Intracranial Progression Research Articles

Management of patients with ALK-positive advanced non-small cell lung cancer who received brain radiotherapy on study in the phase 3 CROWN trial.

9063 Background: Approximately 30% of patients with ALK-positive non-small cell lung cancer (NSCLC) present with brain metastases at diagnosis. Lorlatinib is a potent brain-penetrant ALK tyrosine kinase inhibitor (TKI) that showed improved time to intracranial (IC) progression compared with crizotinib in patients with and without brain metastases at baseline. This post hoc analysis from the phase 3 CROWN study summarizes the management of patients who received brain radiotherapy (RT) during the study. Methods: In the CROWN study, 296 patients with previously untreated ALK-positive advanced NSCLC were randomized 1:1 to receive oral lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). Patients who received brain RT while on study treatment or after the initiation of subsequent systemic anticancer therapy were included in this post hoc analysis. Results: As of September 20, 2021, at approximately 3 years of follow-up, median time to IC progression was not reached (NR; 95% CI, NR-NR) in the lorlatinib arm and was 16.6 (95% CI, 11.1-NR) months in the crizotinib arm. At the time of this analysis, 4 of 149 patients (2.7%) in the lorlatinib arm and 20 of 147 patients (13.6%) in the crizotinib arm received brain RT; study treatment was ongoing in 2 of 4 patients (50.0%) in the lorlatinib arm and discontinued in all 20 patients in the crizotinib arm. Median time from randomization to first brain RT was 18.2 (range, 6.4-31.3) months in the lorlatinib arm and 11.1 (range, 2.5-37.5) months in the crizotinib arm. In patients who had brain RT, median duration of treatment was 20.0 (IQR, 6.3-37.1) months with lorlatinib and 7.8 (IQR, 4.0-11.1) months with crizotinib. In the lorlatinib arm, 2 of 4 patients (50.0%) received concomitant brain RT and continued lorlatinib beyond progression. In the crizotinib arm, patients received brain RT while on study treatment or on subsequent systemic anticancer therapies with ALK TKIs or chemotherapy. Follow-up analysis is ongoing. Conclusions: At approximately 3 years of follow-up in the CROWN study, fewer patients in the lorlatinib arm received brain RT than those in the crizotinib arm. At the time of this analysis, study treatment was ongoing in 2 of 4 patients (50.0%) in the lorlatinib arm but was discontinued in all patients in the crizotinib arm. Patients were mostly managed with other ALK TKIs and/or chemotherapy following brain RT in the crizotinib arm. ClinicalTrials.gov: NCT03052608. Clinical trial information: NCT03052608 .

Outcome of immune checkpoint inhibitors in patients with extensive-stage small-cell lung cancer and brain metastases.

e20625 Background: Brain metastases (BMs) are common in extensive-stage small-cell lung cancer (SCLC) and are underrepresented in pivotal clinical trials that demonstrate the efficacy of immune checkpoint inhibitors (ICIs). We conducted a retrospective analysis to assess the role of ICIs in BM lesions in less selected patients. Methods: Patients with histologically confirmed extensive-stage SCLC who were treated with ICIs were included in this study. Objective response rates (ORRs) were compared between the with-BM and without-BM groups. Kaplan‒Meier analysis and the log-rank test were used to evaluate and compare progression-free survival (PFS). The intracranial progression rate was estimated using the Fine-Gray competing risks model. Results: A total of 133 patients were included, 45 of whom started ICI treatment with BMs. In the whole cohort, the overall ORR was not significantly different for patients with and without BMs (p = 0.856). The median progression-free survival for patients with and without BMs was 6.43 months (95% CI: 4.70-8.17) and 4.37 months (95% CI: 3.71-5.04), respectively (p = 0.054). In multivariate analysis, BM status was not associated with poorer PFS (p = 0.101). Our data showed that different failure patterns occurred between groups, with 7 patients (8.0%) without BM and 7 patients (15.6%) with BM having intracranial-only failure as the first site progression. The cumulative incidences of brain metastases at 6 and 12 months were 15.0% and 32.9% in the without-BM group and 46.2% and 59.0% in the BM group, respectively (Gray’s p < 0.0001). Conclusions: Although patients with BMs had a higher intracranial progression rate than patients without BMs, the presence of BMs was not significantly associated with a poorer ORR and PFS with ICI treatment in multivariate analysis.

Outcome of immune checkpoint inhibitors in patients with extensive-stage small-cell lung cancer and brain metastases.

Brain metastases (BMs) are common in extensive-stage small-cell lung cancer (SCLC) and are underrepresented in pivotal clinical trials that demonstrate the efficacy of immune checkpoint inhibitors (ICIs). We conducted a retrospective analysis to assess the role of ICIs in BM lesions in less selected patients. Patients with histologically confirmed extensive-stage SCLC who were treated with ICIs were included in this study. Objective response rates (ORRs) were compared between the with-BM and without-BM groups. Kaplan-Meier analysis and the log-rank test were used to evaluate and compare progression-free survival (PFS). The intracranial progression rate was estimated using the Fine-Gray competing risks model. A total of 133 patients were included, 45 of whom started ICI treatment with BMs. In the whole cohort, the overall ORR was not significantly different for patients with and without BMs (p = 0.856). The median progression-free survival for patients with and without BMs was 6.43 months (95% CI: 4.70-8.17) and 4.37 months (95% CI: 3.71-5.04), respectively (p =0.054). In multivariate analysis, BM status was not associated with poorer PFS (p = 0.101). Our data showed that different failure patterns occurred between groups, with 7 patients (8.0%) without BM and 7 patients (15.6%) with BM having intracranial-only failure as the first site progression. The cumulative incidences of brain metastases at 6 and 12 months were 15.0% and 32.9% in the without-BM group and 46.2% and 59.0% in the BM group, respectively (Gray's p<0.0001). Although patients with BMs had a higher intracranial progression rate than patients without BMs, the presence of BMs was not significantly associated with a poorer ORR and PFS with ICI treatment in multivariate analysis.

Intracranial and Extracranial Progression and Their Correlation With Overall Survival After Stereotactic Radiosurgery in a Multi-institutional Cohort With Brain Metastases

Clinical trials for metastatic malignant neoplasms are increasingly being extended to patients with brain metastases. Despite the preeminence of progression-free survival (PFS) as a primary oncologic end point, the correlation of intracranial progression (ICP) and extracranial progression (ECP) events with overall survival (OS) is poorly understood for patients with brain metastases following stereotactic radiosurgery (SRS). To determine the correlation of ICP and ECP with OS among patients with brain metastases completing an initial SRS course. This multi-institutional retrospective cohort study was conducted from January 1, 2015, to December 31, 2020. We included patients who completed an initial course of SRS for brain metastases during the study period, including receipt of single and/or multifraction SRS, prior whole-brain radiotherapy, and brain metastasis resection. Data analysis was performed on November 15, 2022. Non-OS end points included intracranial PFS, extracranial PFS, PFS, time to ICP, time to ECP, and any time to progression. Progression events were radiologically defined, incorporating multidisciplinary clinical consensus. The primary outcome was correlation of surrogate end points to OS. Clinical end points were estimated from time of SRS completion via the Kaplan-Meier method, while end-point correlation to OS was measured using normal scores rank correlation with the iterative multiple imputation approach. This study included 1383 patients, with a mean age of 63.1 years (range, 20.9-92.8 years) and a median follow-up of 8.72 months (IQR, 3.25-19.68 months). The majority of participants were White (1032 [75%]), and more than half (758 [55%]) were women. Common primary tumor sites included the lung (757 [55%]), breast (203 [15%]), and skin (melanoma; 100 [7%]). Intracranial progression was observed in 698 patients (50%), preceding 492 of 1000 observed deaths (49%). Extracranial progression was observed in 800 patients (58%), preceding 627 of 1000 observed deaths (63%). Irrespective of deaths, 482 patients (35%) experienced both ICP and ECP, 534 (39%) experienced ICP (216 [16%]) or ECP (318 [23%]), and 367 (27%) experienced neither. The median OS was 9.93 months (95% CI, 9.08-11.05 months). Intracranial PFS had the highest correlation with OS (ρ = 0.84 [95% CI, 0.82-0.85]; median, 4.39 months [95% CI, 4.02-4.92 months]). Time to ICP had the lowest correlation with OS (ρ = 0.42 [95% CI, 0.34-0.50]) and the longest median time to event (median, 8.76 months [95% CI, 7.70-9.48 months]). Across specific primary tumor types, correlations of intracranial PFS and extracranial PFS with OS were consistently high despite corresponding differences in median outcome durations. The results of this cohort study of patients with brain metastases completing SRS suggest that intracranial PFS, extracranial PFS, and PFS had the highest correlations with OS and time to ICP had the lowest correlation with OS. These data may inform future patient inclusion and end-point selection for clinical trials.

Survival and Clinical Characteristics of Patients with Glioblastoma with Primitive Neuronal Component (P13-13.004)

<h3>Objective:</h3> Evaluate the survival and clinical characteristics of patients with diagnosis of glioblastoma with primitive neuronal component (GBM-PNC) on initial diagnosis compared to patients diagnosed with GBM-PNC at recurrence following prior diagnosis of malignant glioma without primitive component. <h3>Background:</h3> A subset of malignant gliomas are found to have solid-looking primitive nodules which confer a diagnosis of glioblastoma with primitive neuronal component (GBM-PNC). At initial diagnosis, GBM-PNC is associated with increased responsiveness to platinum-based therapies and high rates of cerebrospinal fluid dissemination. It is unknown if the same characteristics and risks exist when primitive neuronal component develops at recurrence after an initial diagnosis with a malignant glioma. <h3>Design/Methods:</h3> The University of Washington pathology database was queried between the years of 2005 to 2021 to identify patients with a pathological diagnosis of GBM-PNC. Clinical and radiographic data were abstracted. Descriptive statistics and survival analysis were preformed. <h3>Results:</h3> 20 patients with diagnosis of GBM-PNC were identified and 16 had appropriate clinical information for inclusion. 11 patients were diagnosed with GBM-PNC at initial surgery and 6 were diagnosed at surgery for presumed recurrent malignant glioma. For patients found to have GBM-PNC at recurrence, the median overall survival was 40months compared to only 17months for patients diagnosed at initial surgery. Patients diagnosed at recurrence, also had longer time to first progression of 26.5months compared to 12months for patients initially diagnosed with GBM-PNC. The 4 patients who had intracranial progression leading to diagnosis of GBM-PNC all had cystic appearance on MRI. 33% of patients diagnosed with GBM-PNC at recurrence developed leptomeningeal dissemination. <h3>Conclusions:</h3> Patients who are diagnosed at GBM-PNC at recurrence of a prior malignant glioma have improved survival compared to patients who have a primitive neuronal component of the malignant glioma diagnosed at initial resection. This pathology was associated with a cystic radiographic appearance when intracranial. <b>Disclosure:</b> Dr. McGranahan has nothing to disclose. Patrick Cimino has nothing to disclose. Ms. Costanza has nothing to disclose.

Minimizing Intracranial Disease Before Stereotactic Radiation in Single or Solitary Brain Metastases.

Stereotactic radiotherapy (SRT) in multiple fractions (typically ≤5) can effectively treat a wide range of brain metastases, including those less suitable for single-fraction stereotactic radiosurgery (SRS). Prior prospective studies on surgical resection with stereotactic radiation have focused exclusively on SRS, and retrospective studies have shown equivocal results regarding whether surgery is associated with improved outcomes compared with SRT alone. We compared resection with postoperative cavity SRT or SRS to SRT alone in patients with 1 brain metastasis, while including patients receiving SRS alone as an additional reference group. We studied 716 patients in a retrospective, single-institution cohort diagnosed with single or solitary brain metastases from 2007 to 2020. Patients receiving whole-brain radiotherapy were excluded. Cox proportional hazards models were constructed for overall survival and additional intracranial outcomes. After adjustment for potential confounders, surgery with cavity SRT/SRS was associated with decreased all-cause mortality (hazard ratio [HR]: 0.39, 95% CI [0.27-0.57], P = 1.52 × 10 -6 ) compared with SRT alone, along with lower risk of neurological death attributable to intracranial tumor progression (HR: 0.46, 95% CI [0.22-0.94], P = 3.32 × 10 -2 ) and radiation necrosis (HR: 0.15, 95% CI [0.06-0.36], P = 3.28 × 10 -5 ). Surgery with cavity SRS was also associated with decreased all-cause mortality (HR: 0.52, 95% CI [0.35-0.78], P = 1.46 × 10 -3 ), neurological death (HR: 0.30, 95% CI [0.10-0.88], P = 2.88 × 10 -2 ), and radiation necrosis (HR: 0.14, 95% CI [0.03-0.74], P = 2.07 × 10 -2 ) compared with SRS alone. Surgery was associated with lower risk of all-cause mortality and neurological death in cardinality-matched subsets of the cohort. Among surgical patients, gross total resection was associated with extended overall survival (HR: 0.62, 95% CI [0.40-0.98], P = 4.02 × 10 -2 ) along with lower risk of neurological death (HR: 0.31, 95% CI [0.17-0.57], P = 1.84 × 10 -4 ) and local failure (HR: 0.34, 95% CI [0.16-0.75], P = 7.08 × 10 -3 ). In patients with 1 brain metastasis, minimizing intracranial disease specifically before stereotactic radiation is associated with improved oncologic outcomes.

Brain metastases in the elderly - Impact of residual tumor volume on overall survival.

Due to demographic changes and an increased incidence of cancer with age, the number of patients with brain metastases (BMs) constantly increases, especially among the elderly. Novel systemic therapies, such as immunotherapy, have led to improved survival in recent years, but intracranial tumor progression may occur independently of a systemically effective therapy. Despite the growing number of geriatric patients, they are often overlooked in clinical trials, and there is no consensus on the impact of BM resection on survival. The aim of this study was to analyze the impact of resection and residual tumor volume on clinical outcome and overall survival (OS) in elderly patients suffering from BM. Patients ≥ 75 years who had surgery for BM between April 2007 and January 2020 were retrospectively included. Residual tumor burden (RTB) was determined by segmentation of early postoperative brain MRI (72h). Contrast-enhancing tumor subvolumes were segmented manually. "Postoperative tumor volume" refers to the targeted BMs. Impact of preoperative Karnofsky performance status scale (KPSS), age, sex and RTB on OS was analyzed. Survival analyses were performed using Kaplan-Meier estimates for the univariate analysis and the Cox regression proportional hazards model for the multivariate analysis. One hundred and one patients were included. Median age at surgery was 78 years (IQR 76-81). Sixty-two patients (61%) had a single BM; 16 patients (16%) had two BMs; 13 patients (13%) had three BMs; and 10 patients (10%) had more than three BMs. Median preoperative tumor burden was 10.3 cm3 (IQR 5-25 cm3), and postoperative tumor burden was 0 cm3 (IQR 0-1.1 cm3). Complete cytoreduction (RTB = 0) was achieved in 52 patients (52%). Complete resection of the targeted metastases was achieved in 78 patients (78%). Median OS was 7 months (IQR 2-11). In univariate analysis, high preoperative KPSS (HR 0.986, 95% CI 0.973-0.998, p = 0.026) and small postoperative tumor burden (HR 1.025, 95% CI 1.002-1.047, p = 0.029) were significantly associated with prolonged OS. Patients with RTB = 0 survived significantly longer than those with residual tumor did (12 [IQR 5-19] vs. 5 [IQR 3-7] months, p = 0.007). Furthermore, prolongation of survival was significantly associated with surgery in patients with favorable KPSS, with an adjusted HR of 0.986 (p = 0.026). However, there were no significances regarding age. RTB is a strong predictor for prolonged OS, regardless of age or cancer type. Postoperative MRI should confirm the extent of resection, as intraoperative estimates do not warrant a complete resection. It is crucial to aim for maximal cytoreduction to achieve the best long-term outcomes for these patients, despite the fact the patients are advanced in age.

Abstract 37: A novel technique to preclinically assess the ability of targeted therapies to inhibit both primary and metastatic non small cell lung carcinoma

Abstract Lung cancer remains a devastating cancer diagnosis around the world, resulting in 18% of all cancer-related deaths. Lung cancer often metastasizes to the brain, significantly reducing life expectancy. Up to 7% of patients with non-small cell lung cancer (NSCLC) already have brain metastasis when they are first diagnosed, and 20%-40% of patients with NSCLC will develop this complication during disease progression. Currently there are no targeted therapies specific for brain metastases, and the blood-brain barrier can pose a physiologic impediment to many cytotoxic drugs and antibody-based therapies. Here, we will discuss the development and use of xenograft models to address metastatic brain disease via a direct intracranial implant coupled with a subcutaneous “primary” tumor to effectively allow evaluation of the response to treatment at both locations. Treatment with targeted therapies could have significantly different penetration and absorption rates, which will alter pharmacokinetic and/or pharmacodynamic (PK/PD) assessment across either tissue. The dual implant technique can be a powerful tool to assess the simultaneous impact of treatment on established metastatic disease and primary tumor. We have characterized the dual disease induction parameters for two human NSCLC cell lines: NCI-H1975-Luc and PC-9-Luc. Both cell lines have been transfected with luciferase to allow for bioluminescence imaging (BLI) to monitor the intracranial disease progression. Both NCI-H1975-Luc and PC-9-Luc are of interest to the research community due to their unique mutational EGFR T790M status. Consistent with the historical and published data, the H1975-luc and PC-9-luc models behaved as expected, producing reliable tumor progression with minimal intragroup variability. In each case, subcutaneous tumors (primary site) reached an evaluation size of ~1000 mm3 in ~20 days, and intracranial tumors (metastatic site) exhibited a total flux doubling time of ~2 days by BLI. Treatment with Osimertinib, an approved first-line treatment for EGFR+ NSCLC patients, was effective against both the subcutaneous and intracranial tumors. Treatment with Osimertinib at 25 mg/kg, given orally, produced 100% complete regressions (CR) against the subcutaneous tumors, which never re-grew prior to study termination on Day 26 post implant and 100% partial regressions (PR) against the established intracranial tumors, which re-grew following the conclusion of treatment at the same rate as the control brain tumors. These data show a difference between the responsive nature of subcutaneous and intracranial NSCLC tumors representing the difference in responsiveness of primary tumors and brain metastases. Utilizing this in vivo dual implant technique can be effective in comparing and assessing the ability of targeted therapies to inhibit both primary and metastatic diseases. Citation Format: Erin Trachet, Scott Wise. A novel technique to preclinically assess the ability of targeted therapies to inhibit both primary and metastatic non small cell lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 37.

Recent trends of characteristics and treatments in adults with newly diagnosed brain metastases.

We aimed to evaluate recent trends in characteristics and treatments among patients with brain metastases in clinical practice. All newly diagnosed patients with brain metastases during 2016-2021 at a single cancer center were enrolled. We collected the detailed features of each patient and estimated the number of candidates considered to meet the following criteria used in common clinical trials: Karnofsky performance status ≥70 and mutated non-small cell lung cancer, breast cancer or melanoma. The brain metastases treatments were classified as follows: (i) stereotactic radiosurgery, (ii) stereotactic radiosurgery and systemic therapy, (iii) whole-brain radiotherapy, (iv) whole-brain radiotherapy and systemic therapy, (v) surgery, (vi) immune checkpoint inhibitor or targeted therapy, (vii) cytotoxic agents and (ix) palliative care. Overall survival and intracranial progression-free survival were estimated from brain metastases diagnosis to death or intracranial progression. A total of 800 brain metastases patients were analyzed; 597 (74.6%) underwent radiotherapy, and 422 (52.7%) underwent systemic therapy. In addition, 250 (31.3%) patients were considered candidates for common clinical trials. Compared to 2016, the later years tended to shift from whole-brain radiotherapy to stereotactic radiosurgery (whole-brain radiotherapy: 35.7-29.1% and stereotactic radiosurgery: 33.4-42.8%) and from cytotoxic agents to immune checkpoint inhibitor/targeted therapy (cytotoxic agents: 10.1-5.0 and immune checkpoint inhibitor/targeted therapy: 7.8-10.9%). There was also an increase in the proportion of systemic therapy combined with radiation therapy (from 26.4 to 36.5%). The median overall survival and progression-free survival were 12.7 and 5.3months, respectively. This study revealed the diversity of brain metastases patient characteristics, recent changes in treatment selection and the percentage of candidates in clinical trials.

Abstract P1-10-10: Radiation Treatment Patterns for Elderly Women with Breast Cancer Brain Metastases

Abstract Background Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in elderly patients, there is limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of elderly breast cancer patients with BM (≥ 65 yo) treated at our institution and compared them to younger patients. Methods An IRB-approved single-institutional review of biopsy-proven breast cancer patients with BM treated with 1 to 5-fraction stereotactic radiation therapy (SRT) from 2015 to 2020 was performed. Primary endpoint was intracranial progression free survival (PFS) defined as time interval between end of SRT to date of first CNS progression. Secondary endpoints were overall survival (OS) from end of SRT, and radiation treatment patterns. Kaplan-Meier estimates, and Cox proportional hazard regression method were used for survival analyses. SPSS v26.0 was used for statistical analysis and p-value &amp;lt; 0.05 was considered significant. Results A total of 115 metastatic breast cancer patients with BMs were included of which N=29 were ≥65 yo and N=86 were &amp;lt; 65 yo. They received a total of 43 and 143 courses of stereotactic linac-based radiation therapy (RT) respectively to a mean number of 4.3 BM lesions (range 1-22). Median age at RT was 70 years (range 65-84) compared to 50.5 years (31-64) in younger patients. About 55.2% of elderly patients were ER/PR positive/Her2 negative (vs 24.4% in younger cohort), 31% were Her2 positive (vs 41.9%) and 13.8% were triple negative (vs 33.7%). Among patient characteristics, there was significant difference among elderly and young patients in hormone receptor status (p = 0.016); CNS only oligometastatic disease (0% vs 11.2%, p = 0.005); and the presence of extracranial disease at SRS (97.7% vs 79.7%, p &amp;lt; 0.001). There was no significant difference between the two age groups in Karnofsky performance score (KPS) (62.7% vs 45.5% with KPS ≤ 80, p = 0.131), number of brain lesions treated (23.2% vs 30.1% with ≥ 5 BMs, p = 0.445), number of patients receiving prior whole brain radiotherapy (WBRT) (10.3% vs 19.8%, p = 0.062), surgery (23.2% vs 30.1%, p = 0.592), systemic therapy (including chemotherapy, targeted therapy and endocrine therapy) after SRT (86% vs 86.7%, p = 0.543), and salvage WBRT (10.3% vs 19.8%, p = 0.134). Median OS after RT was poorer in patients ≥ 65 yo compared to younger patients (7.9 months vs 14.4 months, p = 0.020), while intracranial PFS from RT was similar (8.5m vs 6.5m, p =0.345). The rates of freedom from neurological death and leptomeningeal disease (LMD) at 1 year were similar between the two groups (83.3% vs 87%, p = 0.780 and 87.6% vs 73.3%, p = 0.627, respectively). On univariate analysis, significant predictors of survival were age ≥65 yo (hazard risk, HR = 1.56), KPS &amp;lt; 80 (HR = 1.69), extracranial progression at RT (HR = 2.44), systemic therapy after RT (HR = 0.28) and LMD (HR = 1.57). On multivariate analysis, age was not a significant factor for survival after adjusting for KPS, extracranial progression and systemic therapy. Conclusions Although elderly women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and outcomes for breast cancer patients with BMs and personalized decision making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in elderly patients. Citation Format: Rituraj Upadhyay, Haley K. Perlow, Nicole Williams, Brett Klamer, Julia White, Jose G. Bazan, Sachin R. Jhawar, Dukagjin M. Blakaj, John Grecula, Andrea Arnett, Evan Thomas, Arnab Chakravarti, Raju R. Raval, Maryam Lustberg, Joshua Palmer, Sasha Beyer. Radiation Treatment Patterns for Elderly Women with Breast Cancer Brain Metastases [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-10.

A phase II study of nivolumab with ipilimumab and cabozantinib in patients with untreated renal cell carcinoma brain metastases.

TPS745 Background: A SEER analysis from 2010 to 2013 demonstrated that the incidence of brain metastases(mets) at the diagnosis of renal cell carcinoma(RCC) is 1.51%, and around 12% of patients(pts) with advanced RCC (aRCC) also had mets to the brain. Brain mets confer a poor prognosis. Local management strategies for brain mets from RCC include surgical resection, stereotactic radiosurgery and whole brain radiation therapy. Although systemic therapies including tyrosine kinase inhibitors and immune checkpoint inhibitors have been explored in aRCC pts with brain mets, prospective data is lacking. Cabozantinib is a potent small molecule inhibitor of multiple tyrosine kinases that was approved by FDA for pts with aRCC alone or in combination with nivolumab. Cabozantinib has demonstrated activity in patients with intracranial tumors. A phase III trial (COSMIC-313) recently evaluated cabozantinib in combination with nivolumab and ipilimumab compared to nivolumab plus ipilimumab and demonstrated significantly improved progression-free survival (PFS) in previously untreated pts with aRCC. The combination was found to be safe as frontline systemic treatment. The role of this combination in patients with aRCC with brain mets remains undefined. As such, we propose a study to assess the safety and efficacy of cabozantinib in combination with nivolumab/ipilimumab in RCC pts with untreated brain mets. We believe the results from this trial could provide additional treatment options for pts with RCC brain mets who are typically excluded from clinical trials. Methods: This is a phase II study to assess the safety and efficacy of the combination of nivolumab with ipilimumab and cabozantinib in pts with untreated brain mets from RCC until disease progression or intolerable toxicities or patient withdrawal. Planned accrual is 40 pts. Pts will be treated with nivolumab (3mg/kg) and ipilimumab (1mg/kg) IV every 3 weeks for 4 doses and cabozantinib 40mg daily. Then pts will be treated with nivolumab 480mg IV Q 4 weeks and cabozantinib 40mg daily until progression or intolerable toxicities or patient’s withdrawal. A lead-in group of 6 pts will be closely monitored for dose limiting toxicities(DLT). If stopping criteria (&gt;3 patients develop DLTs) is met, then treatment will be switched to nivolumab plus cabozantinib omitting ipilimumab. The primary objective is intracranial progression free survival(PFS). Secondary objectives include intracranial safety, objective response rate (intracranial + extracranial) by modified RECIST v1.1 and RECIST v1.1, extracranial PFS and overall survival. This phase II trial is currently enrolling pts. Clinical trial information: NCT05048212 .

Abstract 35: Changes In Sickle Cell Vasculopathy After Hematopoietic Stem Cell Transplantation

Introduction: Cerebral vasculopathies (stenoses and aneurysms) are a major cause of stroke and disability in adults and children with sickle cell disease (SCD). HSCT has been shown to prevent or improve large vessel intracranial stenosis in children when compared to standard care (Verlhac 2020). We sought to determine the impact of HSCT on the development and progression of cerebral vasculopathies in adults with SCD. Methods: The study population included patients with SCD (HbSS, HbSC, and HbS/beta-thalassemia) that were enrolled in NIH studies (14-H-0077, 09-H-0225, 03-H-0170) and underwent HSCT from 2004-19 and received pre- and post-transplant MRI/MRA studies. MRA images were reviewed by two independent readers and scored for stenoses in eight intracranial arteries, Moyamoya collateralization, and presence and progression of intracranial aneurysms. Changes in vasculopathy were compared before and after transplantation. Results: Eighty-seven patients were included in the study, mean age 32.2 yrs. and 58% male. Median follow-up period was 3.3 yrs. (range: 0.5-17 yrs.), and 28% had evidence of vasculopathy at transplant; 17% with stenotic vasculopathy and 13% with aneurysm(s). None of the patients without vasculopathy developed stenoses or aneurysms after HSCT. MRA stenoses scores improved after HSCT in 62% of patients with vasculopathy, with a median change of 1.0 (range: 1-6; p=0.01). All intracranial aneurysms identified at transplant remained unchanged in follow-up. Conclusions: Hematopoietic stem cell transplantation improved or prevented the development of vasculopathy in adults with sickle cell disease.

Intraoperative ultrasound is valuable for detecting intracranial hematoma progression and decreasing mortality in traumatic brain injury.

Our aim was to explore the clinical benefit of intraoperative ultrasound in decompressive craniectomy (DC) for traumatic brain injury (TBI). From January 1, 2018, through April 30, 2021, 54 patients who developed acute subdural hematoma (SDH) due to blunt injury and underwent DC with or without intraoperative ultrasound assistance were retrospectively included in our study. Logistic regression analyses were performed to compare the therapeutic efficacy in the two groups. In the ultrasound group (14 patients, 25.93%), intraoperative ultrasound was used for assisting hematoma removal and/or ventriculostomy during DC. In the control group (40 patients, 74.07%), ultrasound was not used during the operation and ventriculostomy was not performed. No statistically significant differences in age, sex, initial Glasgow Coma Scale (GCS) score, blood loss, postoperative intracranial pressure (ICP), duration of hyperosmolar therapy, or Glasgow Outcome Scale Extended (GOS-E) score 6months after injury were observed. No mortality was recorded in the ultrasound group. The mortality rate in the control group during hospitalization was 25% (p < 0.05). Intraoperative ultrasound is helpful for intracranial hematoma removal and ventriculostomy with cerebrospinal fluid drainage and decreases mortality in experienced hands. The reason for higher mortality rate in the control group might result from poor hematoma clearance rate and poor postoperative intracranial pressure control. It is a useful tool for diagnosing and assisting with treatment in cases of TBI.

Abstract B032: Immune landscape of resected brain metastases in patients treated with and without immune checkpoint blockade immunotherapy

Abstract Background: The brain metastatic niche has been historically difficult to study and thus poorly understood. Although brain metastases portend high morbidity and mortality, increasing evidence has shown that immune checkpoint blockade (ICB) can confer long-lasting responses in patients. How ICB remodels the brain tumor microenvironment is still relatively unknown. Here, we examine the immune microenvironment of resected brain metastases in a cohort of 19 patients pre-operatively treated with and without ICB using single-cell methods. Methods: Tumor tissue was obtained from patients who underwent surgical resection of brain metastases at our institution, and single-cell RNA sequencing (scRNAseq) and multiplex immunofluorescence (mIF) analyses were performed, including unsupervised clustering and multivariate regression. Results: A total of 8 patients with pre-operative exposure and 11 patients without pre-operative exposure to ICB were included. Represented histologies included melanoma, breast, lung, and endometrial cancers. Basic demographic and clinical characteristics, including age, sex, body mass index, performance status, stage at initial diagnosis, and time from initial diagnosis to development of brain metastases were not significantly different between the two groups. mIF revealed an immune exclusion phenotype in ICB naïve samples compared to ICB-treated samples, manifested by the lower density and percentage of lymphoid infiltrate and presence of immune perivascular cuffing. T cells in the ICB-treated group had higher expression of both effector and exhaustion markers (IFNG, GZMH, PDCD1, HAVCR2, TOX, NR4A2, NR4A1); while myeloid cells exhibited increased interferon-stimulated gene expression (CXCL9, CXCL10, STAT1, GBP1, GBP4, GBP5, MHC-II genes). One particular cluster of CD8+ T cells, the TCF and CD226-expressing progenitor population, correlated with overall survival. Furthermore, ICB-treated samples showed decreased CD14+ CD206+ perivascular macrophages, suggesting that these macrophages play a role in restraining immune cell extravasation and tumor infiltration. Conclusion: This work contributes to the growing understanding of the brain metastatic niche and the impact of ICB on this unique microenvironment. While it is not surprising that we found increased T cell numbers and activation in ICB-treated samples, we also found increased evidence of TIL exhaustion. This may be a result of selection bias, as patients who undergo resection after ICB treatment typically do so due to poor response and intracranial progression, or from chronic antigen stimulation from checkpoint inhibition. Interestingly, our studies suggest that the myeloid populations, particularly the perivascular macrophages, are an important mediator of the brain tumor microenvironment. Further functional studies are needed to investigate the role of these perivascular macrophages and elucidate the cross-talk between these cells, infiltrating lymphocytes, and the brain vasculature. Citation Format: Eileen F. Shiuan, Lu Sun, Jeremy Reynoso, Shanpeng Li, Gang Li, Jiyoon Kim, Won Kim, Robert Prins. Immune landscape of resected brain metastases in patients treated with and without immune checkpoint blockade immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B032.

JMJD3 is Involved in Intracranial Aneurysm Development by Regulating DLX2 Expression through H3K27me3 Modification.

Intracranial aneurysms are dilatations in the arteries that supply blood to the brain. Rupture of an intracranial aneurysm leads to a subarachnoid hemorrhage, which is fatal in about 50% of the cases. Microarray-based mRNA expression studies provide unbiased information about molecular mechanisms of intracranial aneurysm and the foundation for functional studies. In this study, by using a Gene Expression Omnibus (GEO) dataset, we identified distal-less homeobox 2 (DLX2) as a significantly upregulated gene in intracranial aneurysms and set to dissect its functional role and upstream mechanism. Here, we found that DLX2 expression was elevated in intracranial aneurysm patients. Silencing of DLX2 suppressed the proliferative capacity of human aortic vascular smooth muscle cells (HA-VSMC) and promoted their apoptosis. Moreover, loss of DLX2 promoted collagen I and collagen III and inhibited the levels of MMP2/9 and pro-inflammatory factors. Additionally, jumonji domain-containing protein 3 demethylase (JMJD3) promoted DLX2 expression by inhibiting H3K27me3 modification. Depletion of JMJD3 exerted the same function as DLX2 in vitro and in vivo, whereas overexpression of DLX2 in the presence of JMJD3 knockdown led to accentuated intracranial aneurysm progression and enhanced HA-VSMC survival. We conclude that JMJD3 promotes DLX2 expression through inhibition of H3K27me3 modification, thereby promoting intracranial aneurysm formation.

Long-term outcomes with reduced-dose whole-brain radiotherapy and a stereotactic radiosurgery boost for primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is an aggressive diffuse large B-cell lymphoma. Treatment approaches are historically associated with neurotoxicity, particularly with high-dose whole-brain radiotherapy (WBRT). We hypothesized that reduced dose-WBRT (rd-WBRT) followed by a stereotactic radiosurgery (SRS) boost could provide durable disease control without significant adverse effects. We retrospectively reviewed PCNSL patients treated with rd-WBRT plus an SRS boost at Duke University between 2008 and 2021. Progression-free survival and overall survival (OS) were estimated using competing risk and Kaplan-Meier methods. We identified 23 patients with pathologically confirmed PCNSL. Median age at diagnosis was 69 years (Q1Q3: 52-74) and median Karnofsky Performance Scale (KPS) was 80 (Q1Q3: 70-80). Median follow-up was 21 months. Median doses for rd-WBRT and SRS were 23.4 Gy (Q1Q3: 23.4-23.4) and 12 Gy (Q1Q3: 12-12.5), respectively. The cumulative incidence of intracranial progression at 2 years was 23% (95% CI: 8-42). Six patients (26%) developed distant radiographic progression while 2 patients (9%) developed both distant and local progression. Ten patients (44%) were alive without progression at last follow-up. By Kaplan-Meier estimate, the 2-year OS was 69% (95% CI: 46-84). There were no reported grade 3 + radiation-induced toxicities. The combination of rd-WBRT with an SRS boost appears well-tolerated with durable intracranial control. This approach may represent a treatment option for select patients, such as those with progressive or refractory disease. Further prospective studies are needed to validate these findings and determine whether this approach could be incorporated into consolidation strategies.

Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases.

Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months (P = .0007). The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

Prognostic factors for overall survival and intracranial progression in patients with renal cancer metastasis into the brain after neurosurgical treatment

Introduction. Treatment of patients with brain metastases is an important problem that should be considered in the framework of combination approach. Introduction of new techniques of drug therapy as well as radiotherapy and neurosurgical treatment allows to significantly increase patient survival. Effective drug therapy and local control of brain metastases are of utmost importance in prediction of overall survival and patient quality of life.Aim. To investigate the prognostic factors for overall survival and intracranial progression (local recurrences, distant metastases) in patients with brain metastases of renal cancer after neurosurgical resection.Materials and methods. Retrospective analysis of the treatment results of 114 patients with metastatic brain lesions due to renal cancer who underwent neurosurgical resection (NSR) at the N. N. Blokhin National medical Research Center of Oncology was performed. Clinical data of 102 (89.5 %) of 114 patients for whom data on survival was available were evaluated. Among them, 80 (78.4 %) of patients died, 22 (21.5 %) are under observation. Extracranial disease status at the time of NSR was known in 82 (71.9 %) patients: 45 (54.8 %) patients had extracranial metastases, and 37 (45.1 %) did not. Total resection of brain metastases with perifocal and perivascular zones was performed in 92 (90.1 %) patients; in other cases, fragmental lesion resection was performed.Results. median overall survival after NSR was 13.8 months (95 % confidence interval 10.3–18.6). per study data, factors affecting overall survival of patients with brain metastases of renal cancer after neurosurgical resection were presence / absence of extracranial metastases and patient’s functional status. Local recurrences in the postoperative cavity after NSR were observed in 24 (21 %) of 114 patients. median time of local recurrence was not achieved. Statistically significant factor of high risk of recurrence in the postoperative cavity was presence of lesions with maximal diameter ≥2 cm. Development of new (distant) metastases was observed in 31 (27.2 %) of 114 patients. median survival without distant metastases in patients with brain metastases after NSR was not achieved. frequencies of distant metastases at 6, 12 and 24 months were 15.5; 24.1 and 35.8 % respectively. per multifactor analysis, factors affecting development of distant metastases in the brain after NSR are multiple metastatic brain lesions and presence of extracranial metastases.Conclusion. Neurosurgical resection in patients with cerebral metastases of renal cancer in the total group leads to median overall survival of 13.8 months. predictors of better overall survival are absence of extracranial metastases and high functional status.

Cerebrospinal fluid-derived circulating tumor DNA is more comprehensive than plasma in NSCLC patients with leptomeningeal metastases regardless of extracranial evolution

IntroductionMetastases to the central nervous system (CNS) are devastating neurological complications. Circulating cell-free tumor DNA (ctDNA) from cerebrospinal fluid (CSF) better represents genomic alterations in CNS tumors compared to plasma (PLA). However, the clinical value of cerebrospinal fluid (CSF) as a liquid biopsy medium in non-small cell lung cancer patients with leptomeningeal metastases (NSCLC-LM), regardless of extracranial evolution, remains unclear. Patients and methods14/48 NSCLC-BM patients and 34/48 NSCLC-LM patients were enrolled in this study. The genomic mutation profiles in CSF and matched PLA for patients with single CNS progression (cohort one, N = 22) or intracranial progression with extracranial disease progression (cohort two, N = 12) were compared. ctDNA in the CSF and simultaneously collected PLA was subjected to next-generation target sequencing (NGS) of 168 cancer-relevant genes. ResultsCSF is more comprehensive of driver genomic mutation profile than in matched PLA in patients with a single CNS progression. In addition, potential prognostic markers are much higher in CSF samples than related PLA. For example, the detection rate of EGFR-amp in CSF was more than twice of the rate in matched PLA. Moreover, CDKN2A/B, PIK3CA/G, CDK4/6, and MET were detected uniquely in CSF samples and, all of these genetic mutations were correlated with poor outcomes.Almost all genetic mutation profiles detected in PLA could be seen in matched CSF samples in cohort two. With the driver genes, such as EGFR or ALK, have a higher detection rate in CSF compared to PLA. Moreover, the potential survival maker genes CDK4/6 (6/12, 50%), CDKN2A/B (2/12, 17%), EGFR-amp (1/12, 8%), MET (1/12, 8%), and PIK3CA (1/12, 8%) were unique to the CSF samples. ConclusionFor NSCLC -LM patients, regardless of single intracranial progression or intracranial progression simultaneously with extracranial evolution, CSF is superior to matched PLA.

Decoding molecular programs in melanoma brain metastases

Melanoma brain metastases (MBM) variably respond to therapeutic interventions; thus determining patient’s prognosis. However, the mechanisms that govern therapy response are poorly understood. Here, we use a multi-OMICS approach and targeted sequencing (TargetSeq) to unravel the programs that potentially control the development of progressive intracranial disease. Molecularly, the expression of E-cadherin (Ecad) or NGFR, the BRAF mutation state and level of immune cell infiltration subdivides tumors into proliferative/pigmented and invasive/stem-like/therapy-resistant irrespective of the intracranial location. The analysis of MAPK inhibitor-naive and refractory MBM reveals switching from Ecad-associated into NGFR-associated programs during progression. NGFR-associated programs control cell migration and proliferation via downstream transcription factors such as SOX4. Moreover, global methylome profiling uncovers 46 differentially methylated regions that discriminate BRAFmut and wildtype MBM. In summary, we propose that the expression of Ecad and NGFR sub- classifies MBM and suggest that the Ecad-to-NGFR phenotype switch is a rate-limiting process which potentially indicates drug-response and intracranial progression states in melanoma patients.