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Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy, and targeted therapy. Advances in the basic scientific understanding of MBM, including the role of astrocytes and metabolic adaptations to the brain microenvironment, are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single-cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in the coming years and render novel treatment approaches that might improve MBM patient outcomes.

There is a critical need for effective treatments for leptomeningeal disease (LMD). We conducted a single-arm, first-in-human phase I/Ib study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in melanoma patients with LMD. The primary endpoints were determination of safety and the recommended IT nivolumab dose. The secondary objective was overall survival (OS). Patients were treated with IT nivolumab alone in cycle 1; IV nivolumab 240 mg was included in subsequent cycles, which were administered every two weeks. The dose escalation portion evaluated 5, 10, 20, and 50 mg of IT nivolumab. Twenty-five patients were enrolled and treated (twenty-one previously treated with anti-PD1): 2 with 5 mg, 3 with 10 mg, 14 with 20 mg, and 6 with 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level; 10 patients experienced grade 1 or 2 toxicities, possibly related to IT nivolumab. The recommended IT dose of nivolumab was 50 mg (with IV nivolumab 240 mg) every 2 weeks. The median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. Concurrent IT and IV nivolumab is safe, feasible and appears to have a preliminary efficacy signal in patients with melanoma LMD, including in patients with previous anti-PD1 therapy.

Simple Summary For brain tumor patients, surgeons must resect as much of the tumor as possible while preserving the patient’s function and quality of life. This requires preoperative imaging that accurately identifies important parts of the brain. Transcranial magnetic stimulation is a way of preoperatively finding the areas of the brain connected to motor function. However, few studies have investigated the accuracy and clinical relevance of the data. In this study, we examine the functional outcomes of patients who had TMS points resected and patients who did not. We aim to address key technical barriers to performing this analysis. We also aim to discern the appropriate role of TMS tractography in preoperative diagnostic imaging. Insights gained from this study can be used to select the right patients and plan for the optimal surgeries. Abstract Surgeons must optimize the onco-functional balance by maximizing the extent of resection and minimizing postoperative neurological morbidity. Optimal patient selection and surgical planning requires preoperative identification of nonresectable structures. Transcranial magnetic stimulation is a method of noninvasively mapping the cortical representations of the speech and motor systems. Despite recent promising data, its clinical relevance and appropriate role in a comprehensive mapping approach remains unknown. In this study, we aim to provide direct evidence regarding the clinical utility of transcranial magnetic stimulation by interrogating the eloquence of TMS points. Forty-two glioma patients were included in this retrospective study. We collected motor function outcomes 3 months postoperatively. We overlayed the postoperative MRI onto the preoperative MRI to visualize preoperative TMS points in the context of the surgical cavity. We then generated diffusion tensor imaging tractography to identify meaningful subsets of TMS points. We correlated the resection of preoperative imaging features with clinical outcomes. The resection of TMS-positive points was significantly predictive of permanent deficits (p = 0.05). However, four out of eight patients had TMS-positive points resected without a permanent deficit. DTI tractography at a 75% FA threshold identified which TMS points are essential and which are amenable to surgical resection. TMS combined with DTI tractography shows a significant prediction of postoperative neurological deficits with both a high positive predictive value and negative predictive value.

Background: The role of microbiome in different steps of tumor development and progression has been shown across various tumor types. However, the contribution of microbiome to brain tumors is yet to be understood. A crosstalk between the gut and oral microbiota and the brain microenvironment has been demonstrated in the context of neurological and neurodegenerative diseases. We hypothesize that distinct gut and oral microbial signatures are associated with primary and metastatic brain tumors. Methods: Matched stool, saliva, and buccal swab samples were collected prospectively from patients with primary or metastatic brain tumors who underwent surgical tumor resection at the University of Texas MD Anderson Cancer Center. Samples were collected using the OMNIgene microbiome collection and stabilization kits (DNAgenotek, Kit Number OM-200, OMR-120, and OM-505 for stool, buccal swab, and saliva, respectively). Samples were then processed, aliquoted, and stored at -80 C. Samples from 10 patients for each disease type were sequenced via metagenomic shotgun sequencing. Taxonomic profiling was conducted through MetaPhlAn and Virmap, for bacterial and viral taxa, respectively. Beta diversity was analyzed using Bray-Curtis and UniFrac analyses. Biom files were further analyzed to identify the signatures associated with each disease type, using the Phyloseq and Microbiome packages in R and heatmaps were generated using the Pheatmap package. Results: Microbiome beta diversity analysis demonstrated distinct clustering of stool, saliva, and buccal swab samples in both primary and metastatic brain tumor patients, which confirmed high sample quality and lack of cross-contamination between buccal swab and oral samples during sample collection. Analysis of oral microbiome samples demonstrated distinct bacterial and viral signatures that were enriched in metastatic brain tumors in comparison to primary brain tumors. In contrast, the composition of gut microbial taxa was comparable between metastatic and primary brain tumors and demonstrated enrichment in Bacteroides and Microviridae families. Conclusion: Our analysis of gut and oral microbiome in patients with primary and metastatic brain tumors suggest that distinct bacterial and viral taxa within the oral microbiome are enriched in metastatic brain tumors. We are in the process of expanding our clinical cohort to further validate these findings. Moreover, mechanistic studies are ongoing to understand the contribution of microbial signatures to the development and progression of metastatic and primary tumors. (These studies were supported by the National Institute of Health (F32CA260769) and the Glioblastoma Moonshot Program at the MD Anderson Cancer Center.) Citation Format: Golnaz Morad, Matthew Lastrapes, Matthew Wong, Pranoti Sahasrabhojane, Sherise Ferguson, Nadim Ajami, Jennifer Wargo. Distinct oral microbial signatures are associated with primary and metastatic brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3045.

Background: Treatment options for patients (pts) with leptomeningeal metastasis (LM) are limited, and the prognosis is poor (median overall survival (OS) ~ 4-5 months). Tucatinib is a potent and highly selective HER2-targeted tyrosine kinase inhibitor approved for use in combination with trastuzumab and capecitabine in pts with metastatic HER2+ breast cancer who have received ≥1 prior HER2-based regimen in the metastatic setting, including pts with brain metastases. TBCRC049 (NCT03501979) is an investigator-initiated, phase 2, single-arm study evaluating the safety and efficacy of tucatinib, trastuzumab and capecitabine in HER2+ breast cancer with newly diagnosed LM. We have previously demonstrated therapeutic levels of tucatinib in CSF in pts with HER2+ LM (Stringer-Reasor et al, ASCO 2021). We now report efficacy outcomes of the study. Methods: Eligible pts were adults with HER2+ metastatic breast cancer, Karnofsky performance status (KPS) > 50, and newly diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Pts with treated or concurrent/new brain metastases were allowed. Pts received tucatinib 300 mg orally twice daily starting with cycle 1, day 1 (C1D1); capecitabine 1000 mg/m2 orally twice daily on days 1-14 of a 21-day cycle, starting on C1D1; and trastuzumab loading dose of 8 mg/kg IV on C1D1, and then 6 mg/kg IV once every 21 days, starting with C2D1. The primary endpoint was OS. Planned enrollment was 30 pts; however, due to lack of accrual since the FDA approval of tucatinib (4/2020), the study was closed after 17 patients were enrolled. Results: Baseline disease characteristics at LM diagnosis are shown in Table 1. Eight pts (47%) had abnormal CSF cytology (positive or equivocal). All pts had MRI evidence of LM in the brain, and 14/17 (82%) had brain metastases, of which 11 (65%) had received prior treatment for brain metastases. Median age at study treatment initiation was 53 years. Median number of treatment cycles received was 5 (range: 2-27). Median OS time was 11.9 months (95% CI: 4.1, NR). At data cutoff (6/22/21), 7/17 pts (41%) remained alive and median followup was 17 months(8-26). Median time to CNS progression was 6.9 months (95% CI: 2.8, 13.8). Conclusions: In pts with LMD from HER2+ metastatic breast cancer who were treated with tucatinib, trastuzumab, and capecitabine, the median OS time was nearly 1 year. This is the first prospective evidence of clinical benefit with a systemic regimen for HER2+ LM. Further studies evaluating brain-penetrant oral drugs in this rare pt population are needed. Baseline Disease Characteristics (N=17)Number%Baseline CSF cytologyPositive529%Negative847%Equivocal318%None obtained1*6%Symptoms attributable to LMDYes1588%No212%MRI evidence of LMDBrain only1165%Brain and Spine635%History of brain metastasisYes1482%Prior treatment1165%New/concurrent diagnosis – no prior treatment318%No318%Extra-CNS DiseaseYes1165%No635%*One patient had VP shunt and difficulty sampling fluid; all CSF sent for research PK and non-PK studies Citation Format: Rashmi K Murthy, Barbara O'Brien, Donald A Berry, Akshara Singareeka-Raghavendra, Maria Gule Monroe, Jason Johnson, Jason White, Jennifer Childress, Justin Sanford, Jill Schwartz-Gomez, Michelle Melisko, Aki Morikawa, Sherise Ferguson, John F de Groot, Ian Krop, Vicente Valero, Mothaffar Rimawi, Antonio Wolff, Debu Tripathy, Nancy U Lin, Erica Stringer-Reasor. Safety and efficacy of a tucatinib-trastuzumab-capecitabine regimen for treatment of leptomeningeal metastasis (LM) in HER2-positive breast cancer: Results from TBCRC049, a phase 2 non-randomized study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-02.

Previous immune profiling in brain tumors has mostly focused on the high-density tumor areas, and as such, little is known about the nature and types of immunological responses that occur across the tumor landscape, including at the tumor-central nervous system (CNS) interface. En bloc resections of glioblastomas (n=10) and CNS lung metastases (n=10) were oriented on slides as whole mount wedges spanning three anatomical areas including the invasive edge, tumor region, and necrotic core. Tumor segmentation was performed and regional differences were immunologically analyzed for 770 immune genes using the NanoString nCounter System with CIBERSORT analysis to delineate immune gene signatures. The analysis was validated using multiplex immunohistochemistry (IHC). The top upregulated immune genes in the GBM necrotic core were associated with macrophages, including the CD163 lineage marker, chemotactic factors (such as CCL18 and SAA1), and the phagocytosis stimulatory factors (such as IL-8 and MARCO). The necrotic core downregulates GBM antigens (such as IL13RA2 and MAGEB2), markers of dendritic cells (such as LILRA4), and immune stimulatory processes including MHC, IFN, IL-12, TNF, and ICOS expression. In direct contrast, the infiltrating edge of the GBM relative to the tumor is enriched with stimulators for NK cytotoxicity (i.e., CD244, the fractalkine receptor for immune cells), chemokines for thymocytes and dendritic cells, and immune stimulatory IL-12 receptors. Glioblastoma has rare focal isolated areas of CD3 T-cell reactivity within the tumor. Similar to GBM, the necrotic center of lung metastases is enriched in immune suppressive macrophages, as reflected by CD163 IHC staining and arginase expression; however, they are more frequently infiltrated with M1 macrophages. Yet the majority of lung cancers are more diffusely infiltrated with CD3 T cells, especially at the infiltrating edge. In general, we noted distinct inter- and intratumoral immune gene signatures, with macrophages dominating the brain tumors, especially the necrotic core.