Treatment Of Melanoma Brain Metastases Research Articles

Antipsychotic Zuclopenthixol Inhibits Melanoma Growth and Brain Metastasis by Inducing Apoptosis and Cell Cycle Arrest.

The incidence of melanoma brain metastasis (MBM) is high and significantly compromises patient survival and quality of life. Effective treatment of MBM is made difficult by the blood-brain barrier (BBB), since it restricts the entry of drugs into the brain. Certain anti-psychotic drugs able to cross the BBB have demonstrated efficacy in suppressing brain metastasis in preclinical studies. However, the activity of zuclopenthixol against MBM is not yet clear. Cell viability assays were employed to investigate the potential of zuclopenthixol in the treatment of MBM. Subsequently, the mechanism of action was investigated by RNA-sequencing (RNAseq), flow cytometry-based cell cycle and apoptosis assays, protein expression analysis, and autophagy flux detection. Additionally, the efficacy of zuclopenthixol against tumor growth was investigated in vivo, including MBM models. Zuclopenthixol inhibited the proliferation of various melanoma cell lines at minimal doses by causing cell cycle arrest in the G0/G1 phase and mitochondrial-mediated intrinsic apoptosis. Zuclopenthixol also induced cytoprotective autophagy, and inhibition of autophagy enhanced the anti-melanoma effects of zuclopenthixol. Furthermore, zuclopenthixol inhibited the growth of human melanoma tumors in nude mice, as well as the growth of intracranial metastases in a mouse model of MBM. These results demonstrate that zuclopenthixol has significant potential as an effective therapeutic agent for MBM.

P10.19.A COMBINED TREATMENT USING MAPK AND PI3K SIGNALING PATHWAYS INHIBITORS EFFECTIVELY REDUCES GROWTH OF MELANOMA BRAIN METASTASIS CELLS IN VITRO

Abstract BACKGROUND Brain metastasis is associated with poor prognosis, and median survival time from the time of diagnosis for cancer patients with brain metastases is only a few months. Brain metastases are estimated to occur in 20-40% of cancer patients. All solid tumors may spread to the brain, but the risk of developing brain metastases is higher in breast cancer, lung cancer and melanoma. Standard treatment of melanoma brain metastases (MBM) includes radiation therapy and surgery. In melanoma, the mitogen activated protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K) signaling pathways are often activated by genetic alterations. An activation mutation (BRAFV600E) in the MAPK pathway is commonly found in melanoma refractory to therapy. This mutation leads to increased proliferation and tumor cell survival. Previous studies show that BRAF-inhibitors block the increase in cell proliferation induced by the activated BRAF gene, however, many of the patients develop drug resistance within a few months. Objectives: In this project, we aimed to show that drugs targeting BRAF (vemurafenib) and PI3K pathways (buparlisib) used in combination effectively inhibit growth of treatment resistant MBM cells. MATERIAL AND METHODS Our research lab has previously developed human MBM cell lines, which have been made resistant towards vemurafenib treatment. To study the potential antitumoral effects of combined treatment we used these cells in several in vitro assays such as cell viability and proliferation, cell migration, colony forming assay, spheroid growth, apoptosis by IncuCyte and western blot to confirm effects on signaling pathways. RESULTS We found that combination treatment reduced the viability of resistant MBM cells, as well as their ability to proliferate. Further, the cells showed less ability to migrate after therapy. Altered cell morphology was also seen. Initial results show effects on colony formation and increased apoptosis after combined treatment. CONCLUSION A combination of MAPK and PI3K inhibitors effectively inhibits growth and viability of treatment resistant human MBM cells, compared to single drug treatment alone. The results support clinical use of combined therapy for melanoma patients with metastatic disease.

Current Treatment of Melanoma Brain Metastases.

Melanoma is a type of skin cancer in which there is a strong correlation between its occurrence and exposure to ultraviolet radiation. Although it is not the most common skin cancer, it has the highest mortality rate of all skin cancers. The prognosis of patients is significantly worsened by melanoma metastasis to the brain, which often occurs in patients with advanced disease. The formation and development of melanoma metastases to the brain involve a very complex process, and their mechanisms are not fully understood. One of the ways for metastatic melanoma cells to survive and develop cancer in the brain environment is the presence of oncogenic BRAF mutation, which occurs in up to 50% of metastatic melanoma cases. Before discovering new methods of treating metastases, the overall survival of patients with this disease was 6 months. Currently, research is being conducted on new drugs using immunotherapy (immune checkpoint inhibitors: anti-PD-1, anti-CTLA-4) and targeted therapy (BRAF and MEK inhibitors) to improve the prognosis of patients. In this article, we summarize the current state of knowledge about the results of treating brain metastases with new systemic therapies.

Immunotherapy as a Turning Point in the Treatment of Melanoma Brain Metastases.

The incidence of tumor metastases in the brain is many times more frequent than primary brain tumors, affecting a very large share of patients suffering from systemic cancer. Advanced malignant melanoma is well known for its ability to invade the brain space and current treatment options, such as surgery and radiation therapy, are not very efficient and cause notable complications and morbidity. The aim of this review is to explore the recent advances and future potential of using immunotherapy in the treatment of melanoma brain metastases. Several FDA approved immunotherapeutic drugs have shown to be able to at least double the overall survival rates in such patients. Clinical trials of varying phases are underway and available results are promising, significantly prolonging survival rates in patients with previously untreated melanoma brain metastases. Nevertheless, not all patients respond to these immunotherapies, facing a high percentage of resistant cases, without yet knowing the mechanisms and causes of resistance behind. Also, at the time of immunotherapy, a small percentage of patients is affected by pseudoprogression, which can be difficult to distinguish from true progression given the similarity of symptoms. Therefore, there is a pressing need for future research about treatment effectiveness in patients with brain metastases from melanoma, including outcomes from the perspective of patients.

A Role of Therapy that Targets Immune Checkpoint Proteins for the Treatment of Melanoma Brain Metastasis, Liver, Breast, Pancreatic Cancer and Pancreatic Adenocarcinoma

Checkpoint inhibitors are a type of immune therapy used to treat different types of cancers. These drugs block different checkpoint proteins, for example, CTLA-4, PD-1, and PD-L1 inhibitors. They block proteins that stop the immune system from attacking the cancer cells. Checkpoints are also described as a type of monoclonal antibody that antagonizes binding between B7 to CTLA-4 and PD-L1 to PD-1. Immune checkpoint inhibitors are used to treat BARCA mutated triple-negative breast cancer (TNBCS) in patients who do not respond to chemotherapy, and also in the treatment of highly mutated and solid tumors such as brain tumors, liver, and pancreatic cancers. Immune checkpoint inhibitors exhibit an effect on solid tumors by suppressing CTLA-4, PD-1, and PDL-1. Anti-PD-1 is less toxic than anti-CTLA-4. For melanoma Brain metastasis immune checkpoint therapy is more effective and Combination therapy has great efficacy and less toxicity which improves overall survival rather than individual therapy liver cancer as hepatocellular carcinoma and cholangiocarcinoma used treatment with Genetics based therapy while using alternative immune checkpoint ligands, co-inhibitory (eg. LAG-3) or decreased t-cell infiltration causing therapy failure. Clinical studies for pancreatic cancer have not been completed yet and treating PDA needs more research as immune checkpoint inhibitors is a new treatment against PDA. A new potent class of nivolumab, pembrolizumab, and ipilimumab have been FDA approved. For mutated tumors, Combination therapy between checkpoint inhibitors and chemotherapy has great efficacy and improves the city of life and overall survival, rather than individual therapy when using radiation or chemotherapy alone.

Radiosurgery fractionation and post-treatment hemorrhage development for intact melanoma brain metastases.

To assess, for intact melanoma brain metastases (MBM), whether single-fraction stereotactic radiosurgery (SRS) versus fractionated stereotactic radiotherapy (fSRT) is associated with a differential risk of post-treatment lesion hemorrhage (HA) development. A single institution retrospective database review identified consecutive patients with previously unresected MBM treated with robotic SRS/fSRT between 2013 and 2021. The presence of lesion HA was determined by multi-disciplinary imaging review. Dosimetric variables were reported as biologically effective doses using an α/β ratio of 2.5 (BED2.5). Statistical analysis was performed using mixed effect logistic regression for post-treatment HA and Cox frailty modeling for local control (LC). The cohort included 48 patients with 226 intact MBM treated with SRS/fSRT. Of lesions without prior HA, 63 of 133 lesions (47.4%) receiving SRS demonstrated evidence of post-treatment HA versus 2 of 24 lesions (8.3%) treated with fSRT (p = 0.01). A larger maximum BED2.5 was observed in lesions developing HA compared to no HA (238.3Gy vs. 211.4Gy; p = 0.022). 12-month LC was 65.7% (95% CI 37.2-87.3%) and 77.5% (95% CI 58.5-91.2%) for lesions demonstrating pre-treatment and post-treatment HA, respectively, with no local failure events observed within 12months for non-hemorrhagic lesions (p < 0.001). We found an increased incidence of post-treatment HA for intact MBM receiving a larger maximum BED2.5, which was significantly higher for single fraction treatments within our cohort. The presence of lesion HA, either pre- or post-treatment, was indicative of inferior LC. Further investigations of optimal dose and fractionation schedules for treatment of MBM in the era of immunotherapy are warranted.

Real World Outcomes of Melanoma Brain Metastases Treated with Immunotherapy with or without Stereotactic Radiosurgery

<h3>Purpose/Objective(s)</h3> Immunotherapies (IT) are effective for melanoma with extracranial metastases based on multiple phase 3 clinical trials. For patients with melanoma brain metastases (MBM), however, the role of IT is less clear. We hypothesized that treatment of MBM with IT and SRS in combination results in longer survival compared to IT alone. <h3>Materials/Methods</h3> Using the National Cancer Database, we identified 775 adult patients diagnosed with MBM between 2010 and 2017 treated with IT. We excluded those who received whole-brain radiotherapy, had a history of prior cancer, or had incomplete records. We then compared receipt of both IT and SRS (IT/SRS) vs. IT alone (IT/noSRS). Cohort assignments were based only on therapies received during the patient's first course of treatment. Our primary endpoint was overall survival (OS)—the number of days between diagnosis of MBM and last follow up or death. As a subset analysis on the IT/SRS cohort, we assessed the association between the relative timing of therapies and OS. This involved multiple statistical analyses using different definitions for relative timing: days from start of SRS to IT, proximity of therapies (IT started ≤ 28 vs. > 28 days from SRS), and sequence of therapies (IT started after vs. before SRS). Adjusted hazard ratios (aHR) were calculated using multivariable Cox regression modeling and reported with 95% confidence intervals (CI). <h3>Results</h3> Of the 775 adult patients with MBM treated with IT, 546 (70.5%) were male, 759 (98.3%) were white, and 654 (84.4%) were diagnosed in 2014-2017. Those with lung, liver, and bone metastasis numbered 275 (56.9%), 100 (20.6%), and 84 (17.4%), respectively. 492 (63.5%) patients were treated with IT/SRS, and 283 (36.5%) received IT/noSRS. The median OS was 29.5 months (95% CI: 22.3 - 44.8 mo) for IT/SRS and 11.9 months (95% CI: 9.2 - 17.2 mo) for IT/noSRS with an aHR of 0.70 (95% CI: 0.56-0.88, p < 0.01). Six-month survival probability was 83.1% (95% CI: 79.5-86.1%) for IT/SRS and 68.4% (95% CI: 62.6-73.5%) for IT/noSRS. For the IT/SRS cohort, there was no significant association between the relative timing of therapies and OS using any of the following definitions of relative timing: days from start of SRS to IT (aHR: 1.001, 95% CI: 0.998-1.004, p = 0.47), IT started ≤ 28 vs. > 28 days from SRS (aHR: 0.99, 95% CI: 0.73-1.35, p = 0.94), and IT started after vs. before SRS (aHR: 1.03, 95% CI: 0.74-1.43, p = 0.88). <h3>Conclusion</h3> Patients with MBM treated with both IT and SRS appear to have longer survival compared to IT without intracranial radiation, and the relative timing of IT and SRS does not seem to impact survival. This study is limited by a lack of records in the NCDB regarding patient performance status and radiographic characteristics, which may influence treatment decisions. These findings can guide practice while results from randomized trials (e.g., ABC-X Study, ClinicalTrials.gov, NCT03340129) are not available.

Single-Fraction vs. Fractionated Radiosurgery and the Development of Post-Treatment Hemorrhage for Intact Melanoma Brain Metastases

<h3>Purpose/Objective(s)</h3> To assess whether intracranial stereotactic radiotherapy fractionation is associated with increased risk of post-treatment lesional hemorrhage in patients with intact melanoma brain metastases (MBM). <h3>Materials/Methods</h3> A single institution retrospective review was performed of patients with previously unresected MBM treated with robotic SRS/fSRT between 2013 to 2021. The presence of lesional hemorrhage was determined by multi-disciplinary neuroradiology review of magnetic resonance imaging (MRI). Dosimetric variables were reported as biologically effective doses using an estimated α/β ratio of 2.5 (BED_2.5) for melanoma to permit comparison across varying fractionation schedules. The effect of fractionation and additional prognostic factors on the rate of post-treatment development of hemorrhage was statistically analyzed using logistic regression with random effects to account for interactions between lesions of the same patient. A Cox model was used for local control (LC) with a frailty term to account for dependence between lesions. <h3>Results</h3> The cohort included 48 patients with 226 intact MBM treated with SRS/fSRT. Evidence of hemorrhage prior to treatment was demonstrated in 69 of 226 metastases (30.5%). For lesions without signs of prior hemorrhage, 65 of 157 (41.4%) demonstrated evidence of hemorrhage after radiosurgical treatment. 63 of 133 lesions (47.4%) receiving single-fraction SRS demonstrated evidence of post-treatment hemorrhage versus 2 of 24 lesions (8.3%) treated with fSRT (<i>p=0.01</i>). Treatment factors including lesion size, prescription isodose line, as well as receipt of corticosteroids, targeted, or immune therapy were not predictive of hemorrhage occurrence. A larger maximum BED_2.5 was observed in lesions developing hemorrhage compared to no hemorrhage (mean 238.3 Gy vs. 211.4 Gy; <i>p=0.022</i>). LC at twelve-months was 65.7% (95% CI 37.2-87.3%) and 77.5% (95% CI 58.5-91.2%) for lesions demonstrating pre-treatment and post-treatment hemorrhage, respectively, with no local failure events observed in non-hemorrhagic lesions (<i>p=<0.001</i>). <h3>Conclusion</h3> Intact MBM without prior evidence of hemorrhage receiving single-fraction SRS were associated with an increased incidence of post-treatment hemorrhage when compared to those treated with fractionated stereotactic radiotherapy. The presence of lesion hemorrhage, either pre- or post-treatment, was associated with inferior local control. Post-treatment hemorrhage was correlated with a larger maximum BED_2.5. Further investigations of the clinical impact of lesional hemorrhage, factors influencing lesion control, as well as optimal dose and fractionation schedules for treatment of MBM in the era of immunotherapy are warranted.

CCT196969 effectively inhibits growth and survival of melanoma brain metastasis cells

Melanomas frequently metastasize to the brain. Despite recent progress in the treatment of melanoma brain metastasis, therapy resistance and relapse of disease remain unsolved challenges. CCT196969 is a SRC family kinase (SFK) and Raf proto-oncogene, serine/threonine kinase (RAF) inhibitor with documented effects in primary melanoma cell lines in vitro and in vivo. Using in vitro cell line assays, we studied the effects of CCT196969 in multiple melanoma brain metastasis cell lines. The drug effectively inhibited proliferation, migration, and survival in all examined cell lines, with viability IC50 doses in the range of 0.18–2.6 μM. Western blot analysis showed decreased expression of p-ERK, p-MEK, p-STAT3 and STAT3 upon CCT196969 treatment. Furthermore, CCT196969 inhibited viability in two B-Raf Proto-Oncogene (BRAF) inhibitor resistant metastatic melanoma cell lines. Further in vivo studies should be performed to determine the treatment potential of CCT196969 in patients with treatment-naïve and resistant melanoma brain metastasis.

MCP-1/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma brain metastasis progression.

Development of resistance to chemo- and immunotherapies often occurs following treatment of melanoma brain metastasis (MBM). The brain microenvironment (BME), particularly astrocytes, cooperate toward MBM progression by upregulating secreted factors, among which we found that monocyte chemoattractant protein-1 (MCP-1) and its receptors, CCR2 and CCR4, were overexpressed in MBM compared with primary lesions. Among other sources of MCP-1 in the brain, we show that melanoma cells altered astrocyte secretome and evoked MCP-1 expression and secretion, which in turn induced CCR2 expression in melanoma cells, enhancing in vitro tumorigenic properties, such as proliferation, migration, and invasion of melanoma cells. In vivo pharmacological blockade of MCP-1 or molecular knockout of CCR2/CCR4 increased the infiltration of cytotoxic CD8+ T cells and attenuated the immunosuppressive phenotype of the BME as shown by decreased infiltration of Tregs and tumor-associated macrophages/microglia in several models of intracranially injected MBM. These in vivo strategies led to decreased MBM outgrowth and prolonged the overall survival of the mice. Our findings highlight the therapeutic potential of inhibiting interactions between BME and melanoma cells for the treatment of this disease.

P10.16.A Repurposing thioridazine as a novel treatment of melanoma brain metastasis

Abstract Background Melanoma shows increasing incidence and has the highest propensity to metastasize to the brain of all primary malignant tumors. Untreated, the median survival time is 2-3 months after diagnosis, while aggressive treatment extends survival to only 4-12 months. Even though targeted therapies and immunotherapy has changed the therapeutic landscape, many of these patient relapse. In this respect, drug repurposing, using old drugs for new purposes, has had several successes for other diseases. The anti-psychotic drug thioridazine (THD) is a dopamine receptor 2 antagonist, with properties to cross an intact blood brain barrier, has shown promising effect on melanoma cells that has escaped prior treatment and on cancer stem cells. However, the therapeutic effects on melanoma brain metastasis (MBM) have not been previously investigated. Material and Methods All experiments were done on MBM cell lines (H1, H2, H3 and H10), which were developed in our lab from patient biopsies obtained after surgery. A monolayer viability assay (WST-1) was used to determine IC50 doses. Migration and proliferation after treatment was studied by IncuCyte live cell imaging. Colony forming properties and the ability of cells to grow in an anchorage free environment after THD treatment was investigated using a 2D clonogenic assay and a 3D soft agar model. Potential drug effects were also studied on normal human astrocytes (NHA) and on fetal rat brain organoids (FRBO), using a Live/Dead viability kit and confocal imaging. Apoptosis and necrosis was studied by Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis after 72 hours of treatment. Results THD shows a strong cytotoxic effect on MBM cell lines. Cell viability studies showed that THD exerted a dose-dependent inhibition of tumor cell viability (IC50 doses 9-12 µM), while NHA tolerated similar drug concentrations. Tumor cell migration and proliferation were almost completely inhibited with concentrations below the IC50 doses. An inhibition of clonogenic formation and 3D growth was also observed. Bright field microscopy showed changes in MBM morphology in monolayers, but FRBOs were intact after drug treatment. Further, apoptosis in MBM cells was induced after treatment with THD. Conclusion Our preliminary data shows that THD has a strong selective cytotoxicity in MBM cells with minimal effects on NHA and FBRO.

In Patients With Melanoma Brain Metastases, Is Combination Immune Checkpoint Inhibition a Safe and Effective First-Line Treatment? A Critically Appraised Topic.

Combined PD-1/PD-L1 and CTLA-4 immune checkpoint inhibition for the has been shown to produce superior results in the treatment of malignant melanoma when compared to monotherapy. However, patients with intracranial disease were excluded from these studies given their poor prognosis. The objective of this study was to critically assess current evidence supporting the co-administration of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of melanoma brain metastases. The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. A recent, open-label, non-comparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and safety of nivolumab alone or in combination with ipilimumab in 79 adult patients with untreated, asymptomatic melanoma brain metastases. The rates of the primary outcome (intracranial response at ≥12wk) in the primary endpoint cohort were 46% for cohort A (combination therapy) and 20% for cohort B (nivolumab monotherapy). No treatment related deaths were observed in the study. Grade 4 adverse events occurred in 9% of patients in cohort A and none in cohort B. Co-administration of ipilimumab and nivolumab as first-line therapy is effective in the treatment of asymptomatic melanoma brain metastases, with an acceptable safety profile.

Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities.

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.

The role of systemic therapy in melanoma brain metastases: a narrative review.

Melanoma is a disease notorious for the development of brain metastases, with consequently poor outcomes for patients who develop melanoma brain metastases (MBM). The treatment options for patients with MBM were limited to radiotherapy and surgery. MBM patients, particularly those with symptomatic disease, were excluded from clinical trials of immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors. Recent post-approval studies have, demonstrated important roles for existing systemic ICIs and BRAF/MEK inhibitors in untreated MBM, dramatically altering the landscape of melanoma patients in general and MBM in particular. These trials have also identified key areas for which more effective strategies are needed including: symptomatic MBM, and leptomeningeal disease (LMD). PubMed, Scopus and Embase databases were systematically queried to obtain records pertaining to the etiology of and treatment for MBM. Clinical trial databases were reviewed to obtain details regarding MBM clinical trials. We discuss the etiopathogenesis of MBM and the novel immune, molecular and metabolic features of MBM that make this disease a unique therapeutic challenge. We review advances in systemic therapy with ICIs and BRAF/MEK inhibitors in untreated MBM, along with novel combinations. Finally, we debate challenging situations such as LMD, and delineate novel treatments and new paradigms for therapeutic interventions. The historically poor outcomes for MBM patients have been transformed with the advent of effective systemic therapies including ICIs and BRAF/MEK inhibitors. An improved understanding of the molecular and immunogenomic characterization of MBMs has provided new targets that are being exploited in the clinic.

CA-4948 for the treatment of melanoma brain metastasis.

2011 Background: Melanoma is a growing clinical health concern where the incidence has doubled over the last 30 years. A major driver of melanoma associated deaths is the development of brain metastases (MBM). It is estimated that 40-60% of patients with metastatic melanoma will develop MBM. Current treatment strategies have a great local control rate, but do not prevent recurrent disease, with a distant intracranial failure rate of 50% at 1 year. Novel treatments and an improved understanding of the MBM tumor microenvironment are needed. Toll-like receptor signaling is activated in cutaneous melanoma, triggering innate inflammatory activation downstream through the adapter proteins MyD88 and interleukin (IL)-1 receptor-associated kinase (IRAK-1 and -4). Increased expression of IRAK-4 stimulates transcription of multiple cellular kinases and transcription factors, and production of inflammatory chemokines and cytokines. This places IRAK-4 as a central driver of both intrinsic tumorigenicity and immune evasion in melanoma. In this study we examine IRAK-4 activation in MBM, as well as preclinical responsiveness to CA-4948, an oral first-in-class small molecule inhibitor of IRAK-4 that has demonstrated clinical activity and has an acceptable safety in cancer patients. Methods: Using multiparameter IHC and proteomics analysis IRAK-1, IRAK-4, and NF-κB pathway activation were examined in patient MBM tissues and compared to normal controls. Plasma, cerebrospinal fluid, and brain tissue were assessed via UPLC-MS/MS for CA-4948 drug concentration following single oral high dose in a murine model. Using an aggressive preclinical model of MBM, B16F10, downstream biomarker response to treatment including phospho-NF-κB, phospho-ERK1/2, and phospho-P38 was measured in control and CA-4948 treated animals using multi-parameter IHC. Survival response was also tested using the B16F10 model. Results: Our data confirm elevated IRAK-1, IRAK-4, and NF-κB signaling in patient MBM. We also demonstrate that CA-4948 is capable of achieving therapeutically relevant concentrations in the brain parenchyma, and shows single agent activity in an aggressive preclinical model of MBM. We further confirm decreased ERK1/2, MAPK and NF-κB activation in response to CA-4948 treatment. Conclusions: We present here for the first time that IRAK-4 is a strong candidate for targeted therapy in MBM. We further validate CNS penetrance of the oral IRAK-4 inhibitor CA-4948, where single agent markedly reduces the proliferative capacity of aggressive preclinical MBM, resulting in improved survival. These data warrant further investigation of CA-4948 for the treatment of melanoma brain metastases, with far reaching potential as an adjunct to standard of care.

Current Treatment Approaches and Global Consensus Guidelines for Brain Metastases in Melanoma.

BackgroundUp to 60% of melanoma patients develop melanoma brain metastases (MBM), which traditionally have a poor diagnosis. Current treatment strategies include immunotherapies (IO), targeted therapies (TT), and stereotactic radiosurgery (SRS), but there is considerable heterogeneity across worldwide consensus guidelines.ObjectiveTo summarize current treatments and compare worldwide guidelines for the treatment of MBM.MethodsReview of global consensus treatment guidelines for MBM patients.ResultsSubstantial evidence supported that concurrent IO or TT plus SRS improves progression-free survival (PFS) and overall survival (OS). Guidelines are inconsistent with regards to recommendations for surgical resection of MBM, since surgical resection of symptomatic lesions alleviates neurological symptoms but does not improve OS. Whole-brain radiation therapy is not recommended by all guidelines due to negative effects on neurocognition but can be offered in rare palliative scenarios.ConclusionWorldwide consensus guidelines consistently recommend up-front combination IO or TT with or without SRS for the treatment of MBM.

Neurooncological Challenges in Relapsing Intracranial Melanoma Metastases: A Case Report

Introduction: Treatment of melanoma brain metastases (MBM) is a complex interdisciplinary challenge. Relapsing MBMs pose an extra challenge due to limited therapeutic options and higher complication rate. Multiple surgical interventions and radiation can be indicated in the case of intracranial relapse with extracranial disease control under oncological therapy e.g., immunotherapy. Case Presentation: Here, we report on a 37-year-old female patient with stage IV metastatic melanoma, who underwent six neurosurgical procedures, including five tumor resections, and three courses of different irradiation protocols in 26 months, all while receiving multiple regimens of immunotherapy. Throughout the different therapies, the patient showed varying neurological deficits, including facial nerve palsy, hemiparesis and reduction of cognitive function. The patient died due to symptoms related to leptomeningeal spread of the tumor. Conclusion: With this case, we want to share our experience with multiple neurosurgical interventions and repeated brain irradiation procedures in a patient with relapsing MBM. Neurosurgical interventions contributed to symptom relief, saved steroids and potentially prolonged survival. Therefore, based on the events of this case, repeated surgery could be considered for progressive brain metastases.

Stereotactic radiosurgery combined with immune checkpoint inhibition for the treatment of melanoma brain metastases is associated with high levels of extracranial disease control and survivorship - an abscopal effect?

Abstract Aims Melanoma brain metastases (MBM) are a common presentation to the neuro-oncology MDT. Stereotactic radiosurgery (SRS) is a highly effective treatment for cerebral metastases, with at least 70% control rates of individual metastases,[1] whilst immune checkpoint blockade has revolutionised the management of metastatic melanoma in recent years.[2] Recent studies have demonstrated that immune checkpoint inhibition alone also has activity in the brain, with MBM response rates of 50% or more.[3, 4] When MBM are treated with combination immunotherapy and SRS together, 12-month intracranial progression free survival (PFS) rates of 85% have been achieved.[4, 5] The aim of the current study was to evaluate the local control of MBM treated at our tertiary referral centre, which benefits from specialist neuro-radiology peer review of SRS contour volumes, and further to investigate whether overall survival is also improved, and what the mechanism of this may be. Method A retrospective analysis of all patients treated with SRS for brain metastases at our teriary SRS centre between June 2017 – January 2020 was performed. Inclusion criteria included patients treated for MBM, who received at least 2 doses of any combination of immune checkpoint inhibition concurrently with (defined as at the time of or commenced within 3 months of) SRS. The primary endpoints were the intracranial and extracranial response rates and survival rate at 12 months. Response was defined as complete response, partial response or stable disease. Secondary endpoints included the rate of imaging-defined radionecrosis, median lesional progression free survival (mPFSlesion), non-lesional intracranial PFS (mPFSintracranial), extracranial PFS (mPFSextracranial) and overall survival (mOS), measured from the start date of SRS to the date of event or censored at the start date of data collection. Kaplan-Meier curves and survival statistics were generated using SPSS v26. Results 33 MBM from 18 patients were identified. The median follow up was 25.8 months (minimum 12 months). Of the 18 patients: the median age was 60 (IQR 48 – 72); 17 (94%) patients were ECOG performance status 0-1; the median number of extracranial disease sites was 2 (pre-immunotherapy) and 1 (pre-SRS); the median duration of immunotherapy treatment was 17.6 (12.9 – 28.5) months, and the median number of metastases treated per patient was 2. Of the 33 metastases: 31 (94%) were supratentorial; 6 (18%) underwent prior neurosurgical resection; the median GTV volume (cc) of unresected metastases was 0.5cc (0.1 – 2.7), and 21 (64%) were treated with single fraction SRS. The median OS and PFS for all subtypes were not reached. The rates of OS, PFSlesion, PFSintracranial and PFSextracranial at 12 months were 93.9%, 87.9%, 81.8% &amp; 75.8% respectively. Conclusion Our cohort of MBM patients appear to perform favourably when compared with the current literature. When compared to a recent extensive systematic review of modern management of MBM, our lesional control rate is as good as the weighted average of concurrent SRS + immunotherapy studies (87.9% vs 85.4% 12-month PFS), however we demonstrate a significantly improved 12-month OS rate (93.9% vs 52.8%) compared to the same (mOS of 15.8 – 17.4 months in other studies).[6,7] Our extra-lesional PFS is high and, compared to extracranial PFS rates from 51% at 6-months to 70.4% at 9-months in the literature,[3,4] our 75.8% control at 12 months suggests that extracranial control could drive the OS benefit. This suggests a benefit of SRS beyond the local control of MBM and questions whether patients without brain metastases may benefit from body SABR to extracranial metastases, to elicit a similar, potentially abscopal type effect.

Oncolytic Virotherapy for Melanoma Brain Metastases, a Potential New Treatment Paradigm?

Introduction: Melanoma brain metastases remain a devastating disease process with poor prognosis. Recently, there has been a surge in studies demonstrating the efficacy of oncolytic virotherapy for brain tumor treatment. Given their specificity and amenability to genetic modification, the authors explore the possible role of oncolytic virotherapy as a potential treatment option for patients with melanoma brain metastases. Methods: A comprehensive literature review including both preclinical and clinical evidence of oncolytic virotherapy for the treatment of melanoma brain metastasis was performed. Results: Oncolytic virotherapy, specifically T-VEC (Imlygic™), was approved for the treatment of melanoma in 2015. Recent clinical trials demonstrate promising anti-tumor changes in patients who have received T-VEC; however, there is little evidence for its use in metastatic brain disease based on the existing literature. To date, only two single cases utilizing virotherapy in patients with metastatic brain melanoma have been reported, specifically in patients with treatment refractory disease. Currently, there is not sufficient data to support the use of T-VEC or other viruses for intracranial metastatic melanoma. In developing a virotherapy treatment paradigm for melanoma brain metastases, several factors must be considered, including route of administration, need to bypass the blood–brain barrier, viral tumor infectivity, and risk of adverse events. Conclusions: Evidence for oncolytic virotherapy treatment of melanoma is limited primarily to T-VEC, with a noticeable paucity of data in the literature with respect to brain tumor metastasis. Given the promising findings of virotherapy for other brain tumor types, oncolytic virotherapy has great potential to offer benefits to patients afflicted with melanoma brain metastases and warrants further investigation.

P14.29 The treatment of melanoma brain metastases with stereotactic radiosurgery concurrently with immune checkpoint inhibition is associated with improved extracranial disease control and overall survival compared to the overall metastatic melanoma cohort - a synergistic effect reaching beyond local control?

Abstract BACKGROUND Melanoma brain metastases (MBM) are an increasingly common referral to the neuro-oncology MDT in the context of lengthening survivorship of metastatic melanoma (MM) patients in the immunotherapy era. Stereotactic radiosurgery (SRS) and immune checkpoint inhibition (ICI) are both effective in the management of MBM and, when combined, 12-month local control rates of &amp;gt;85% and overall survival (OS) &amp;gt;80% have been reported.[4,5] Recent local analysis of patients treated at our tertiary SRS referral centre has revealed even greater outcomes in this patient cohort. This study aimed to compare the outcomes of patients with MBM treated with concurrent SRS and ICI compared to the overall metastatic melanoma cohort, to elucidate whether the addition of SRS to ICI may improve disease control outside of the brain as well as within. MATERIAL AND METHODS A retrospective analysis of our local SRS database and an ARIA ePrescribing database search was performed to identify a cohort of patients treated with concurrent SRS and ICI for MBM, as well as a control cohort of MM patients who received ICI alone, over a 4 year period until February 2020. The primary endpoints were the extracranial progression free survival (PFS) and overall survival (OS) at 12 months. Secondary endpoints were the median PFS (mPFS) and OS (mOS). Kaplan-Meier curves and survival statistics were generated using SPSS v26. RESULTS A total of 34 MBM from 19 patients were identified in the SRS+ICI group and there were 200 patients in the control group. The minimum follow up was 12 months. The median patient age, duration of ICI and use of combination ICI favoured the SRS+ICI group. The number of sites of extracranial disease pre-ICI and overall anti-PD-1 usage was well matched. In the SRS+ICI group, there were no cases of extracranial progression and no deaths within 12 months. In the control group, the 12-month PFS and OS rates were 50.5% and 77.5% respectively. In terms of mPFS, this was not reached (estimated 37.6 months) in the SRS+ICI group, versus 13.4 months in the control group (log rank test, p=0.001). In terms of mOS, this was not reached in the SRS+ICI group, versus 55.8 months in the control group (log rank test, p=0.016). CONCLUSION We demonstrate improved extracranial disease control and survivorship amongst metastatic melanoma patients who develop brain metastases and are treated with concurrent SRS and ICI compared to those who do not. The outcomes of our control cohort are comparable to the 4-year follow up of the CheckMate 067 trial (n=945),[6] which strengthens the validity of the statistical comparisons made in this study. The improved extracranial disease control seen when SRS and ICI are combined in the treatment of MBM questions whether an abscopal effect may be at play, and therefore further accents the utility of SRS in MBM beyond that of local control alone. This could influence management in cases of borderline decisions for SRS.