Intracranial Progression Research Articles

Radiologic and Clinical Outcomes of Stereotactic Radiosurgery for Intraventricular Metastases

The optimal management of intraventricular metastases remains debatable. The aim of this study is to define the safety and efficacy of Gamma-Knife radiosurgery in the treatment of intraventricular metastases. This retrospective, single-center study involved patients that were treated with stereotactic radiosurgery (SRS) for intraventricular metastases. The study end points included SRS-related toxicity, local and distal intracranial tumor control, as well as the incidence of post-treatment hydrocephalus and leptomeningeal dissemination. Factors associated with radiologic and clinical outcomes were also analyzed. The cohort included 17 consecutive patients who underwent stereotactic radiosurgery for treatment of 41 intracranial metastases, of which 23 were primary intraventricular (intraventricular metastasis). Median overall survival from primary tumor diagnosis and from SRS treatment were 28 and 5 months, respectively. With a median radiological follow-up of 3 (interquartile range 3) months, 7 patients (41.18%) experienced overall intracranial disease progression, whereas 7 (27.27%) intraventricular metastases progressed radiologically. Four (23.53%) and 3 (17.65%) patients developed hydrocephalus and leptomeningeal dissemination post-SRS, respectively. Four patients (23.53%) died due to intracranial disease progression. SRS offers a reasonable chance of local tumor control for patients with intraventricular brain metastasis. However, the risk of hydrocephalus and leptomeningeal spread of disease is not inconsequential and merits close follow-up for patients with brain metastasis involving the ventricular system.

P59.01 Clinical Characteristics of Patients With MET Amplification-Positive NSCLC After EGFR-TKI Therapy

Patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) ultimately acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) during treatment. In 5–22% of these patients, resistance is mediated by aberrant mesenchymal epithelial transition factor (MET) gene amplification. Here, we evaluated the emergence of MET amplification after EGFR-TKI treatment failure based on clinical parameters. We retrospectively analyzed 186 patients with advanced EGFR-mutant NSCLC for MET amplification status by in situ hybridization (ISH) assay after EGFR-TKI failure. We collected information including baseline patient characteristics, metastatic locations and generation, line, and progression free survival (PFS) of EGFR-TKI used before MET evaluation. Multivariate logistic regression analysis was conducted to evaluate associations between MET amplification status and clinical variables. View Large Image Figure ViewerDownload Hi-res image Download (PPT) Regarding baseline EGFR mutations, exon 19 deletion was predominant (57.5%), followed by exon 21 mutation (39.2%). The proportions of MET ISH assays performed after first/second-generation and third-generation TKI failure were 66.7% and 33.1%, respectively. The median PFS for the most recent EGFR-TKI treatment was shorter in MET amplification-positive patients than in MET amplification-negative patients (mPFS of 1st/2nd generation TKI cohort, 7.0 vs. 10.4 months, p = 0.003, PFS of 3rd generation TKI cohort, 7.2 vs. 11.0 months, p=0.163). Multivariate logistic regression demonstrated that a history of smoking, short PFS on the most recent TKI, and less intracranial progression were associated with a high probability of MET amplification (all p < 0.05). Our results demonstrated the distinct clinical characteristics of patients with MET amplification-positive NSCLC after EGFR-TKI therapy. Our clinical prediction can aid physicians in selecting patients eligible for MET amplification screening and therapeutic targeting.

P14.03 Shifting trends and entity-specific aspects in patients with brain metastasis: real-life analysis from 6031 individuals over an observation period of 30 years

Abstract BACKGROUND We aimed to investigate the changing clinical characteristics of patients with brain metastases (BM) over the last three decades as the foundation for modern BM specific clinical trial planning. MATERIAL AND METHODS 6031 patients with newly diagnosed BM from different solid tumors treated between 1986–2020 were identified from the Vienna Brain Metastasis Registry. RESULTS The fraction of BM originating from the most common BM causing primary tumors (lung cancer, breast cancer and melanoma) was stable over the observation period from 1986–2020. BM from renal cell carcinoma, colorectal cancer and cancer of unknown primary (CUP) decreased over time (p&amp;lt;0.001). Synchronous diagnosis of BM and primary tumor was more frequently observed in lung cancer and CUP patients compared to breast cancer patients (p&amp;lt;0.001). An increasing fraction of patients presented with asymptomatic BM (1986–1999: 20.2% vs. 2010–2020: 30.4%; p&amp;lt;0.001), specifically in lung cancer (p&amp;lt;0.001), melanoma (p&amp;lt;0.001) and renal cell cancer (p=0.004). A decrease of neurosurgical procedures (1986–1999: 39.3% vs. 2010–2020: 20.4%) and an increase of radiation treatments (1986–1999: 56.5% vs. 2010–2020: 73.0%) and systemic therapies (1986–1999: 0.6% vs. 2010–2020: 2.4%; p&amp;lt;0.001) was observed. Furthermore, median overall survival significantly increased across entities (1986–1999: 5 months vs. 2010–2020: 7 months; p=0.001). Intracranial progression as the cause of death increased across entities (p&amp;lt; 0.001). The prognostic DS-GPA (Hazard ratio [HR] 1.42; p&amp;lt; 0.001) and the Lung-molGPA (HR 1.67; p&amp;lt;0.001) could be validated. CONCLUSION We observed changes of BM presentation and clinical parameters during the observation period depending on primary tumor origins. Future BM studies should follow an entity-specific approach and address the characteristics of modern BM cohorts.

Intracranial effect of osimertinib in relapsed EGFR-mutated T790M-positive and -negative non-small cell lung cancer patients: results from a phase II study

Introduction Osimertinib is effective for relapsed T790M-positive patients with brain metastases. The high brain permeability suggests that also such patients without T790M could benefit. Therefore, we evaluated the effect of osimertinib on brain metastases in both T790M-positive and -negative patients. Methods The TREM-study was an investigator-initiated phase II, single-arm, multi-institutional clinical trial conducted in Northern Europe. Patients with resistance to prior EGFR-TKIs received osimertinib until radiological progression, unacceptable toxicity or death. Baseline brain scans were performed in patients with known or suspected brain metastases and repeated every 8–12 weeks. We assessed intracranial efficacy in patients with baseline brain metastases. Results Brain metastases were detected in 48/199 patients at baseline. Of these, 63% were T790M-positive, 27% -negative and 10% had unknown T790M-status. The majority (73%) of the patients had received prior whole brain radiotherapy and additionally 8% had received stereotactic radiosurgery (SRS). Brain scans were available for review for 42 patients. The intracranial progression free survival was 39.7 versus 3.5 months for T790M + and T790M- patients, respectively (p < 0.001). The overall intracranial disease control rate (iDCR) was 81%, and for T790M + and T790M- patients the DCR was 89% versus 55%, respectively. The estimated risk of CNS progression was 0.8% at 6 months and 6% at 12 months for T790M-positive patients, and 14% and 17% at 6 and 12 months, respectively, for the T790M-negative. Conclusion This subgroup analysis confirms CNS efficacy of osimertinib in patients with the T790M resistance mutation, while other treatment options should be considered for EGFR-TKI relapsed T790M-negative patients with brain metastases.

Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation

IntroductionManagement of central nervous system (CNS) metastases in patients with driver-mutated NSCLC has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases. MethodsData were retrospectively collected from three academic institutions. Two treatment groups (CNS-penetrant TKI alone versus TKI + CNS radiation therapy) were compared for both EGFR- and ALK-positive cohorts. Outcome variables included time to progression, time to intracranial progression, and time to treatment failure, measured from the date of initiation of CNS-penetrant TKI therapy. ResultsA total of 147 patients were included (EGFR n = 94, ALK n = 52, both n = 1). In patients receiving radiation, larger metastases, neurologic symptoms, and receipt of steroids were more common. There were no significant differences between TKI and CNS radiation therapy plus TKI groups for any of the study outcomes, including time to progression (8.5 versus 6.9 mo, p = 0.13 [EFGR] and 11.4 versus 13.4 mo, p = 0.98 [ALK]), time to intracranial progression (14.8 versus 20.5 mo, p = 0.51 [EGFR] and 18.1 versus 21.8 mo, p = 0.65 [ALK]), or time to treatment failure (13.8 versus 8.6 mo, p = 0.26 [EGFR] and 13.5 versus 23.2 mo, p = 0.95 [ALK]). ConclusionsThese results provide preliminary evidence that intracranial activity of CNS-penetrant TKIs may enable local radiation to be deferred in appropriately selected patients without negatively affecting progression.

RADI-17. Outcomes for patients with triple negative breast cancer treated with upfront stereotactic radiosurgery for brain metastases

Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype with high propensity of developing brain metastases (BM). Clinical outcomes and prognostic factors after stereotactic radiosurgery (SRS) for BM were not well defined. Methods We identified 57 consecutive TNBC patients (pts) treated with single fraction SRS for BM during 05/2008–04/2018. Overall survival (OS) from BM diagnosis and freedom from BM progression (FFBMP) after initial SRS were evaluated. BM progression was defined as local and/or distant brain failure (LBF, DBF) after SRS. Kaplan-Meier analyses and Cox proportional hazard regression were used to estimate survival outcomes and identify prognostic factors. Results The median time to BM development from TNBC diagnosis was 23.7 months (mo) (range 0.7‒271.1). Median OS was 13.1 mo (95%CI 8.0‒19.5). On univariate analysis, Karnofsky performance score (KPS) &amp;gt;70 (p=0.03), number of BMs &amp;lt;3 (p=0.016), and BM among the first metastatic sites (p=0.04) were associated with longer OS. On multivariate analysis, KPS ≤70 was associated with higher risk of death (HR 3.0, p=0.03). Of 46 pts with adequate imaging follow-up, 29 (63%) had intracranial progression with a median FFBMP of 7.4 mo (95% CI 5.7–12.7). At 12 mo the estimated cumulative DBF rate was 61.1% (95%CI 40.8%–74.4%) and LBF rate was 17.8% (95%CI 2%–31.1%). Number of BMs (≥3 vs &amp;lt;3) was not associated with FFBMP (p=0.7). Of the 29 pts with BM progression, additional radiation therapy (RT) (vs. no RT) was associated with improved survival (21.7 vs. 7.0 mo, p&amp;lt;0.0001). Conclusions TNBC pts with BM treated with SRS had an OS of 13.1 mo and FFBMP of 7.4 mo. Good KPS was an independent prognostic factor for OS. Further studies with more pts or conducted prospectively are needed to better understand and to improve treatment outcomes in this pt population.

RADI-21. Feasibility of Gamma Knife Surgery for patients with 20 or more brain metastases

BackgroundThe current standard-of-care treatment for brain metastases (BM)≥20 is Whole Brain Radiotherapy (WBRT), which can cause neurocognitive decline detrimental to patients’ quality of life, especially if their functional status is good on presentation. The benefits of Gamma Knife Surgery (GKS) have been shown for BM≤10, but there is no consensus on the upper limit where GKS is no longer beneficial. We hypothesize that selected patients with ≥20 BM may benefit by replacing WBRT with GKS to preserve neurocognition without compromising intracerebral tumor control and overall survival, with additional treatments as needed.MethodologyThis is retrospective analysis of 31 patients with ≥20 BM who underwent single-session GKS between 2016–2021. Twenty-two patients had ECOG of 0 at the time of GKS. Median number of BM at GKS was 30 (20–79) with median total tumour volume 4cm3 (2–28 cm3). Median marginal dose was 20Gy (10-25Gy).ResultsMedian overall survival following GKS was 14-months (95%CI 4-24months), justifying GKS in this population. 11/12 patients that died succumbed due to extracranial disease, while 1 patient, who was treated with WBRT before GKS, succumbed to intracranial tumor progression. Local tumor control achieved was achieved for 63% of patients at 2-years and distal tumor control in 24% of patients at 1.5-years without additional radiation treatment. Salvage GKS was given in seven patients and salvage WBRT in three. One local recurrence was surgically resected. Systemic treatment given to most patients probably contributed to intracranial tumor control. No patients developed significant neurocognitive deficits attributable to GKS during the follow-up period of median 7-months (Q1-Q3: 3-12months).ConclusionMost patients treated with GKS for ≥20 BM have sufficient survival time to benefit from the treatment. Local and distal recurrences can be managed with systemic treatment, salvage GKS, or WBRT, resulting in intracerebral tumor control in vast majority of cases.

OTHR-10. Diverse survival outcomes of HER2+ Breast Cancer Brain Metastases (BrCBM) presenting with isolated brain relapse compared to those with concurrent extracranial disease

BackgroundIn patients with isolated HER2+ BrCBM and no extracranial disease (ECD), there are no consensus guidelines on optimal treatment approaches following CNS-directed therapy. Our goal was to determine the implications of ECD at time of first HER2+ BrCBM on intracranial progression-free survival (PFS1) and overall survival (OS).MethodsRetrospective analysis was performed on 77 patients with HER2+ BrCBM who received 1st CNS radiation from 2006–2020. Demographics, dates of metastatic and intracranial diagnosis, ECD status at 1st BrCBM, and outcomes were collected. The primary endpoint was PFS1 defined as time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from 1st CNS radiation and 1st metastatic disease to date of death/last known alive. ECD status was defined by RECIST1.1 from staging scans within 30 days of 1st BrCBM.ResultsIn this patient cohort, 25% (19/77) had isolated brain relapse/no ECD. Median age was 50 years. Most patients (58%) developed first BrCBM during adjuvant or early-line metastatic therapy. All patients with no ECD presented with isolated brain relapse as first metastatic presentation. Patients with concurrent ECD presented with first BrCBM at a median of 16.6m (95% CI: 10.5 to 25.3) after initial metastatic presentation. Median OS from initial metastatic presentation to death was worse for patients with isolated brain relapse (25.3m, 95% CI: 16.8 to 35.3) compared to those with concurrent ECD (49.7m, 95% CI: 43.2 to 62; p=0.01). Median OS from first CNS involvement to death was not statistically different amongst groups.ConclusionsPatients with isolated HER2+ BrCBM as their initial metastatic event have substantially worse OS compared to patients with concurrent ECD developing CNS metastases later in their disease course. This population with isolated brain relapse deserves investigation of novel treatment algorithms, including earlier introduction of brain-penetrable HER2-targeted agents.

Care Patterns for Stereotactic Radiosurgery in Small Cell Lung Cancer Brain Metastases

IntroductionThe historical standard of care for brain metastases (BMs) from small cell lung cancer (SCLC) has been whole-brain radiotherapy (WBRT). However, there is growing interest in upfront stereotactic radiosurgery (SRS) for select SCLC patients. Materials and MethodsWe invited United State-based Radiation Oncologists (ROs) via email to answer an anonymous survey using a branching logic system addressing their use of SRS and WBRT for SCLC BMs. Wilcoxon rank-sum test and Fisher's exact test were used to compare differences in continuous and categorical variables, respectively. Multivariable logistic regression analyses were fitted for outcome variables including covariates with P < .10 obtained on univariable analysis. ResultsIn total, 309 ROs completed the survey and 290 (95.7%) reported that they would consider SRS for SCLC BMs under certain clinical circumstances. Across patient characteristics, the number of BMs was the most heavily weighted factor (mean 4.3/5 in importance), followed by performance status, cognitive function, and response to prior therapy. Fewer BMs were correlated with increased SRS use (55.8% offered SRS “very frequently” [>75% of cases] or “often” [51%-75% of cases] for 1 BM vs. 1.1% for >10 BM, P < .001). In situations where WBRT was preferred, concern for rapid intracranial progression (45.3%) and lack of high-level data (36.9%) were the most important factors. The majority (60.6%) were aware of a large recent international retrospective analysis (the FIRE-SCLC study) reporting similar OS between upfront SRS and WBRT; awareness of this study was the only respondent variable predictive of SRS use for limited BMs (19.2% of those aware of the study preferring SRS for limited [≤4] BMs before vs. 61% preferring SRS after the publication, P < .001). The majority of respondents (88.2%) expressed a willingness to enroll patients on a recently opened recently opened randomized trial, NRG-CC009, comparing SRS versus hippocampal-avoidance WBRT. ConclusionsIn the first survey of SRS for SCLC BMs, we observed a high level of physician openness to upfront SRS in SCLC, particularly for patients with limited numbers of BMs, as well as significant interest in generating prospective randomized data to clarify the role of SRS in this population.

LncRNA ANRIL Facilitates Vascular Smooth Muscle Cell Proliferation and Suppresses Apoptosis via Modulation of miR-7/FGF2 Pathway in Intracranial Aneurysms.

Proliferation and apoptosis of vascular smooth muscle cells (VSMCs) are linked to intracranial aneurysm (IA) formation and progression. Long antisense noncoding RNA in the INK4 locus (ANRIL) has been reported to regulate VSMC functions in several cardiovascular diseases. However, little is known about how ANRIL influences VSMC proliferation and apoptosis during IA pathogenesis. The expression level of ANRIL in the plasma and arterial wall tissues of patients with IA was detected by real-time quantitative polymerase chain reaction. The functional role of ANRIL in the regulation of VSMC proliferation and apoptosis and its downstream regulatory mechanism were determined using Cell Counting Kit 8, immunofluorescence, terminal-deoxynucleotidyl transferase-mediated UTP nick end labeling, western blotting, luciferase reporter assay, and RNA immunoprecipitation assay. ANRIL was downregulated in the plasma and arterial wall tissues of patients with IA, when compared with control groups. Overexpression of ANRIL significantly promoted VSMC proliferation and blocked cell apoptosis. Mechanistic studies demonstrated that ANRIL directly bound to microRNA-7 (miR-7) and that overexpression of miR-7 overturned the increased cell proliferation and decreased cell apoptosis, which was induced by ANRIL restoration. Besides, further study showed that ANRIL positively regulated fibroblast growth factor 2 (FGF2) expression via targeting miR-7. These results suggested that ANRIL affects VSMC proliferation and apoptosis via regulation of the miR-7/FGF2 pathway in IA, which provided a potential novel strategy for the treatment of IA.

Brigatinib versus other second-generation ALK inhibitors as initial treatment of anaplastic lymphoma kinase positive non-small cell lung cancer with deep phenotyping: study protocol of the ABP trial

BackgroundAvailability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK+ non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK+ NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines.Methods/designIn this exploratory prospective phase II clinical trial, newly diagnosed ALK+ NSCLC patients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy.DiscussionBesides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK+ NSCLC according to molecular features. Patients with low molecular risk and the perspective of a “chronic disease” will be distinguished from “high-risk” cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies.Trial registrationClinicaltrials.gov, NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938Eudra-CT, 2019–001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36

Distinct Characteristics and Clinical Outcomes to Predict the Emergence of MET Amplification in Patients with Non-Small Cell Lung Cancer Who Developed Resistance after Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

Simple SummaryMET amplification is one of the resistance determinants after EGFR-TKI therapy in EGFR mutant NSCLC. In this study, we evaluated the emergence of MET amplification after EGFR-TKI treatment failure. The median progression-free survival associated with the most recent EGFR-TKI treatment was shorter in MET amplification-positive patients than in negative patients. Smoking history and less intracranial progression are associated with MET amplification. Suboptimal responses with previous EGFR-TKI are associated with MET amplification. Proper MET amplification screening for therapeutic targeting is needed.Objectives: Patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) ultimately acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) during treatment. In 5–22% of these patients, resistance is mediated by aberrant mesenchymal epithelial transition factor (MET) gene amplification. Here, we evaluated the emergence of MET amplification after EGFR-TKI treatment failure based on clinical parameters. Materials and Methods: We retrospectively analyzed 186 patients with advanced EGFR-mutant NSCLC for MET amplification status by in situ hybridization (ISH) assay after EGFR-TKI failure. We collected information including baseline patient characteristics, metastatic locations and generation, line, and progression-free survival (PFS) of EGFR-TKI used before MET evaluation. Multivariate logistic regression analysis was conducted to evaluate associations between MET amplification status and clinical variables. Results: Regarding baseline EGFR mutations, exon 19 deletion was predominant (57.5%), followed by L858R mutation (37.1%). The proportions of MET ISH assays performed after first/second-generation and third-generation TKI failure were 66.7% and 33.1%, respectively. The median PFS for the most recent EGFR-TKI treatment was shorter in MET amplification-positive patients than in MET amplification-negative patients (median PFS 7.0 vs. 10.4 months, p = 0.004). Multivariate logistic regression demonstrated that a history of smoking, short PFS on the most recent TKI, and less intracranial progression were associated with a high probability of MET amplification (all p < 0.05). Conclusions: Our results demonstrated the distinct clinical characteristics of patients with MET amplification-positive NSCLC after EGFR-TKI therapy. Our clinical prediction can aid physicians in selecting patients eligible for MET amplification screening and therapeutic targeting.

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer

BackgroundThe improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC).Patients and methodsThis study included all epidermal growth factor receptor-mutated (EGFR+, n = 108) and anaplastic lymphoma kinase-rearranged (ALK+, n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed (n = 34; 24%) or no LT (n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases.ResultsMedian overall survival (OS) was 49.1 months for ALK+ and 19.5 months for EGFR+ patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and ‘short’ EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR+ and ALK+ subsets.ConclusionsDespite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR+/ALK+ NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR/ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management.

Clinical Value of Upfront Cranial Radiation Therapy in Osimertinib-Treated Epidermal Growth Factor Receptor–Mutant Non-Small Cell Lung Cancer With Brain Metastases

As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib has a powerful ability to penetrate the blood-brain barrier and a high potency for controlling brain metastases (BMs) from EGFR-mutant non-small cell lung cancer (NSCLC). The clinical value of cranial radiation therapy in osimertinib-treated NSCLC with BMs remains largely unknown. Patients with NSCLC and BMs and receiving osimertinib treatment as the standard of care were retrospectively enrolled from 2 institutions. Cranial radiation therapy (RT; whole-brain radiation therapy [WBRT] or/and stereotactic radiosurgery [SRS]) performed before disease progression (PD) to osimertinib was categorized as upfront cranial radiation therapy (ucRT group), excluding those treatments performed during prior EGFR-TKI treatment. Overall survival (OS), progression-free survival (PFS), and the time to intracranial progression (iTTP) were compared between the 2 groups, with adjustment by covariates in propensity-score matched (PSM) analyses. The state of having 1 to 3 BM lesions, with a maximal size of ≤3 cm, was defined as having oligo-BM; otherwise; the cases were defined as having multiple BMs. Of the 205 patients enrolled, osimertinib was used as first-line therapy in 74 and second-line therapy in 131. There were 48 patients who received ucRTs, including WBRT in 24 and SRS in 24. All patients with oligo-BM in the ucRT group received SRS alone (n=17), whereas most (n=28; 90.3%) patients with multiple BMs received WBRT. Failure pattern analyses indicated that in the non-ucRT group, 40.2% of the initial PD involved the brain and 76.9% of the cranial PD involved the original sites, indicating the potential roles of ucRT. Indeed, the iTTP was significantly prolonged (P=.010) in the ucRT group among the whole population. In the PSM oligo-BM cohort, the ucRT group showed superior PFS (P=.033) and OS (P=.026) compared with the non-ucRT group, and the differences remained after multivariate Cox analyses. No such differences were observed in the subpopulation with multiple BMs. In osimertinib-treated NSCLC patients with BMs, oligo-BM status could be used as a potential factor to select patients for upfront cranial RT. Further investigation by well-designed clinical trials is warranted.

Effect of continuing osimertinib with chemotherapy in the post-progression setting on progression-free survival among patients with metastatic epidermal growth factor receptor (EGFR) positive non-small cell lung cancer.

9124 Background: Continuing a 1st generation EGFR TKI with chemotherapy upon TKI progression was not shown to be beneficial in the IMPRESS trial. However, the validity of this approach with osimertinib remains under explored. We attempted to characterize the efficacy of continuing osimertinib with chemotherapy in the post-progression setting. Methods: A single-center retrospective review of patients with metastatic EGFR mutant NSCLC who had progressed on osimertinib was performed. Clinical characteristics and treatment outcomes were noted. Progression free survival (PFS), duration of treatment (DOT), overall survival (OS) and rates of intracranial progression were captured. ANOVA or a Fisher exact test were used to identify associations between cohort characteristics and treatment outcomes. Differences in PFS, DOT and OS were assessed using a log-rank test. A Cox proportional hazard model was used to adjust for potential confounders. Results: 73 patients with EGFR mutant NSCLC with post-osimertinib treatment outcomes were identified. Cohort characteristics are summarized in Table. Median duration of follow up was 41 months. Upon progression, osimertinib was discontinued in 34 patients (Cohort A) and continued with next line of therapy in 39 patients (Cohort B). Survival analyses were adjusted for prior lines of therapy, use of platinum doublet chemotherapy, and use of immune checkpoint inhibitors in the post-progression setting. After adjusting for covariates, continuing osimertinib post-progression was associated with an improved PFS (7 vs 4 months; HR 0.58; 95% CI 0.34 – 1.00; p = 0.003) and DOT (7 vs 4 months; HR 0.52; 95% CI 0.31 – 0.87; p = 0.006). There was no difference in OS between Group A and B (52 vs 41 months; HR 0.73; 95% CI 0.43 – 1.24; p = 0.234). Rates of intracranial progression were similar between Group A and B (28% vs 23%; p = 0.649). Conclusions: After adjusting for covariates, continuing osimertinib with chemotherapy in the post-progression setting was associated with a significant difference in PFS and DOT, but with no differences in OS. Continuing osimertinib does not appear to influence the rate of subsequent intracranial progression. Prospective studies are needed to identify the optimal practice pattern.[Table: see text]

Safety and efficacy outcomes with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma and brain metastases: results from the CheckMate 920 trial.

4515 Background: Combination therapy with nivolumab plus ipilimumab (NIVO+IPI) has demonstrated long-term efficacy and tolerability in patients with previously untreated advanced renal cell carcinoma (aRCC). Previous phase 3 clinical trials of patients with advanced or metastatic cancers have mostly excluded patients with brain metastases. CheckMate 920 is an ongoing, phase 3b/4 clinical trial of NIVO+IPI treatment in patients with aRCC with a high unmet medical need. We present updated safety and efficacy results for the cohort of patients with aRCC of any histology and brain metastases from CheckMate 920 (NCT02982954). Methods: Patients with previously untreated advanced/metastatic aRCC of any histology, with asymptomatic brain metastases (not currently receiving corticosteroids or radiation), and Karnofsky performance status ≥ 70% were assigned to treatment with NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks × 4 doses followed by NIVO 480 mg every 4 weeks for ≤ 2 years or until disease progression/unacceptable toxicity. The primary endpoint was incidence of grade ≥ 3 immune-mediated adverse events (imAEs) within 100 days of last dose of study drug. Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 (both per investigator). Exploratory endpoints included overall survival (OS). Results: Of 28 treated patients with brain metastases, 85.7% were men; median (range) age was 60 (38–87) years, and 14.3% had sarcomatoid features. With 24.5 months minimum follow-up of the 28 patients enrolled, median duration of therapy (range) was 3.4 (0.0–23.3) months for NIVO and 2.1 (0.0–3.3) months for IPI. No grade 5 imAEs occurred. Grade 3–4 imAEs by category were diarrhea/colitis (7.1%), hypophysitis (3.6%), rash (3.6%), hepatitis (3.6%), and diabetes mellitus (3.6%). Of the 25 patients who were evaluable for ORR, the ORR was 32.0% (95% CI, 14.9–53.5). No patients achieved complete response, 8 achieved partial response, and 10 patients had stable disease. Median time to response (range) was 2.8 (2.4–3.0) months. Median duration (range) of response was 24.0 (3.9–not estimable [NE]) months; 4 of 8 responders remain without reported progression. Of 28 patients, 7 (25%) had intracranial progression. Median PFS (n = 28) was 9.0 (95% CI, 2.9–12.0) months. Median OS (n = 28) was still not reached (95% CI, 14.1 months–NE). Conclusions: In patients with previously untreated aRCC and brain metastases, a population with high unmet medical need that is often underrepresented in clinical trials, the approved treatment regimen of NIVO+IPI followed by NIVO for aRCC showed no new safety signals and continues to show encouraging antitumor activity with longer follow-up. Clinical trial information: NCT02982954.

A phase II trial combining nivolumab and stereotactic brain radiosurgery for treatment of brain metastases in patients with NSCLC.

2023 Background: Previous studies suggested activity of anti-PD-1 in brain metastases from non-small cell lung cancer (NSCLC) and renal cell cancer (RCC). This investigator initiated phase 2 trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with brain metastases from NSCLC and RCC. Methods: This is a multicentre open-label trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated brain metastases, no whole brain radiotherapy and no prior immunotherapy were eligible. Study treatment commenced with a dose of nivolumab (240mg or 480mg IV), which was continued for up to 2 years at bi-weekly or monthly intervals until progression. SRS (15-21Gy) to all visible un-irradiated brain lesions was administered within 14 days after the first dose of nivolumab (cycle 1). Patients were followed by brain MRI, CT scan of the chest, abdomen and pelvis, neurocognitive and quality of life questionnaires (FACT-Br) every 3 months. The primary endpoint was intracranial progression free survival (icPFS), with death and disease progression within the brain as events. Results from NSCLC patients are presented here. Results: Of the 26 study patients, 22 NSCLC patients were enrolled between Aug 2017 and January 2020. Patients had a median of 2 (1-9) brain metastases. The median diagnosis-specific graded prognostic score was 2 (1-3). Median treatment and follow-up durations were 4.3 months (0-24.8 months) and 11 months (0-24.8 months), respectively. Forty-two percent of the patients had received prior cytotoxic chemotherapy, and 1 patient had received prior brain SRS. PD-L1 status was known for 21 of the 22 NSCLC (12 with ≥50% PD-L1 expression (DAKO 22C3). Median icPFS was 5.0 months (3 intracranial progression and 8 deaths without progression in the brain). Accounting for death as a competing risk, the 1-year cumulative incidence of intracranial relapse was 17.4%. Median extracranial PFS and overall survival were 2.9 months and 14 months, respectively. Four grade 3 adverse events in 2 patients were related to nivolumab or SRS. The rate of survival free of neurocognitive decline (Hopkins Verbal Learning Test total recall) was estimated to be 89% by 4 months. Mean FACT-Br total scores were 89.4 at baseline and improved (p = 0.01) to 139.3 within 2-4 months. Conclusions: Neurocognitive and quality of life assessments suggest that upfront SRS during nivolumab is well tolerated. High intracranial control was observed, but deaths from extracranial disease progression resulted in short icPFS. Studies evaluating the strategic addition of SRS combined with more efficacious systemic treatments are needed. Clinical trial information: 02978404.

A prospective data analysis of targeted therapy combined with concurrent radiation therapy for brain metastasis from NSCLC with driver gene mutation.

e14006 Background: Previous studies have shown that brain metastases of non-small cell lung cancer (NSCLC) with positive driver genes have poor prognosis. There is still lack of prospective studies on the efficacy and safety of targeted therapy combined with concurrent radiotherapy for brain metastases(BM). Methods: NSCLC patients, with ECOG score 0-2, having MRI confirmed brain or meningeal metastases were eligible. Patients must have driver gene mutation and received corresponding targeted therapy. The intracranial radiotherapy regimen was SRS or whole brain radiotherapy. The primary objective was iPFS (intracranial progression-free survival); Secondary objectives were: iORR (intracranial objective response rate), PFS (progression-free survival), OS (overall survival). MMSE (Mini Mental State Examination) and FACT-Br was carried out before/after weekly radiotherapy and during systematic treatment. Treatment-related toxicities were assessed according RTOG/EORTC criteria. Tumor responses were evaluated using RECIST V1.1 criteria. Survival analysis was performed using the Graphprism version 6.0 by Kaplan-Meier method and log-rank test. Results: 23 NSCLC with BM was included. Among them, 10 patients were newly diagnosed with NSCLC BM. 2 patients’ BM progressed after targeted therapy. 11 NSCLC patients were newly diagnosed with BM after targeted therapy. 91.3% of patients presented an EGFR mutation, including primarily EGFR 19-exon deletion, EGFR 21-L8585R. 11.5% presented with c-MET mutation. Median age was 58.34 yrs(44-71yrs). Patients were mostly treated with Erolotinib and Gefitinib. All patients were adenocarcinoma. At last follow-up, for patients newly diagnosed with NSCLC BM, 8 patients had achieved intracranial progression, and 7 patients had reached OS, of which 1 died before completing WBRT. The median iPFS was 9.3m(95%CI:0.571-4.055) and the median OS was 11.9m (95%CI:0.2752 -2.732). As for patients who progressed after targeted therapy, one patient’s OS was 4.4m, iPFS of the other patient was 3.9m. Among NSCLC patients who were newly diagnosed with BM after targeted therapy, 8 patients had achieved intracranial progression and 5 patients had reached OS. The median iPFS was 6.13m (95%CI:0.247-1.751) and the mOS was 13.8m (95%CI:0.3660-3.634). Common adverse effects include dry skin, fatigue, dizziness, headache, anorexia, and grade I myelosuppression and no serious adverse events (SAEs); MMSE and FACT-Br scores were no significant differences at baseline and follow-up. Conclusions: In stage IV brain metastatic NSCLC with driver gene mutation, targeted therapy combined with concurrent radiotherapy for BM is tolerable, and there is no significant impact on the quality of life and cognitive function after radiotherapy. The evaluation of efficacy requires further follow-up. Support:LC2019ZD009,81972853 and 81572279.

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.

Impact of extracranial disease status on survival after initial central nervous system (CNS) involvement and radiation therapy in HER2+ breast cancer brain metastases (BCBM).

1041 Background: BCBMs are very common in metastatic HER2+ breast cancer. CNS-directed local therapy is the gold standard for treatment, followed by systemic HER2-targeted therapies. In patients with HER2+ BCBM and stable extracranial disease (ECD), consensus guidelines recommend continuing current systemic therapy after local therapy. Our goal was to determine the implications of ECD status at time of HER2+ BCBM first CNS involvement on outcomes including intracranial progression-free survival (PFS1) and overall survival (OS). Methods: Retrospective analysis was performed on data extracted from 77 patients with HER2+ BCBM who received CNS radiation at Duke between 2006 and 2020 following initial documentation of CNS involvement. Demographics, dates of metastatic and intracranial diagnosis, ECD status at first CNS involvement, systemic therapy, and outcomes were collected. The primary endpoint was PFS1 defined as the time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from first CNS radiation and first metastatic disease to date of death or last known alive. ECD status was defined by RECIST1.1 from systemic staging scans within 30 days of first CNS involvement. Results: In this patient cohort of HER2+ BCBMs undergoing CNS radiation at first CNS involvement, &gt;50% of patients had extracranial disease control: no ECD (25%) or stable/responding disease (31%). 52% of patients’ tumors were ER+. Median age was 50 years (range 27 – 75). Most patients (58%) developed first CNS involvement during adjuvant or first/second line metastatic therapy. For first CNS radiation, 49% received SRS and 48% WBRT. All patients with no ECD presented with isolated CNS disease as first metastatic presentation. Median OS in this cohort from initial metastatic disease to death was markedly worse for patients with no ECD (25.3m, 95% CI: 16.8 to 35.3) compared to those with progressive or stable/responding ECD (48.8m, 95% CI: 28.1 to 65; and 52.9 months, 95% CI: 43.7 to 73.3, respectively; p=0.03). Median OS from first CNS involvement to death was not statistically different amongst groups. This analysis did not detect median PFS1 differences based on ECD after first CNS radiation: progressive ECD (6.3m), no ECD (8.7m), or stable/responding ECD (10.6m) (p=0.13), though clinically meaningful differences were observed. Conclusions: Patients with isolated HER2+ BCBM with no ECD at the time of their initial CNS involvement (25% of population) have substantially worse OS compared to patients who present with ECD and develop CNS metastases later in their disease course. This population with isolated CNS disease at metastatic presentation deserves investigation of novel treatment algorithms, including earlier introduction of brain penetrable HER2-targeted agents.