3rd generation TKI and revealed significant better OS than those without 3rd TKI. (OS 15.3 months vs 3.7 months, p = 0.03). ConclusionsLM show poor prognosis for patients with EGFR-mutant lung adenocarcinoma, compared with other types of brain metastases. Younger age and initial M1b associated with higher risk. Patients with 3rd generation TKI may bring benefit to these patients. Legal entity responsible for the studyThe authors. FundingTaipei Veterans General Hospital. DisclosureC-H. Chiu: Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Roche. All other authors have declared no conflicts of interest.

529P - Osimertinib for patients with EGFR-mutant advanced NSCLC and asymptomatic brain metastases: An open-label, two-arm, phase II study

BackgroundOsimertinib is an EGFR TKI selective for both EGFR TKI sensitizing and Thr790Met resistance mutations. While intracranial activity of osimertinib has been observed in patient subgroups within larger trials, a study focusing exclusively on patients with brain metastases has not yet been reported. We assessed the intracranial activity of osimertinib in EGFR-mutant, NSCLC patients with asymptomatic brain metastases, either as first-line therapy or following progression in pre-treated Thr790Met-positive patients. MethodsIn this phase 2, open-label, two-arm study we enrolled patients with EGFR-mutant, metastatic NSCLC and at least one asymptomatic brain metastasis of 4 mm or larger in diameter. Treatment-naïve patients (arm A) and Thr790Met-positive patients who progressed on EGFR-TKI therapy (arm B) received osimertinib 80 mg once daily. Dose escalation to 160 mg once daily was performed in cases of intracranial progression without symptomatic systemic progression. The primary endpoint in both arms was intracranial metastasis response. Here we present a preliminary analysis upon the trial outstanding results. ResultsBetween 31/05/16 - 30/08/18 (data cutoff) 21 patients with asymptomatic brain metastases started osimertinib treatment (arm A = 15, arm B = 5 arm C = 1). Median duration of follow-up was 43 weeks. Intracranial response was achieved in 11 (73%; 95% CI 45%-92%) of 15 treatment-naïve patients (arm A) and in four (80%; 95% CI 28%-99%) of five previously treated Thr790Met-positive patients (arm B). Dose escalation was performed in four patients (arm A = 2, Arm B = 2), with one continuous response. 10 of 15 patients (67%) in arm A and 1 of 5 patients (20%) in arm B continue responding to osimertinib 80 mg at data cutoff. Toxicity side effects were similar to previously reported studies. ConclusionsOsimertinib shows equal intracranial and systemic activity with minor side effects in EGFR-mutant, treatment-naïve NSCLC and in previously treated Thr790Met-positive patients. Therefore, we suggest that osimertinib is a reasonable first treatment option for patients with EGFR-positive NSCLC and newly diagnosed asymptomatic brain metastases, and may postpone or even defer the need for brain irradiation. Clinical trial identificationNCT02736513. Legal entity responsible for the studyNir Peled. FundingAstraZeneca. DisclosureN. Peled: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BI, BMS, Lilly, MSD, Novartis, Pfizer, Roche, FMI, NovellusDx, Gaurdant360, Takeda. E. Dudnik: Advisory / Consultancy, Travel / Accommodation / Expenses: BI, Merck/MSD, Roche Pharmaceuticals, AstraZeneca. All other authors have declared no conflicts of interest.

Clinical factors associated with treatment outcomes in EGFR mutant non-small cell lung cancer patients with brain metastases: a case-control observational study

BackgroundNon-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations often develop brain metastases. Treatment with EGFR-tyrosine kinase inhibitors (TKIs) has shown the effectiveness; however, knowledge of the clinical factors associated with outcomes in NSCLC patients with EGFR mutations remains limited.MethodsTreatment-naive patients diagnosed with advanced non-squamous NSCLC with brain metastases harboring EGFR mutations and treated with an EGFR-TKI as first-line therapy were enrolled with analysis of their medical records.ResultsA total of 134 advanced NSCLC patients with brain metastases harboring EGFR mutations received an EGFR-TKI (gefitinib: 62, erlotinib: 49, and afatinib: 23) as the first-line therapy. Sixty-nine had exon 19 deletions (51.5%), and 56 (41.8%) had L858R mutations. There was no statistically significant difference in progression-free survival (PFS) and overall survival (OS) among the EGFR-TKIs. Significantly shorter OS was noted in patients with multiple brain metastases (hazard ratio [HR]: 2.43, p = 0.007), uncommon EGFR mutations (HR: 3.75, p = 0.009), and liver metastases. Thirty-eight patients (29.1%) received brain radiotherapy for brain metastases before disease progression, and had a significantly longer time until intracranial progression. However, the brain radiotherapy had no statistically significant impact on PFS or OS.ConclusionsPatients with uncommon mutations, multiple brain metastases, and concomitant liver metastases tended to have shorter OS. Brain radiotherapy could delay the time to intracranial disease progression but had no impact on survival. The different first-line EGFR-TKIs achieved similar treatment responses in terms of PFS and OS in the EGFR-mutated NSCLC patients with brain metastases.

Clinical observation of crizotinib in the treatment of ALK-positive advanced non-small cell lung cancer

BackgroundALK is a prognostic and predictive tumor marker in non-small cell lung carcinoma (NSCLC), and is more often found in lung adenocarcinomas. MethodsThe clinical and pathological data of 87 patients confirmed to have NSCLC by pathology or cytology were selected from April 2014 to January 2017 at the Tumor Hospital of Hebei Province. ResultsOf the 87 ALK-positive-patients, 47 patients were treated with oral administration of crizotinib. The objective response rate (ORR) was 61.7%, the disease control rate (DCR) was 93.6%, and the mPFS was 19 months. In an analysis of the number of metastatic sites, the patients who had more than three metastatic sites, the ORR, DCR, and mPFS were 63.9%, 94.5%, and 19 months, compared with the 45.5%, 91%, and 11 months in the patients with less sites (P = 0.040). For patients of 60 years or older, ORR and DCR were 40% and 100%, the other group was 71.9% and 90.6%, respectively(P = 0.036). The timing of treatment was analyzed. At the first application of crizotinib, ORR and DCR were 78.2% and 100% corresponding 45.8% and 87.5% at the second and final application of crizotinib group (P = 0.022). Baseline brain metastases were present in 25.5% (12/47) of patients in this study. 9 of the patients who developed disease progression during crizotinib treatment had new brain metastases or increased preexisting cranial foci. Most of them took the treatment strategy of continuing crizotinib or replacing the second/third generation ALK-TKI treatment combined with local radiotherapy for brain metastases. ConclusionsThe efficacy of crizotinib in patients with advanced NSCLC is related to the number of metastatic organs, age and timing of treatment. The use of crizotinib is prone to intracranial progression, and progression of simple brain metastases is not an indication that crizotinib is discontinued. Patients will continue to benefit from combination of local radiotherapy.

Effects of different brain surveillance strategies on outcomes for patients with EGFR-mutant metastatic lung adenocarcinoma under targeted therapy

ObjectivesBrain metastasis (BM) is common in patients with epidermal growth factor receptor (EGFR)-mutant lung cancer. However, the brain surveillance strategy during treatment in advanced lung cancer patients varies, and the impact on clinical outcome is unclear. Here we aimed to evaluate the effect of different brain surveillance strategies on the clinical characteristics and treatment outcome in patients with EGFR-mutant lung adenocarcinoma treated with first-line EGFR tyrosine kinase inhibitors (EGFR-TKIs). Materials and methodsThis is a retrospective observational study conducted in a medical center in an area with high prevalence of EGFR mutation. Patients with initially diagnosed stage IV EGFR-mutant lung adenocarcinoma were included. Patients undergoing regular brain magnetic resonance imaging (MRI) every 3-6 months were categorized in the regular follow-up (RFU) group, and the rest were categorized in the liberal follow-up (LFU) group. Clinical outcomes were collected and analyzed. ResultsA total of 310 patients were included, and 43.5% initially had brain metastases. Patients in the LFU group were significantly older than those in the RFU group (median age: 67 vs 62, p < 0.001). The overall survival and time-to-treatment failure of patients with initial EGFR-TKIs treatment showed no statistical difference between the two groups. However, the intracranial progression free survival was significantly shorter in the RFU group than in the LFU group (p = 0.009). The risk of mortality was similar in the LFU and RFU groups. There was no difference in the intracranial progression patterns and cause of death between the two groups. ConclusionsFor EGFR-mutant lung adenocarcinoma patients who used EGFR-TKIs as the frontline therapy, regular or liberal brain MRI follow-up showed no significant impact on the outcome, irrespective of initial brain metastasis.

Nrf-2 signaling inhibits intracranial aneurysm formation and progression by modulating vascular smooth muscle cell phenotype and function

BackgroundOxidative stress and vascular smooth muscle cell (VSMC) phenotypic modulation influence intracranial aneurysm (IA) formation and progression. Oxidative stress plays an important role in phenotype switching, and nuclear factor erythroid 2-related factor 2 (Nrf-2) is one of the main antioxidant systems. Unfortunately, little is known about how Nrf-2 signaling influences VSMC phenotype switches during IA pathogenesis.MethodsWe examined the effect of Nrf-2 activation IA on formation and progression in an elastase-induced rat IA model. We also developed a hydrogen peroxide (H2O2)-induced VSMC oxidative damage model. Then, we analyzed VSMC phenotype changes in the setting of Nrf-2 activation or inhibition in vitro. The proliferation, migration ability, and apoptosis rate of VSMCs were tested. Lastly, we measured the expression levels of antioxidant enzymes and inflammatory cytokines downstream of Nrf-2.ResultsNrf-2 activation suppressed IA formation and progression in vivo. We confirmed Nrf-2 nuclear translocation and a VSMC switch from the contractile to synthetic phenotype. Nrf-2 activation inhibited the proliferation, migratory ability, and apoptosis rate enhanced by H2O2. Quantitative real-time polymerase chain reaction (PCR) and western blot analysis revealed that Nrf-2 activation promoted antioxidant enzymes and VSMC-specific marker gene expressions but decreased pro-inflammatory cytokine levels.ConclusionThese results suggest that Nrf-2 exerts protective effects against IA development by preventing VSMCs from changing to a synthetic phenotype.

1594TiP - Radiosurgery followed by tumour treating fields (TTFields) for brain metastases (1-10) from NSCLC in the phase III METIS trial

BackgroundTumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The METIS study [NCT02831959] investigates the efficacy and safety of TTFields in NSCLC patients with brain metastases. Trial designNSCLC patients (N=270) with 1-10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150kHz, > 18hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays, while patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. In August 2018, an independent Data Monitoring Committee (DMC) performed a review of the METIS trial data collected to that point. The DMC concluded that no unexpected safety issues have emerged on the study, and recommended to continue the METIS study as planned. Clinical trial identificationNCT02831959. Legal entity responsible for the studyNovocure. FundingNovocure. DisclosureM. Mehta: Advisory / Consultancy: Varian Medical Systems ; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: Tocagen; Advisory / Consultancy: AbbVie; Leadership role: Oncoceutics ; Shareholder / Stockholder / Stock options, Officer / Board of Directors: Pharmacyclics; Advisory / Consultancy: Cavion, Novocure, Varian, Agenus, Insys, Remedy, IBA. M. Ahluwalia: Advisory / Consultancy: Monteris Medical ; Advisory / Consultancy: AstraZeneca ; Advisory / Consultancy: Bristol-Myers Squibb ; Advisory / Consultancy: AbbVie; Advisory / Consultancy: CBT Pharmaceuticals; Advisory / Consultancy: Kadmon ; Advisory / Consultancy: VBI Vaccines ; Shareholder / Stockholder / Stock options: MimiVax ; Honoraria (self): Prime Oncology ; Research grant / Funding (institution): Novartis ; Research grant / Funding (institution): Novocure; Research grant / Funding (institution): Boehringer Ingelheim ; Research grant / Funding (institution): Aztra zeneca; Research grant / Funding (institution): Lilly/ImClone . P. Brown: Advisory / Consultancy: Novella Clinical. All other authors have declared no conflicts of interest.

P1.01-39 Is There an Association Between Intracranial Progression and Overall Survival or Neurologic Death in Patients with EGFR Positive NSCLC?

Many studies have examined the incidence of Brain Metastases (BrM) in EGFRm+ NSCLC, and their impact on radiographic and survival outcomes. We have examined the incidence of ND and predictive factors in a retrospective cohort. The clinical significance of ICP remains controversial; patients who develop new lesions may be treated with further locoregional treatment such as stereotactic radiosurgery (SRS). This study examines the association between ICP and survival or ND, to help define appropriate endpoints for future trials. All patients treated for BrM from EGFRm+ NSCLC between 2004 and 2016 were identified from an institutional registry. Clinical data regarding demographics, progression events, pattern of progression, and treatment were extracted from medical records and verified with imaging reports. A multivariable competing-risks model was constructed to test the association between ICP at 6, 12 and 18 months and the outcome of ND. A separate model tested the association between ICP and OS. 198 patients were included in the study. Median age was 61 years, 67% of patients were female, 46% had BrM at NSCLC diagnosis. Median DS-GPA was 2.5. Median OS for the group was 20 months, and the 5-year cumulative incidence of neurologic death was 40%. 111 patients (56%) had ICP and median intracranial PFS was 16 months; 29% had ICP within 6 months and 33% between 6 and 12 months, 18% at 12-18 months and 21% at >18 months. ICP was due to new BrM in 51%, progression of existing BrM in 34% and leptomeningeal carcinomatosis in 15%. Among patients with ICP, earlier progression was associated with ND (HR 2.48, p=0.01, see table). In addition, pattern of ICP was significant; patients with leptomeningeal spread (HR 3.74, p<.001) had higher risk of ND than those with new BrM or progression of existing lesions. In a multivariable model, early ICP, pattern of ICP and more initial BrM were independently associated with higher risk of ND and also shorter OS.Tabled 1Regression models of ND and OSCovariateUnivariate Model of Neurologic DeathMultivariable Model of Neurologic DeathMultivariable Model of Overall SurvivalHR (95% CI)P valueHR (95% CI)P valueHR (95% CI)P valueIntracranial Progression < 6 months 6-12 months 12-18 months >18 months2.48 (1.21-5.08) 1.56 (0.75-3.23) 1.61 (0.72-3.57) ref0.013 0.24 0.254.88 (2.13-11.19) 2.69 (1.06-6.80) 3.85 (1.44-10.29) ref<.001 0.036 0.00711.22 (5.11-24.64) 5.31 (2.47-11.42) 4.82 (2.16-10.77) ref<.001 <.001 <.001Pattern of Progression New lesion Progression of existing BrM Leptomeningeal Spreadref 1.29 (0.70-2.35) 3.74 (1.96-7.15)0.41 <.001ref 1.12 (0.55-2.26) 4.70 (2.11-10.48)0.76 <.001ref 1.54 (0.93-2.57) 3.19 (1.64-6.20)0.10 <.001Number of Initial BrM 1-4 5-10 >10ref 1.92 (0.95-3.86) 2.94 (1.60-5.39)0.07 <.001ref 2.43 (1.05-5.62) 2.57 (1.11-5.90)0.038 0.027ref 3.27 (1.61-6.62) 3.74 (1.96-7.15)0.001 <.001First Line CNS Treatment WBRT SRS Systemic aloneRef 0.69 (0.38-1.24) 0.58 (0.27-1.23)0.22 0.15Ref 1.17 (0.49-2.75) 0.88 (0.42-1.87)0.73 0.88Ref 1.10 (0.57-2.11) 1.28 (0.70-2.34)0.79 0.43EGFR Exon 19 vs 210.73 (0.44-1.23)0.240.71 (0.40-1.24)0.230.72 (0.52-1.00)0.05BrM at Diagnosis0.93 (0.54-1.60)0.781.45 (0.77-2.73)0.260.93 (0.65-1.32)0.69 Open table in a new tab Among patients with brain metastases from EGFRm+ NSCLC, shorter time to intracranial progression was associated with higher rates of neurologic death, as was the pattern of progression. This supports the validity of studies using intracranial progression as an endpoint, particularly if pattern of disease is taken into account.

1482O - Outcomes with pembrolizumab (pembro) monotherapy in patients (pts) with PD-L1–positive NSCLC with brain metastases: Pooled analysis of KEYNOTE-001, -010, -024, and -042

1482O - Outcomes with pembrolizumab (pembro) monotherapy in patients (pts) with PD-L1–positive NSCLC with brain metastases: Pooled analysis of KEYNOTE-001, -010, -024, and -042

404P - Radiographic phenotyping to identify intracranial disseminated recurrence in brain metastases treated with radiosurgery using contrast-enhanced MR imaging

BackgroundEarly intracranial progression (ICP) reduce the efficacy of first line radiosurgery (SRS) for brain metastases. We aim to develop and validate a MR imaging-derived radiomic signature (RS) via deep learning approach for the prediction of 1-year disseminated ICP (DICP; more than or equal to 3 lesions and leptomeningeal carcinomatosis) in brain metastases patients treated with SRS. MethodsA total of 1304 MRI-based radiomic features of pretreatment tumors were obtained from 208 patients with 451 lesions, who received first line SRS during August 2008 to January 2018. Variational autoencoder (VAE), trained with symmetric two encoded and decoded layers of neural network and 1,649,560 trainable parameters, was applied to reduce the dimensionality of radiomc features to 128 VAE-radiomic features. Penalized regression with 10-fold cross validation using least absolute shrinkage and selection operator performs features selection and construct RS to predict 1-year DICP events in train set of 150 patients, which was validated in test set of 58 patients. Harrell’s C-index was used to evaluate the discriminative ability of RS in both sets. The correlation of VAE-radiomic features and molecular features was analyzed by student t-test. Survival analysis was calculated using the Kaplan-Meier method. ResultsThe RS yielded 1000 times bootstrapping corrected C-index of 0.746 and 0.747 for discrimination of 1-year DICP in the train and test cohorts, respectively. As for the subgroup of patients with lung (n=175) and breast (n=23) origin, the RS also showed good predictive performance with C-indices of 0.735 and 0.755, respectively. EGFR-mutation (n=113) and ER (n=22) status were associated with selected VAE-radiomic features No. 98 (p=0.035) and No.127 (p=0.44), respectively. Dichotomized risk category using RS of -0.769 (Youden index) as cut-off point yielded median overall survival of 57.7 months in low risk compared to 20.5 months in high risk group (p<0.01). ConclusionsThe RS model provides a novel approach to predict 1-year DICP and survival in brain metastases receiving SRS, and is warranted to be integrated into GPA for optimal selection of patients treated with first line SRS. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

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.

P1.01-100 Effect of Osimertinib in Non-Small Cell Lung Cancer Patients with Brain Metastases After Progression Following Front-Line EGFR-TKI Therapy

Osimertinib has been adopted as the standard of care for T790M-mediated acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. In this study, we aim to investigate the effect of osimertinib in advanced NSCLC with brain metastases after the failure of first-line therapy. We retrospectively studied 43 NSCLC patients with BM received osimertinib after progression following front-line EGFR-TKI therapy from January 2013 to December 2016 at our institution. Overall survival (OS) was measured from the date of brain metastases. Among the 43 patients, 25(58.1%) received EGFR-TKIs as first-line therapy, 15(34.9%) were treated with EGFR-TKIs therapy after the progression of chemotherapy, and there’re also 3(7.0%) received the combination of EGFR-TKIs and chemotherapy as first-line therapy. 16(37.2%) were EGFR T790M positive, 4(9.3%) were EGFR T790M negative and 23(53.5%) were unknown T790M status. 34(79.1%) patients had received local radiation therapies (RT). The median overall survival (OS), and the median intracranial progression free survival (iPFS) was 32.0 months, 14 months, respectively. Patients with EGFR T790M mutation had the median OS of 24.7 months, these without T790M mutation had the median OS of 17.0 months, and the patients with unknown status of T790M showed the longest OS of 34.4months, although it did not reach statistical significance (P =0.727). There was also no difference in iPFS among the T790M-positive group, T790M-negetive group and the unknown status group (5.0 vs. 7.0 vs. 18.0 months, P=0.195). Similar results in OS were found among the first line TKIs group, chemotherapy followed by EGFR-TKI therapy group and the combination of TKIs and chemotherapy group (P=0.491). Three patients had leptomeningeal metastasis (LM), showed to have a worse iPFS of 12 months compared to 14 months of these without LM (P=0.991). Osimertinib had a good efficacy in patients with brain metastasis of advanced non–small-cell lung cancer in whom disease had progressed following front-line EGFR-TKIs.