Melanoma Brain Metastases Research Articles

Long-term neurocognitive function after whole-brain radiotherapy in patients with melanoma brain metastases in the era of immunotherapy

BackgroundWhole-brain radiotherapy (WBRT) used to be standard of care for patients suffering from melanoma brain metastases (MBM) and may still be applicable in selected cases. Deterioration of neurocognitive function (NCF) is commonly seen during and after WBRT. Knowledge on long-term effects in melanoma patients is limited due to short survival rates. With the introduction of immune checkpoint inhibitors, patients may experience ongoing disease control, emphasizing the need for paying more attention to potential long-term adverse effects.MethodsIn this single-center study, we identified in a period of 11 years all long-term survivors of MBM who received WBRT at least 1 year prior to inclusion. NCF was assessed by Neuropsychological Assessment Battery (NAB) screening and detailed neurological exam; confounders were documented.ResultsEight patients (median age 55 years) could be identified with a median follow-up of 5.4 years after WBRT. Six patients reported no subjective neurological impairment. NAB screening revealed an average-range score in 5/8 patients. In 3/8 patients a NAB score below average was obtained, correlating with subjective memory deficits in 2 patients. In these patients, limited performance shown in modalities like memory function, attention, and spatial abilities may be considerably attributed to metastasis localization itself. Six out of 8 patients were able to return to their previous work.ConclusionFive of 8 long-term survivors with MBM after WBRT experienced little to no restriction in everyday activities. In 3 out of 8 patients, cognitive decline was primarily explained by localization of the metastases in functionally relevant areas of the brain. The results of our small patient cohort do not support general avoidance of WBRT for treatment of brain metastases. However, long-term studies including pretreatment NCF tests are needed to fully analyze the long-term neurocognitive effects of WBRT

Impact of cranial stereotactic radiotherapy associated with immunotherapy with nivolumab and ipilimumab on overall survival in patients with melanoma brain metastases: a real-world evidence.

To evaluate the impact of cranial stereotactic radiotherapy (SRT) on overall survival (OS) of melanoma brain metastases (MBM) patients treated with combined nivolumab and ipilimumab (CNI) in a contemporary and real-world setting. The study was performed by using TriNetX, a global health network dataset of electronic medical records from patients in 49 healthcare organizations. We queried for patients with specific terms between January 2016 and December 2020 and run a propensity score matching (PSM) analysis. OS was estimated by Kaplan-Meier and log-rank test was applied. After initial query and PSM, 114 patients were selected in each cohort. Median OS was 327days in CNI and not reached in the CNI + SRT cohort, with OS probability of 54.4 and 40.9%, respectively (log-rank P = .0057). CNI + SRT was associated with significantly decreased mortality (HR, 0.57; 95% CI 0.377-0.853; proportionality P = .0034). This real-world analysis showed that CNI + SRT led to an improvement in OS compared to CNI.

Melanoma Brain Metastases: An Update on the Use of Immune Checkpoint Inhibitors and Molecularly Targeted Agents.

Brain metastases from melanoma are no longer uniformly associated with dismal outcomes. Impressive tumor tissue-based (craniotomy) translational research has consistently shown that distinct patient subgroups may have a favorable prognosis. This review provides a historical overview of the standard-of-care treatments until the early 2010s. It subsequently summarizes more recent advances in understanding the biology of melanoma brain metastases (MBMs)and treating patients with MBMs, mainly focusing upon prospective clinical trials of BRAF/MEK and PD-1/CTLA-4 inhibitors in patients with previously untreated MBMs. These additional systemic treatments have provided effective complementary treatment approaches and/oralternatives to radiation and craniotomy. The current role of radiation therapy, especially in conjunction with systemic therapies, is also discussed through the lens of various retrospective studies. The combined efficacy of systemic treatments with radiation has improved overall survival over the last 10 years and has sparked considerable research interest regarding optimal dosing and sequencing of radiation treatments with systemic treatments. Finally, the review describes ongoing clinical trials in patients with MBMs.

Cost Analysis of Adjuvant Whole-Brain Radiotherapy Treatment Versus No Whole-Brain Radiotherapy After Stereotactic Radiosurgery and/or Surgery Among Adults with One to Three Melanoma Brain Metastases: Results from a Randomized Trial.

PurposeWe aimed to compare Australian health system costs at 12 months for adjuvant whole-brain radiotherapy (WBRT) treatment after stereotactic radiosurgery (SRS) and/or surgery versus observation among adults with one to three melanoma brain metastases. We hypothesized that treatment with adjuvant WBRT and subsequent healthcare would be more expensive than SRS/surgery alone.MethodsThe analysis was conducted alongside a multicentre, randomized phase III trial. A bespoke cost questionnaire was used to measure healthcare use, including hospitalizations, specialist and primary care visits, imaging, and medicines over 12 months. Mean per-patient costs were calculated based on the quantity of resources used and unit costs, reported in Australian dollars ($AU), year 2018 values. Skewness of cost data was determined using normality tests and censor-adjusted costs reported using the Kaplan–Meier sample average method. The analysis of difference in mean costs at each 2-month time point and at 12 months was performed and checked using Kruskal–Wallis, generalized linear models with gamma distribution and log link, modified Park test, ordinary least squares, and non-parametric bootstrapping.ResultsIn total, 89 patients with similar characteristics at baseline were included in the cost analysis (n = 43 WBRT; n = 46 observation). Hospitalization cost was the main cost, ranging from 63 to 89% of total healthcare costs. The unadjusted 12-monthly cost for WBRT was $AU71,138 ± standard deviation 41,475 and for observation $AU69,848 ± 33,233; p = 0.7426. The censor-adjusted 12-monthly cost for WBRT was $AU90,277 ± 36,274 and $AU82,080 ± 34,411 for observation. There was no significant difference in 2-monthly costs between groups (p > 0.30 for all models).ConclusionsMost costs were related to inpatient hospitalizations associated with disease recurrence. Adding WBRT after local SRS/surgery for patients with one to three melanoma brain metastases did not significantly increase health system costs during the first 12 months.Trial RegistrationACTRN12607000512426, prospectively registered 14 September 2007.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-022-00332-8.

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.

PD-0079 Volumetric responses with stereotactic radiosurgery and immunotherapy in melanoma brain metastases

PD-0079 Volumetric responses with stereotactic radiosurgery and immunotherapy in melanoma brain metastases

PO-1159 Stereotactic radiosurgery and combined immunotherapy with ipilimumab and nivolumab for melanoma brain metastases

PO-1159 Stereotactic radiosurgery and combined immunotherapy with ipilimumab and nivolumab for melanoma brain metastases

PO-1151 Impact of SRS to melanoma brain metastases associated with immunotherapy on OS: real-world evidence

PO-1151 Impact of SRS to melanoma brain metastases associated with immunotherapy on OS: real-world evidence

Evaluation of radio-immunotherapy sequence on immunological responses and clinical outcomes in patients with melanoma brain metastases (ELEKTRA)

ABSTRACT In patients with melanoma brain metastases (MBM), a combination of radiotherapy (RT) with immune checkpoint inhibitors (ICI) is routinely used. However, the best sequence of radio-immunotherapy (RIT) remains unclear. In an exploratory phase 2 trial, MBM patients received RT (stereotactic or whole-brain radiotherapy depending on the number of MBM) combined with ipilimumab (ipi) ± nivolumab (nivo) in different sequencing (Rad-ICI or ICI-Rad). Comparators arms included patients treated with ipi-free systemic treatment or without RT (in MBM-free patients). The primary endpoints were radiological and immunological responses in the peripheral blood. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Of 106 screened, 92 patients were included in the study. Multivariate analysis revealed an advantage for patients starting with RT (Rad-ICI) for overall response rate (RR: p = .007; HR: 7.88 (95%CI: 1.76–35.27)) and disease control rate (DCR: p = .036; HR: 6.26 (95%CI: 1.13–34.71)) with a trend for a better PFS (p = .162; HR: 1.64 (95%CI: 0.8–3.3)). After RT plus two cycles of ipi-based ICI in both RIT sequences, increased frequencies of activated CD4, CD8 T cells and an increase in melanoma-specific T cell responses were observed in the peripheral blood. Lasso regression analysis revealed a significant clinical benefit for patients treated with Rad-ICI sequence and immunological features, including high frequencies of memory T cells and activated CD8 T cells in the blood. This study supports increasing evidence that sequencing RT followed by ICI treatment may have better effects on the immunological responses and clinical outcomes in MBM patients.

Stereotactic radiosurgery for melanoma brain metastases: Concurrent immune checkpoint inhibitor therapy associated with superior clinicoradiological response outcomes.

Introduction/purposeThis study assessed long‐term clinical and radiological outcomes following treatment with combination stereotactic radiosurgery (SRS) and immunotherapy (IT) for melanoma brain metastases (BM).MethodsA retrospective review was performed in a contemporary cohort of patients with melanoma BM at a single tertiary institution receiving Gamma Knife® SRS for melanoma BM. Multivariate Cox proportional‐hazards modelling was performed with a P <0.05 for significance.Results101 patients (435 melanoma BM) were treated with SRS between January‐2015 and June‐2019. 68.3% of patients received IT within 4 weeks of SRS (concurrent) and 31.7% received SRS alone or non‐concurrently with IT. Overall, BM local control rate was 87.1% after SRS. Median progression free survival was 8.7 months. Median follow‐up was 29.2 months. On multivariate analysis (MVA), patients receiving concurrent SRS‐IT maintained a higher chance of achieving a complete (CR) or partial response (PR) [HR 2.6 (95% CI: 1.2–5.5, P = 0.012)] and a reduced likelihood of progression of disease (PD) [HR 0.52 (95% CI: 0.16–0.60), P = 0.048]. Any increase in BM volume on the initial MRI 3 months after SRS predicted a lower likelihood of achieving long‐term CR or PR on MVA accounting for concurrent IT, BRAF status and dexamethasone use [HR = 0.048 (95% CI: 0.007–0.345, P = 0.0026)]. Stratified volumetric change demonstrated a sequential relationship with outcomes on Kaplan–Meier analysis.ConclusionConcurrent SRS‐IT has favourable clinical and radiological outcomes with respect to CR, PR and a reduced likelihood of PD. Changes in BM volume on the initial MRI 3 months after SRS were predictive of long‐term outcomes for treatment response.

Real-world data on melanoma brain metastases and survival outcome.

Novel medical therapies have revolutionized outcome for patients with melanoma. However, patients with melanoma brain metastases (MBM) still have poor survival. Data are limited as these patients are generally excluded from clinical trials, wherefore real-world data on clinical outcome may support evidence-based treatment choices for patients with MBM. Patients diagnosed with MBM between 2008 and 2020 were included retrospectively. Patient characteristics, treatment, and outcome data were recorded from The Danish Metastatic Melanoma Database, pathology registries, electronic patient files, and radiation plans. Anti-programmed cell death protein 1 antibodies and the combination of BRAF/MEK-inhibitors were introduced in Denmark in 2015, and the cohort was split accordingly for comparison. A total of 527 patients were identified; 148 underwent surgical excision of MBM, 167 had stereotactic radiosurgery (SRS), 270 received whole-brain radiation therapy (WBRT), and 343 received systemic therapies. Median overall survival (mOS) for patients diagnosed with MBM before and after 2015 was 4.4 and 7.6 months, respectively. Patients receiving surgical excision as first choice of treatment had the best mOS of 10.9 months, whereas patients receiving WBRT had the worst outcome (mOS, 3.4 months). Postoperative SRS did not improve survival or local control after surgical excision of brain metastases. Of the 40 patients alive >3 years after diagnosis of MBM, 80% received immunotherapy at some point after diagnosis. Patients with meningeal carcinosis did not benefit from treatment with CPI. Outcome for patients with MBM has significantly improved after 2015, but long-term survivors are rare. Most patients alive >3 years after diagnosis of MBM received immunotherapy.

Anti-tumor treatment and healthcare consumption near death in the era of novel treatment options for patients with melanoma brain metastases

BackgroundEffective systemic treatments have revolutionized the management of patients with metastatic melanoma, including those with brain metastases. The extent to which these treatments influence disease trajectories close to death is unknown. Therefore, this study aimed to gain insight into provided treatments and healthcare consumption during the last 3 months of life in patients with melanoma brain metastases.MethodsRetrospective, single-center study, including consecutive patients with melanoma brain metastases diagnosed between June-2015 and June-2018, referred to the medical oncologist, and died before November-2019. Patient and tumor characteristics, anti-tumor treatments, healthcare consumption, presence of neurological symptoms, and do-not-resuscitate status were extracted from medical charts.Results100 patients were included. A BRAF-mutation was present in 66 patients. Systemic anti-tumor therapy was given to 72% of patients during the last 3 months of life, 34% in the last month, and 6% in the last week. Patients with a BRAF-mutation more frequently received systemic treatment during the last 3 (85% vs. 47%) and last month (42% vs. 18%) of life than patients without a BRAF-mutation. Furthermore, patients receiving systemic treatment were more likely to visit the emergency room (ER, 75% vs. 36%) and be hospitalized (75% vs. 36%) than those who did not.ConclusionThe majority of patients with melanoma brain metastases received anti-tumor treatment during the last 3 months of life. ER visits and hospitalizations occurred more often in patients on anti-tumor treatment. Further research is warranted to examine the impact of anti-tumor treatments close to death on symptom burden and care satisfaction.

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.

Recommended first-line management of brain metastases from melanoma: A multicenter survey of clinical practice

BackgroundRadiotherapy (RT) and surgery (Sx) are effective in treating brain metastases. However, immune checkpoint inhibitors (ICI) have shown activity against asymptomatic melanoma brain metastases (MBM). BRAF/MEK inhibitors can be used to treat BRAF V600 mutation positive (BRAF+) MBM. MethodWe conducted an international survey among experts from medical oncology (MO), clinical oncology (CO), radiation oncology (RO), and neurosurgery (NS) about treatment recommendations for patients with asymptomatic BRAF+ or BRAF mutation negative (BRAF−) MBM. Eighteen specific clinical scenarios were presented and a total of 267 responses were collected. Answers were grouped and compared using Fisher’s exact test. ResultsIn most MBM scenarios, survey respondents, regardless of specialty, favored RT in addition to systemic therapy. However, for patients with BRAF+ MBM, MO and CO were significantly more likely than RO and NS to recommend BRAF/MEK inhibitors alone, without the addition of RT, including the majority of MO (51%) for patients with 1–3 MBM, all <2 cm. Likewise, for BRAF− MBM, MO and CO more commonly recommended single or dual agent ICI only and dual agent ICI therapy alone was the most common recommendation from MO or CO for MBM <2 cm. When at least 1 of 3 MBM (BRAF+ or BRAF−) was >2 cm, upfront Sx was recommended by all groups with the exception that MO and RO recommended RT for BRAF− MBM. ConclusionsIn most clinical settings involving asymptomatic MBM, experts recommended RT in addition to systemic therapy. However, recommendations varied significantly according to specialty, with MO and CO more commonly recommending dual systemic therapy alone for up to 9 BRAF− MBM <2 cm.

Malignant Melanoma-Derived Exosomes Induce Endothelial Damage and Glial Activation on a Human BBB Chip Model.

Malignant melanoma is a type of highly aggressive tumor, which has a strong ability to metastasize to brain, and 60–70% of patients die from the spread of the tumor into the central nervous system. Exosomes are a type of nano-sized vesicle secreted by most living cells, and accumulated studies have reported that they play crucial roles in brain tumor metastasis, such as breast cancer and lung cancer. However, it is unclear whether exosomes also participate in the brain metastasis of malignant melanoma. Here, we established a human blood–brain barrier (BBB) model by co-culturing human brain microvascular endothelial cells, astrocytes and microglial cells under a biomimetic condition, and used this model to explore the potential roles of exosomes derived from malignant melanoma in modulating BBB integrity. Our findings showed that malignant melanoma-derived exosomes disrupted BBB integrity and induced glial activation on the BBB chip. Transcriptome analyses revealed dys-regulation of autophagy and immune responses following tumor exosome treatment. These studies indicated malignant melanoma cells might modulate BBB integrity via exosomes, and verified the feasibility of a BBB chip as an ideal platform for studies of brain metastasis of tumors in vitro.

Surgical and anatomic factors predict development of leptomeningeal disease in patients with melanoma brain metastases.

Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, of which there is an unclear etiology. The aim of this study is to determine if surgical or anatomic factors can predict LMD in patients with metastatic melanoma. A retrospective chart review was performed of 1162 patients treated at single institution for melanoma brain metastases (MBM). Patients with fewer than 3 months follow-up or lacking appropriate imaging were excluded. Demographic information, surgical, and anatomic data were collected. Eight hundred and twenty-seven patients were included in the final review. On multivariate analysis for the entire cohort, female gender, dural-based and intraventricular metastasis, and tumor bordering CSF spaces were associated with increased risk of LMD. Surgical resection was not significant for risk of LMD. On multivariate analysis of patients who have undergone surgical resection of a metastatic tumor, dural-based and intraventricular metastasis, ventricular entry during surgery, and metastasis in the infratentorial space were associated with increased risk of LMD. On multivariate analysis of patients who did not undergo surgery, chemotherapy after initial diagnosis and metastasis bordering CSF spaces were associated with increased risk of LMD. In a single-institution cohort of MBM, we found that surgical resection alone did not result in an increased risk of LMD. Anatomical factors such as dural-based and intraventricular metastasis were significant for developing LMD, as well as entry into a CSF space during surgical resection. These data suggest a strong correlation between anatomic location and tumor cell seeding in relation to the development of LMD.

Volume of Disease as a Predictor for Clinical Outcomes in Patients With Melanoma Brain Metastases Treated With Stereotactic Radiosurgery and Immune Checkpoint Therapy.

Purpose/ObjectivesClinical trials of anti-Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein (CTLA-4) therapies have demonstrated a clinical benefit with low rates of neurologic adverse events in patients with melanoma brain metastases (MBMs). While the combined effect of these immunotherapies (ITs) and stereotactic radiosurgery (SRS) has yielded impressive results with regard to local control (LC) and overall survival (OS), it has also been associated with increased rates of radiation necrosis (RN) compared to historical series of SRS alone. We retrospectively reviewed patients treated with IT in combination with SRS to report on predictors of clinical outcomes.Materials and MethodsPatients were included if they had MBMs treated with SRS within 1 year of receiving anti-PD-1 and/or CTLA-4 therapy. Clinical outcomes including OS, LC, intracranial death (ID), and RN were correlated with type and timing of IT with SRS, radiation dose, total volume, and size and number of lesions treated.ResultsTwenty-nine patients with 171 MBMs were treated between May 2012 and May 2018. Patients had a median of 5 lesions treated (median volume of 6.5 cm3) over a median of 2 courses of SRS. The median dose was 21 Gy. Most patients were treated with ipilimumab (n = 13) or nivolumab-ipilimumab (n = 10). Most patients underwent SRS concurrently or within 3 months of receiving immunotherapy (n = 21). Two-year OS and LC were 54.4% and 85.5%, respectively. In addition, 14% of patients developed RN; however, only 4.7% of the total treated lesions developed RN. The median time to development of RN was 9.5 months. Patients with an aggregate tumor volume >6.5 cm3 were found to be at increased risk of ID (p = 0.05) and RN (p = 0.03). There was no difference in OS, ID, or RN with regard to type of IT, timing of SRS and IT, number of SRS courses, SRS dose, or number of cumulative lesions treated.ConclusionsIn our series, patients treated with SRS and IT for MBMs had excellent rates of OS and LC; however, patients with an aggregate tumor volume >6.5 cm3 were found to be at increased risk of ID and RN. Given the efficacy of combined anti-PD-1/CTLA-4 therapy for MBM management, further study of optimal selection criteria for the addition of SRS is warranted.

Radiomics for the noninvasive prediction of the BRAF mutation status in patients with melanoma brain metastases.

The BRAF V600E mutation is present in approximately 50% of patients with melanoma brain metastases and an important prerequisite for response to targeted therapies, particularly BRAF inhibitors. As heterogeneity in terms of BRAF mutation status may occur in melanoma patients, a wild-type extracranial primary tumor does not necessarily rule out a targetable mutation in brain metastases using BRAF inhibitors. We evaluated the potential of MRI radiomics for a noninvasive prediction of the intracranial BRAF mutation status. Fifty-nine patients with melanoma brain metastases from two university brain tumor centers (group 1, 45 patients; group 2, 14 patients) underwent tumor resection with subsequent genetic analysis of the intracranial BRAF mutation status. Preoperative contrast-enhanced MRI was manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data. Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses. Twenty-two of 45 patients (49%) in group 1, and 8 of 14 patients (57%) in group 2 had an intracranial BRAF V600E mutation. A linear support vector machine classifier using a six-parameter radiomics signature yielded an area under the ROC curve of 0.92 (sensitivity, 83%; specificity, 88%) in the test data. The developed radiomics classifier allows a noninvasive prediction of the intracranial BRAF V600E mutation status in patients with melanoma brain metastases with high diagnostic performance.

Leptomeningeal disease and brain control after postoperative stereotactic radiosurgery with or without immunotherapy for resected brain metastases

PurposeImmunotherapy has shown activity in patients with brain metastases (BM) and leptomeningeal disease (LMD). We have evaluated LMD and intraparenchymal control rates for patients with resected BM receiving postoperative stereotactic...

Emergent immunotherapy approaches for brain metastases.

Brain metastases from solid tumors are increasing in incidence, especially as outcomes of systemic therapies continue to extend patients’ overall survival. The long-held notion that the brain is an immune sanctuary has now been largely refuted with increasing evidence that immunotherapy can induce durable responses in brain metastases. Single agent immune checkpoint inhibition with anti-CTLA4 and anti-PD1 antibodies induces durable responses in 15%–20% in melanoma brain metastases as long as patients are asymptomatic and do not require corticosteroids. The combination of anti-CTLA4 with anti-PD-1 antibodies induces an intracranial response in over 50% of asymptomatic melanoma patients, and much lower rate of otherwise durable responses (20%) in symptomatic patients or those on steroids. Data in other cancers, such as renal cell carcinoma, are accumulating indicating a role for immunotherapy. Emerging immunotherapy approaches will have to focus on increasing response rates, decreasing toxicity, and decreasing steroid dependency. The path to those advances will have to include a better understanding of the mechanisms of response and resistance to immunotherapy in brain metastases, the use of novel agents such as anti-LAG3 checkpoint inhibitors, targeted therapy (oncogene directed or TKIs), and possibly surgery and SRS to improve the outcomes of patients with brain metastases.