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

Introduction

Cutaneous melanoma exhibits the highest level of cerebral tropism of all cancer types, with up to 30–40% of advanced melanoma patients having melanoma brain metastases (MBM) at diagnosis (1-3), and up to 75% at the time of death in autopsy series (2). MBM are associated with a higher risk of complications and death compared to other cancers (4,5). While surgical resection and stereotactic radiosurgery (SRS) are highly effective for local control of oligometastatic MBM (2,6), patients with multiple brain metastases and/or leptomeningeal disease (LMD) are typically treated with whole-brain radiation therapy (WBRT) with poor outcomes. The prognosis of MBM patients has remained poor, with a median overall survival (OS) of 4–5 months, and a durable survival rate of 5% (6).

Historically, patients with untreated brain metastases were excluded from clinical trials for all currently approved targeted and immune therapies given the uncertain penetrance of the blood-brain barrier (BBB) by systemic agents and consequent perceived uncertainties over central nervous system (CNS) efficacy. Several post-marketing clinical trials subsequently clarified that immune checkpoint inhibitors (ICI) and small molecules targeting BRAF and MEK kinases had intracranial activity in MBM patients. These trials also identified key areas for which more effective strategies are needed. Concurrently, recent translational and preclinical research have provided insights into novel immune, molecular and metabolic features of MBM that mediate the aggressive biology and therapeutic resistance of these tumors. In this systematic review, we review the etiopathogenesis of MBM, and describe the various therapeutics options available with a focus on new paradigms for therapeutic interventions in MBM. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-22-1/rc).

Methods

Without imposing any restriction on the publication language and publication time, the PubMed, Scopus and Embase databases were systematically queried to obtain records published before April 1, 2022, with the following keywords: (“melanoma” OR “brain” OR “melanoma brain metastases”) and (“epidemiology”) and (“tumor microenvironment” OR “TME” or “pathway”) and (“targeted therapy” OR “BRAF” OR “MEK”) and (“immune therapy” OR “programmed cell death 1” OR “PD-1” OR “PD1” OR “programmed death 1 receptor” OR “cytotoxic T-lymphocyte-associated antigen 4” OR “CD152” OR “CTLA-4”) (Table 1). We also used the Emtree terms to increase the sensitivity of our systematic search.

Studies with the following eligibility criteria were included in our study: (I) investigations that studied the effects of targeted or immune therapies on MBM, and (II) studies that described the epidemiology and/or translational molecular immunobiology of MBM. Based on the following criteria, studies were excluded from the current systematic review: (I) studies that did not meet the abovementioned inclusion criteria, (II) review papers, (III) meeting abstracts, (IV) perspectives, (V) book chapters, (VI) editorial articles, (VII) commentaries, (VIII) opinion articles, and (IX) duplicated papers.

Following the systematic search, the records were retrieved and reviewed. Initially, the titles and abstracts of all obtained papers were screened, and those that did not meet criteria were excluded. Subsequently, the full text of all remaining papers and supplementary data were reviewed for consideration to be included in the current study.

The following data were extracted from the included studies: (I) the first author, (II) the year of publication, and (III) the main findings.

Discussion

Epidemiology and etiopathogenesis

Cutaneous melanoma is the third most common cause of metastases to the brain, exceeded only by lung cancer and breast cancer (7). Brain metastases can be seen in patients with non-cutaneous melanoma including mucosal and uveal variants (8,9). However, immunogenomic characterization and translational clinical trial efforts have focused upon cutaneous MBM; hence, we have sought to limit our discussion in this narrative review to MBM arising in the setting of cutaneous melanoma only. Several risk factors are associated with MBM development including male gender, increasing age, primary tumor location (head and neck vs. trunk), primary tumor depth (Breslow depth), ulceration of primary tumor, presence of visceral metastases, elevated serum lactate dehydrogenase (LDH) level, and CCR4 expression (10-14). CCR4 PKB/Akt leads to activation of the PI3K pathway (15), and is linked to MBM formation in preclinical models (10,15).

Melanoma cells primarily spread to the brain hematogenously. Under normal circumstances, the brain is a “sanctuary” site protected from external influences by the BBB that comprises endothelial cells connected by tight junctions and surrounded by a basal lamina composed of pericytes and astrocyte endfeet. The BBB is uniquely equipped with special efflux pumps for drugs and has slow rates of transcytosis (16). This complex, multi-layer system limits the entry of pathogens, drugs, and toxins into the CNS, although melanoma cells have unique adaptations that facilitate BBB penetrance. Upon arrival at the microcapillaries of the brain, they arrest due to their size and remain quiescent (17). Tumor cell extravasation is mediated through various mechanisms: (I) physical disruption of the BBB by the development of cytoplasmic processes that push endothelial cells apart, (II) loosening of tight junctions through the release of angiopoietin-2 and expression of other pro-invasive integrins by the melanoma cells, and (III) cleavage of the basement membrane of BBB by various proteases expressed by the tumor cells (17,18). After extravasation, tumor cells use the blood vessels as tracks for invasion (vessel cooption) (19). This pattern of invasion explains the higher incidence of MBM in regions of the brain with greater blood flow such as frontal lobes. The immune response to tumor invasion in the brain is also complex. Under homeostatic conditions, the brain is an immune-privileged tissue, and the BBB has low expression of adhesion molecules and low leukocyte traffic (20). However, BBB disruption by tumor cells results in increased penetration of CNS by lymphocytes which may be responsible for the unique microenvironment of MBM (21-23).

MBM tumor microenvironment (TME) and role of PI3K/AKT and mitogen-activated protein kinase (MAPK) pathways in MBM

While the TME of MBMs is heterogenous, subgroups differentially enriched in T cells, monocytes and myeloid dendritic cells with commensurately altered survival can be identified (24). The immune infiltrate of MBMs comprises a mixed population of tumor-infiltrating lymphocytes (TILs), and the TIL density in MBM is the highest of all solid tumor CNS metastases (25). Paired analyses of intra- and extra-cranial metastases reveals that the TME of MBMs is significantly enriched with macrophages and gamma delta T cells (γδ T cells), although the frequency of NK cells is reportedly lower in MBM compared to matched primary tumors (23,26).

The genetics of MBM are similar to other systemic metastatic sites of melanoma: activating point mutations in BRAF are found in 42–50% of MBM, while other driver mutations include NRAS (15–28%), and NF1 (22%) (27,28). However, MBM is uniquely characterized by oncogenic activation of the PI3K-AKT pathway (29,30), typically through loss of function mutations in the tumor suppressor gene PTEN, found in 20–30% of melanoma and typically associated with concurrent activating mutations in BRAF (31,32). PI3K/AKT pathway activation facilitates MBM development via upregulation of CCR4, heparanase, VEGF, and STAT3 (15,33,34), and PTEN loss is an adverse prognostic factor in MBM (35).

Recent work has shed light on the role of tumor-intrinsic metabolism on the development and response of MBM to ICIs and targeted therapy. Compared to extracranial metastases and primary melanomas, gene expression and metabolite profiling reveal that MBMs demonstrate increased oxidative phosphorylation (OXPHOS), in turn associated with lower immune infiltrates and reversed, in preclinical studies by addition of direct OXPHOS inhibitor IACS-010759 (24). OXPHOS induction appears to occur secondary to a shift in nutrient dependence from glucose to other amino acids such as glutamine in metastatic cells (36), leading to an upregulation of de novo amino acid synthesis to overcome the dearth of extracellular amino acids in the brain—therapy facilitating cerebral tropism, a phenomenon that has been recapitulated in brain metastases from multiple tumor types (37).

Systemic therapy in MBM

Optimal management of MBM requires a multidisciplinary approach that considers all available treatment modalities that balances the factors that need to be considered in determining a comprehensive treatment approach including: nature of brain disease (number and size of metastases, location of metastases, presence or absence of neurological symptoms and presence or absence of LMD), extracranial disease burden, tumor mutation status (BRAF mutant or wildtype), patient’s functional status, and prior therapy for MBM. In addition, the context of MBM development (i.e., MBM development prior to vs. while on systemic therapy) also helps determine the order of local and systemic therapy. There remain clear roles for radiation therapy (38-40), and surgery (41) in the management of MBM, but these are well-discussed elsewhere. Below, we focus on the systemic therapy options for MBM patients.

Principles of systemic therapy

Historically, patients with untreated MBM were excluded from systemic therapy clinical trials due to concerns about CNS drug penetrance, neurotoxicity and poor prognosis (42,43). In the context of untreated MBM, several case reports unexpectedly suggested that both ICIs and targeted BRAF/MEK had intracranial efficacy. These led to formal phase II studies evaluating BRAF/MEK targeted therapy and ICIs in patients with untreated MBM that are further elaborated upon below. The majority of these studies had fairly stringent criteria, and limited patients based on size of MBM (0.5–3.0 cm), degree of symptoms (asymptomatic or minimally symptomatic), and systemic glucocorticoid use (absent or minimal) due to concerns over rapid disease progression in symptomatic patients (44), and lack of efficacy with concomitant steroid use particularly in patients treated with ICIs (45). LMD was and remains a poorly studied population, and these patients continue to be excluded from clinical trials.

The use of ICIs in MBM

Programmed death-1 (PD-1) is a receptor expressed by activated T cells which binds to programmed death ligand 1 (PD-L1, B7-H1) (46,47), and PD-L2 (B7-DC) (48,49). PD-1 negatively regulates T cell function primarily through the engagement of PD-L1, which is expressed by a wide variety of tissues (46-49) and human tumors, including melanoma, either constitutively or after treatment with IFN-γ (50,51).

Separately, cytotoxic T lymphocyte associated antigen-4 (CTLA-4, CD152) is an activation-induced glycoprotein that belongs to the Immunoglobulin (Ig) superfamily. CTLA-4 is homologous to the T cell co-stimulatory protein CD28; but where CD28 provides the co-stimulatory signal required for antigen-specific T cell activation and expansion after the initial interaction between T cell receptor (TCR) and antigen presenting cells (APCs), CTLA-4 down-regulates T cell responses by acting as a decoy receptor (52-54). CTLA-4 is constitutively expressed on regulatory T cells (Tregs) while expression on CD8⁺ T cells occurs rapidly following TCR engagement (signal 1) (55,56). Both CD28 and CTLA-4 have two natural ligands found on APCs: CD80 (B7.1) or CD86 (B7.2) (57-59), although CTLA-4 has higher avidity and affinity for both compared to CD28 (60-62). Because B7.1/B7.2 provide the positive costimulatory signal (signal 2) through CD28 required for TCR activation, competitive inhibition of CD80 and CD86 by CTLA-4 effectively attenuates T cell activation. CD80 and CD86 are primarily expressed at sites of T-cell priming (e.g., secondary lymphoid organs), and to a lesser extent constitutively expressed to varying degrees on antigen-presenting cells (APC) and activated T cells. Hence, CTLA-4 blockade primarily increases T cell priming, and secondarily reduces Treg-mediated suppression of T cell responses.

Ex vivo, PD-1/PD-L1 pathway blockade in combination with prolonged antigen stimulation augments the frequencies of cytokine-producing, proliferating tumor antigen (TA)-specific CD8⁺ T cells which express markers of T cell activation/exhaustion including PD-1 and CTLA-4 (63,64). Separately, CTLA-4 blockade primarily induces expansion of ICOS+ T_h1-like CD4 effector population, and secondarily increases the number of exhausted/activated CD8⁺ T cells (65). Conversely, combination CTLA-4/PD-1 dual blockade induces distinct changes with increased expression of terminally differentiated CD8⁺ T cells expressing Tbet and EOMES in addition to the afore noted findings with either PD-1 or CTLA-4 blockade singly (66,67).

ICIs targeting the PD-1/PD-L1 and CTLA-4 pathways have transformed the management of melanoma with approvals in the high-risk node negative, node positive, and metastatic settings. In advanced melanoma, blockade of PD-1 singly or in combination with CTLA-4, results in objective response rate (ORR) of 35–41% (pembrolizumab or nivolumab) (68-72), 43% (nivolumab/relatlimab combination), and 55% (nivolumab-1/ipilimumab-3 combination) (73-77), with grade 3–4 immune-related adverse event (irAE) rates of 10%, 19% and 55% respectively. Dropping the dose of ipilimumab (nivolumab-3/ipilimumab-1 combination) is associated with a lower dose of grade 3–4 irAEs but undiminished efficacy (78).

The first report of clinical efficacy of ICIs in untreated MBMs occurred more than a decade ago in two separate patients with advanced metastatic melanoma (79,80). In both instances, patients with untreated, progressive MBM responded favorably to ipilimumab with systemic and CNS responses (79,80). These results were buttressed by data from an Italian Expanded Access Program (EAP) that evaluated ipilimumab in 146 asymptomatic MBM patients of whom 145 were evaluable for response, and reported global ORR of 11% with durable benefit observed in a subset (81). Interesting developments in these reports that foretold future developments in this arena included the development of edema surround MBM (and consequent need for corticosteroids and anti-epileptic drugs), tumor necrosis, delayed regression of MBM, discordant responses in MBM vs. systemic lesions and yet, the possibility of durable benefit in a small subset of treated patients (79-81). These observations led to a plethora of trials, summarized in Table 2 and described below.

These results led to the formal evaluation of ipilimumab 10 mg/kg in untreated MBM in a phase II single-arm trial (CA184-042) that included 2 cohorts: Cohort A with 51 asymptomatic MBM patients who not on corticosteroids, and Cohort B with 21 symptomatic MBM patients maintained on a stable corticosteroid dose (82). The intra-cranial ORR of 16% (Cohort A) and 5% (Cohort B), and median OS of 7.0 months and 3.7 months confirmed the safety and intracranial efficacy of ipilimumab in patients with untreated MBM; but the striking difference in ORR and OS between the two cohorts formed the basis to exclude patients requiring corticosteroids in future MBM trials of ICIs. Given the dose-response relationship observed with ipilimumab at 10 vs. 3 mg/kg, this question was tested in a phase III trial (CA184-169) that included 127 patients with asymptomatic untreated MBM where the results confirmed the superiority of ipilimumab 10 mg/kg (over 3 mg/kg) with significantly greater 1-year progression-free survival (PFS). ORR was similarly greater for ipilimumab 10 mg/kg (over 3 mg/kg), although this difference was not statistically significant (83). Subset analyses revealed that MBM patients derived durable benefit that held up at later follow-up (84). Collectively, these studies established a clear paradigm that ICIs were effective in untreated MBM and primed the field for future developments.

The efficacy of anti-PD-1 ICIs in melanoma spurred the evaluation of anti-PD-1 ICI in MBM patients, initially in the setting of a non-randomized phase II trial that studied pembrolizumab in patients with untreated MBM (85). Driven by the prior experiences with ipilimumab, enrollment was limited by size of intra-parenchymal lesion (5–20 mm) and excluded patients who were either symptomatic and/or needed corticosteroids. The intra-cranial ORR was 22% (4/18) in MBM with concordant brain and systemic responses, and updated reporting demonstrated that responses were durable with all intra-cranial responses ongoing at 24 months—statistics that compared favorably to the single-agent ORRs in either disease (86).

Prompted by the development of dual PD-1/CTLA-4 blockade in advanced melanoma, the efficacy of the ipilimumab/nivolumab combination in MBM was evaluated in two clinical trials: CheckMate-204 and ABC (44,87-89) (Table 2). CheckMate-204 was a phase II study that evaluated ipilimumab/nivolumab at the approved doses (ipilimumab 1 mg/kg with nivolumab 2 mg/kg every 3 weeks for 4 doses; then nivolumab 2 mg/kg every 2 weeks for 2 years) in two cohorts: Cohort A (101 patients) with asymptomatic brain metastases, and Cohort B (18 patients) with symptomatic disease. In a notable departure from prior studies, the primary endpoint of the trial was an efficacy one—specifically, intracranial clinical benefit rate which was defined as the aggregate sum of patients with complete or partial response, and stable disease lasting at least 6 months. The intracranial clinical benefit rate was greater in cohort A compared to B (57% vs. 22%); and while the rate of grade 3/4 adverse events was comparable in both arms, the rate of CNS adverse events was much higher in cohort B (6.9 vs. 16.7%) (44,87). Unlike the CheckMate-204 study which evaluated only the ipilimumab/nivolumab combination albeit in asymptomatic and symptomatic MBM, the ABC study compared the ipilimumab/nivolumab combination (Cohort A, 36 patients) to nivolumab monotherapy (Cohort B, 27 patients) although the study was not designed for a formal comparison between cohorts. Valuably, the ABC study additionally included a 3^rd arm comprising patients with symptomatic MBM, LMD and/or MBM that failed radiation therapy or surgery with a similar primary endpoint (Cohort C, 16 patients) (88,89). The intracranial clinical benefit rate was numerically greater in Cohort A compared to B (46% vs. 20%), clearly demonstrating the superiority of the ipilimumab/nivolumab combination in this patient population, even with extended follow-up (89). Conversely, the intracranial clinical benefit rate was very low (6%, 1 patient) in Cohort C, underscoring the limitations of systemic immunotherapy even with dual PD-1/CTLA-4 blockade in this highly-refractory patient population. Concordant with CheckMate-204, the grade 3/4 adverse event rate was high with ipilimumab/nivolumab combination (Cohort A—46%, Cohort B—4%, Cohort C—13%). Collectively, both CheckMate-204 and ABC studies clearly established the efficacy of ipilimumab/nivolumab combination in patients with asymptomatic first-line MBM.

Targeted therapy use in MBM

The commonest oncogenic alterations in melanoma are in BRAF codon V600 (40–50%), NRAS codons 12, 13, or 61 (15–23%), NF1 (24%) and CKIT (3%) Of these, mutations in the RAF-MEK-ERK MAPK in BRAF and NRAS are typically seen in in melanomas without chronic sun damage (CSD) compared with those associated with CSD (BRAF: 60% vs. 6–22%; NRAS: 20–22% vs. 0–15%), while KIT mutations are significantly more common with CSD associated melanomas (15–30% vs. <1%) and in patients of Asian descent (90-93). Outside of rare instances or in the setting of acquired resistance following exposure to BRAF (or BRAF/MEK) inhibitor therapy, these driver mutations are typically mutually exclusive. BRAF V600E mutations are more common in females, younger patients; while NRAS mutations are commoner in older and male patients (94,95). Targeted kinase inhibitors of both BRAF (vemurafenib, and dabrafenib) and MEK (cobimetinib, and trametinib) demonstrated high radiographic response rates with improved PFS and OS in BRAF V600 mutant melanoma (96-98). However, resistance inevitably develops secondary to BRAF inhibitor-induced paradoxical reactivation of MAPK pathway (99-101). Preclinically, combination BRAF and MEK inhibition (vemurafenib/cobimetinib, dabrafenib/trametinib, and encorafenib/binimetinib) enhances the inhibitory effect on MAPK pathway signaling in BRAF mutant cells and delays emergence of resistance (99-101), and clinically is associated with even greater benefit (improved ORR, PFS and OS) compared to BRAF inhibitor monotherapy without a substantial increase in toxicity (102-105).

Similar to the experience with ICIs, the use of BRAF and BRAF/MEK inhibitors in untreated MBM was triggered by several favorable case reports that hinted at intra-cranial efficacy (106,107). These results led to a surfeit of clinical trials evaluating BRAF inhibitors singly and combination BRAF/MEK inhibitors in MBM, summarized in Table 3.

Single agent BRAF inhibitor therapy was evaluated in 3 trials: 1 each involving vemurafenib (MO25743) and dabrafenib (BREAK-MB) in asymptomatic MBM, and a separate study that evaluated vemurafenib in symptomatic MBM patients (108-110). Both studies enrolled patients with BRAF V600 codon mutant and single or multiple MBM between 0.5–4 cm into separate cohorts depending on prior MBM-directed therapy, although MO25743 permitted LMD that BREAK-MB excluded. The former studies enrolled MBM patients and had relatively similar enrollment criteria: presence of activating BRAF V600 codon mutant, single or multiple MBM between 0.5–4 cm. In general, the studies revealed that MBM patients exhibited clinically meaningful response rates to single agent BRAF inhibitors that were well tolerated and without significant CNS toxicity, although unlike with ICIs, the intra-cranial and extra-cranial response rates are not commensurate, with the intra-cranial rates typically lower than the extra-cranial rates, although the reason for this is not clear as the aforenoted CNS penetration of BRAF (and MEK) inhibitors and their efficacy in primary brain tumors including pediatric gliomas and glioblastoma multiforme (111). Of note, single agent vemurafenib demonstrated safety and efficacy in symptomatic MBM, unlike the experience with ICIs as noted earlier (110).

A separate trial (BUMPER) evaluating the CNS-penetrable pan-PI3K inhibitor buparlisib in untreated MBM demonstrated that buparlisib monotherapy produced no intracranial responses in MBM patients unselected for PI3K pathway activation, although the drug itself was well tolerated (112). The MEK inhibitor binimetinib showed modest efficacy in a pilot study of 11 patients with NRAS mutated MBM who had failed multiple previous lines of therapy (113). ORR was 18%, although interestingly, in 2 patients, responses were deeper intracranially than extracranially.

Based on the enhanced anti-tumor activity and improved OS of combined BRAF/MEK inhibition compared to BRAF monotherapy alone, combination BRAF/MEK inhibitor therapy became the approved standard for BRAF V600 mutant melanoma over BRAF inhibition alone and prompted evaluation in MBM. COMBI-BM evaluated the dabrafenib/trametinib combination in 125 MBM patients in 4 cohorts: BRAF V600E mutant asymptomatic, untreated MBM (cohort A); BRAF V600E mutant asymptomatic, previously treated MBM (cohort B); BRAF non-V600 mutant (V600D/K/R mutant) asymptomatic, previously treated/untreated MBM (cohort C); and BRAF non-V600 mutant symptomatic, previously treated/untreated MBM (cohort D) (114). The majority of patients in each cohort had one or two brain metastases and had extracranial metastatic disease at the time of recruitment. The intra-cranial response rates were similar in all cohorts (cohort A 58%; cohort B 56%; cohort C 44%; cohort D 59%), and typically lower than the commensurate extra-cranial response rates (cohort A 55%; cohort B 44%; cohort C 75%; cohort D 41%), underscoring the trend seen with single agent BRAF inhibitor use. Concordantly, the duration of intra-cranial response was typically lower than for extra-cranial response (6.5 vs. 10.2 months), which pointed towards early CNS failure with BRAF/MEK inhibition—another distinction vis ICI use, wherein intra- and extra- cranial responses were concordant, and responses were typically long-lasting.

Combined TT and ICI therapy in MBM

Preclinical studies demonstrated potential synergies between combined BRAF/MEK inhibition and ICIs for several reasons including:

• Increased T cell effector and DC function following combined BRAF/MEK inhibition in vitro in co-culture experiments (115-117).
• Independent beneficial effects upon multiple components of the tumor immune microenvironment, including increased frequencies and enhanced activation status of TIL, and inhibition of suppressive immune cells including tumor-associated macrophages, and myeloid-derived suppressor cells, and consequent synergy with ICI (118,119).

Based on the above, randomized phase II trials evaluated the addition of anti-PD-1 ICI to BRAF/MEK inhibitor combination in BRAF mutant melanoma and reported higher PFS and greater durations of response with combined immunotherapy and targeted therapy, although notably the toxicity of the triplet regimens was considerable (120-123). Two separate phase III trials reported modest improvements in PFS with combined immunotherapy and targeted therapy compared with targeted therapy alone, and while this was statistically significant in IMspire150 (124), it was not in COMBI-I (125), and overall has not resulted in widespread adoption of the atezolizumab vemurafenib/cobimetinib triplet despite regulatory approval. However, untreated MBM patients were excluded from the studies, and the evidence for efficacy in active MBM is limited.

The combination of ipilimumab and vemurafenib was tested in a small phase II study in advanced melanoma, 6 of whom had MBM (126). Sequential administration of vemurafenib and ipilimumab led to disease control in 7 patients (5 patients with partial response and 2 with stable disease). The median PFS was 8 months, which was an improvement compared to the PFS seen with either drug, however, the combination was particularly toxic leading to discontinuation.

NIBIT-M1 was a phase II study which evaluated the efficacy of ipilimumab in combination with fotemustine, a chemotherapeutic agent with known CNS penetrance (127,128). This combination was based on the hypothesis that fotemustine would generate TA and consequently TA-specific T cells, a response that could be amplified by ipilimumab. 86 patients with advanced melanoma were enrolled, 20 out of which had brain disease. The intra-cranial RR was 50%, with 25% patients achieving partial response or stable CNS disease, and 25% without detectable disease on scans. Median OS in patients with brain disease was 12.7 months and 2- and 3-year survival rates were 38.9% and 27.8% respectively. Median PFS was 3.4 months in this subset of patients. NIBIT-M2 is an ongoing phase III study (Table 3) which plans to enroll 168 patients with MBM wherein fotemustine with or without ipilimumab will be evaluated against the combination of ipilimumab/nivolumab.

Combined local and systemic therapy

Despite the encouraging results seen in the clinical trials, a significant proportion of MBM patients are either resistant to systemic treatment or acquire resistance to systemic treatment over time (129). One of the treatment strategies to overcome this obstacle is combining local (neurosurgery vs. radiosurgery) and systemic therapies. Pooled analyses of various studies have shown improved 1-year survival and improved regional control in patients who receive SRS and ICI concurrently compared to SRS alone (130). When it comes to the synergistic effect seen between BRAF inhibitors and SRS, the radiosensitizing effect of this drug class on melanoma cells plays an important role. This effect, originally seen in preclinical studies (131), has been validated in the clinical setting by pooled analyses which have shown a significant survival advantage with the combination of BRAFi and SRS compared to SRS alone (132). Combination therapy, however, carries the potential for increased toxicities such as the increased risk of radiation necrosis with ICI/SRS combination (133) and intracranial hemorrhage with BRAF inhibitor/SRS combination (132). More data from other retrospective and prospective studies is needed to further characterize adverse events from combined local and systemic therapy (Table 4).

Adoptive cellular therapy (ACT) in MBM

ACT is demonstrably effective in highly refractory melanoma with ORR 36–41% (134,135). Despite early reports of efficacy in MBM (136), the evaluation of ACT in MBM has been unexpectedly slow due to the ACT-specific limitations, in particular the complexity entailed in generation and administration of autologous TIL which has restricted this therapy to specialized centers with expertise in this area.

A phase II study of ACT from NIH that included MBM reported intracranial responses in 5 out of 15 patients with previously treated CNS disease and 6 out of 18 patients with previously untreated CNS disease (137). Of note, the PFS was significantly less in patients with CNS disease compared to patients without CNS disease. In a small, randomized phase II study of ACT with or without antigen-loaded dendritic cells (DC) in a mostly ICI-naïve melanoma patient population, a small fraction of patients had durable responses including patients with untreated MBM. Pooled analyses have showed a significant response rate (32–38%) in patients who received TIL as a second line therapy after ICI failure. However, emerging data is showing poorer response in patients who receive TIL after ICI failure compared to ICI-naïve patients (134).

Sustained response after ACT is dependent on various factors, including higher doses of TIL (≥50 billion), higher absolute number of CD8⁺ cells in transfused cells, “young” TIL, high dose IL-2 and the in vitro conditions during expansion and priming of T-cells which affect T-cell functionality and longevity (134,138). These in vitro conditions are a focus of ongoing research and include potassium concentration (134,139), intracellular concentrations of L-arginine (140), rate of T-cell metabolic activity during in vitro expansion and priming (141), and cholesterol metabolism in T-cells (142). Transduction of T-cells with chimeric antigen receptors (CAR-T) and TCR gene modified T cells are other forms of adoptive cell therapies that are currently under investigation. The one-off nature of ACT and its tolerable toxicities compared to other systemic therapies makes it ACT a promising mode of therapy for MBM, although improving the survival of transduced T cells remains an ongoing challenge. The use of novel IL-2 pathway agonists, and other cytokines such as IL-7, IL-15, IL-18 to expand TIL ex vivo is promising, although it remains unclear if these data can be translated into the MBM setting.

Special circumstances

Leptomeningeal disease

Melanoma LMD carries a dismal prognosis, with median survival being only a few weeks (6), and limited data regarding effective treatment options. While RT may be considered for symptomatic areas of the spine (143), there is a paucity of evidence regarding the role of systemic therapy in LMD. Case reports and series support efficacy of BRAF/MEK inhibitors in BRAF mutated LMD (144-146). In Cohort C of the ABC trial, 4 out of 16 patients had LMD and were treated with single-agent nivolumab, with no intracranial responses being observed (88). Intrathecal (IT) interleukin-2 (IL-2) has been used in a small study of LMD patients with models results (median OS 7.8 months, 1-, 2-, and 5-year OS rates of 36%, 26%, and 13%, respectively) (147). The study also showed an improvement in radiological findings on brain imaging in 39% patients, and in 32% patients on spine imaging. The role of combined IT and systemic anti-PD-1 is being evaluated in a phase I/II study in LMD (NCT03025256).

Future directions

Multiple studies have been developed to improve upon prior results, and are summarized in Table 4. These include systemic ICIs in combination with agents such as VEGF inhibitors lenvatinib (KEYMAKER-U02D, NCT04700072) and bevacizumab (NCT04356729), novel glutamate modulator troriluzole (NCT04899921), and tumor treating fields (TTF) devices such as NovoTTF-100A (NCT04129515) or Sonocloud (SONIMEL01, NCT04021420).

Beyond the systemic administration of ICIs, IT approaches using various immunotherapies are currently being investigated in melanoma. IT IL-2 was first assessed in patients with melanoma patients with LMD. While response rates were low and the associated toxicities significant, a subset of melanoma patients with LMD treated with IT IL-2 achieved durable long-term survival with 1-, 2- and 5-year OS rates of 36%, 26%, and 13% (147). An ongoing study (NCT03025256) is evaluating combined systemic and IT nivolumab in this patient population.

As noted earlier, compelling data suggests synergies between PD-1 or CTLA-4 targeting ICIs and RT for the treatment of MBM, supported by data from retrospective series (148). These have led to a plethora of studies evaluating SRS combined with either single agent anti-PD-1 (NCT02716948, NCT02978404, and NCT02858869) or PD-1/CTLA-4 doublet (NCT03340129) in MBM.

Other studies are evaluating novel small molecules including the class I selective oral HDAC inhibitor HBI-8000 (NCT04674683) and STAT3 inhibitor WP1066 (NCT01904123).

Conclusions

Despite the recent advances in the understanding of molecular and genetic etiopathogenesis of advanced melanoma and development of effective treatments, MBM remains a challenging disease and thorny management problem underscored by poor prognosis of MBM patients in multiple real-world reports (149-152). ICI and targeted therapy have both led to significant improvements in the intracranial disease control. However, both treatment modalities carry the inherent risk of development of resistance and loss of response. The combination of ICI and targeted therapy has also been evaluated in a small number of clinical trials and has shown modest improvement in outcomes compared to either therapy alone. However, clinical trial data has also shown a significant amplification of toxicities with combination therapy which has led to limited adoption of this treatment model. Despite the current advances and the success of currently available therapies, sub-populations such as LMD and patients with progressive disease remain an extremely challenging population with relatively limited treatment options and poor outcomes. Novel treatments such as ACT have shown favorable outcomes in the heavily pre-treated population and remains an option for salvage treatment, despite the limitations associated with production and administration of engineered T-cells. MBM continues to be an area of immense research interest and multiple clinical trials are underway to evaluate combinations of various systemic agents, combined systemic and local therapy, and systemic agents and implantable devices. Further data is awaited to determine the most favorable combination of systemic and local therapies that can maximize the depth and length of response with minimum toxicities.

Acknowledgments

Funding: DD is supported by Melanoma Research Foundation Breakthrough Consortium (MRFBC), Gateway Foundation for Cancer Research (GFCR), Jack Buncher Foundation, and NIH/NCI awards including U01 CA271407, R01 CA257265 and P50 CA254865.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Simon S. Lo, Balamurugan Vellayappan, Kevin Shiue and Jonathan P. S. Knisely) for the series “The Modern Approaches to the Management of Brain Metastases” published in Chinese Clinical Oncology. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-22-1/rc

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-22-1/coif). The series “The Modern Approaches to the Management of Brain Metastases” was commissioned by the editorial office without any funding or sponsorship. DD is supported by Melanoma Research Foundation Breakthrough Consortium (MRFBC), Gateway Foundation for Cancer Research (GFCR), Jack Buncher Foundation, and NIH/NCI awards including U01 CA271407, R01 CA257265 and P50 CA254865. grants from Arcus, Checkmate Pharmaceuticals, CellSight Technologies, Immunocore, Merck, and Tesaro/GSK; consulting fees from Checkmate Pharmaceuticals, Finch, Shionogi, and Vedanta Biosciences; and payment or honoraria from Med Learning Group and Clinical Options. DD has US Patent 63/124,231, for “Compositions and Methods for Treating Cancer”, Dec 11, 2020; and US Patent 63/208,719, for “Compositions and Methods For Determining Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Chiarion-Sileni V, Guida M, Ridolfi L, et al. Central nervous system failure in melanoma patients: results of a randomised, multicentre phase 3 study of temozolomide- and dacarbazine- based regimens. Br J Cancer 2011;104:1816-21. [Crossref] [PubMed]
2. Sloan AE, Nock CJ, Einstein DB. Diagnosis and treatment of melanoma brain metastasis: a literature review. Cancer Control 2009;16:248-55. [Crossref] [PubMed]
3. Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol 2017;19:1511-21. [Crossref] [PubMed]
4. Vosoughi E, Lee JM, Miller JR, et al. Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies. BMC Cancer 2018;18:490. [Crossref] [PubMed]
5. Lucas JT Jr, Colmer HG 4th, White L, et al. Competing Risk Analysis of Neurologic versus Nonneurologic Death in Patients Undergoing Radiosurgical Salvage After Whole-Brain Radiation Therapy Failure: Who Actually Dies of Their Brain Metastases? Int J Radiat Oncol Biol Phys 2015;92:1008-15. [Crossref] [PubMed]
6. Davies MA, Liu P, McIntyre S, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer 2011;117:1687-96. [Crossref] [PubMed]
7. Sacks P, Rahman M. Epidemiology of Brain Metastases. Neurosurg Clin N Am 2020;31:481-8. [Crossref] [PubMed]
8. Wang Y, Lian B, Si L, et al. Real-world analysis of clinicopathological characteristics, survival rates, and prognostic factors in patients with melanoma brain metastases in China. J Cancer Res Clin Oncol 2021;147:2731-40. [Crossref] [PubMed]
9. Garg G, Finger PT, Kivelä TT, et al. Patients presenting with metastases: stage IV uveal melanoma, an international study. Br J Ophthalmol 2022;106:510-7. [Crossref] [PubMed]
10. Klein A, Sagi-Assif O, Meshel T, et al. CCR4 is a determinant of melanoma brain metastasis. Oncotarget 2017;8:31079-91. [Crossref] [PubMed]
11. Chen G, Chakravarti N, Aardalen K, et al. Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target. Clin Cancer Res 2014;20:5537-46. [Crossref] [PubMed]
12. Bedikian AY, Wei C, Detry M, et al. Predictive factors for the development of brain metastasis in advanced unresectable metastatic melanoma. Am J Clin Oncol 2011;34:603-10. [Crossref] [PubMed]
13. Zhang D, Wang Z, Shang D, et al. Incidence and prognosis of brain metastases in cutaneous melanoma patients: a population-based study. Melanoma Res 2019;29:77-84. [Crossref] [PubMed]
14. Sampson JH, Carter JH Jr, Friedman AH, et al. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 1998;88:11-20. [Crossref] [PubMed]
15. Izraely S, Klein A, Sagi-Assif O, et al. Chemokine-chemokine receptor axes in melanoma brain metastasis. Immunol Lett 2010;130:107-14. [Crossref] [PubMed]
16. Arvanitis CD, Ferraro GB, Jain RK. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer 2020;20:26-41. [Crossref] [PubMed]
17. Abate-Daga D, Ramello MC, Smalley I, et al. The biology and therapeutic management of melanoma brain metastases. Biochem Pharmacol 2018;153:35-45. [Crossref] [PubMed]
18. Kircher DA, Silvis MR, Cho JH, et al. Melanoma Brain Metastasis: Mechanisms, Models, and Medicine. Int J Mol Sci 2016;17:1468. [Crossref] [PubMed]
19. Westphal D, Glitza Oliva IC, Niessner H. Molecular insights into melanoma brain metastases. Cancer 2017;123:2163-75. [Crossref] [PubMed]
20. Muldoon LL, Alvarez JI, Begley DJ, et al. Immunologic privilege in the central nervous system and the blood-brain barrier. J Cereb Blood Flow Metab 2013;33:13-21. [Crossref] [PubMed]
21. Weiss SA, Zito C, Tran T, et al. Melanoma brain metastases have lower T-cell content and microvessel density compared to matched extracranial metastases. J Neurooncol 2021;152:15-25. [Crossref] [PubMed]
22. Kluger HM, Zito CR, Barr ML, et al. Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites. Clin Cancer Res 2015;21:3052-60. [Crossref] [PubMed]
23. Hamilton R, Krauze M, Romkes M, et al. Pathologic and gene expression features of metastatic melanomas to the brain. Cancer 2013;119:2737-46. [Crossref] [PubMed]
24. Fischer GM, Jalali A, Kircher DA, et al. Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases. Cancer Discov 2019;9:628-45. [Crossref] [PubMed]
25. Berghoff AS, Fuchs E, Ricken G, et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology 2015;5:e1057388. [Crossref] [PubMed]
26. Trembath DG, Davis ES, Rao S, et al. Brain Tumor Microenvironment and Angiogenesis in Melanoma Brain Metastases. Front Oncol 2021;10:604213. [Crossref] [PubMed]
27. Rabbie R, Ferguson P, Wong K, et al. The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence. Br J Cancer 2021;124:156-60. [Crossref] [PubMed]
28. Bekaert L, Emery E, Levallet G, et al. Histopathologic diagnosis of brain metastases: current trends in management and future considerations. Brain Tumor Pathol 2017;34:8-19. [Crossref] [PubMed]
29. Niessner H, Forschner A, Klumpp B, et al. Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases. Cancer Med 2013;2:76-85. [Crossref] [PubMed]
30. Davies MA, Stemke-Hale K, Lin E, et al. Integrated Molecular and Clinical Analysis of AKT Activation in Metastatic Melanoma. Clin Cancer Res 2009;15:7538-46. [Crossref] [PubMed]
31. Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene 2003;22:3113-22. [Crossref] [PubMed]
32. Dankort D, Curley DP, Cartlidge RA, et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 2009;41:544-52. [Crossref] [PubMed]
33. Vogt PK, Hart JR. PI3K and STAT3: a new alliance. Cancer Discov 2011;1:481-6. [Crossref] [PubMed]
34. Murry BP, Blust BE, Singh A, et al. Heparanase mechanisms of melanoma metastasis to the brain: Development and use of a brain slice model. J Cell Biochem 2006;97:217-25. [Crossref] [PubMed]
35. Trembath DG, Ivanova A, Krauze MT, et al. Melanoma-specific expression of the tumor suppressor proteins p16 and PTEN is a favorable prognostic factor in established melanoma brain metastases. Melanoma Res 2021;31:264-7. [Crossref] [PubMed]
36. Baenke F, Chaneton B, Smith M, et al. Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells. Mol Oncol 2016;10:73-84. [Crossref] [PubMed]
37. Ngo B, Kim E, Osorio-Vasquez V, et al. Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition. Cancer Discov 2020;10:1352-73. [Crossref] [PubMed]
38. Mori Y, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for cerebral metastatic melanoma: factors affecting local disease control and survival. Int J Radiat Oncol Biol Phys 1998;42:581-9. [Crossref] [PubMed]
39. Wolf A, Kvint S, Chachoua A, et al. Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery. J Neurosurg 2018;128:23-31. [Crossref] [PubMed]
40. Yu C, Chen JC, Apuzzo ML, et al. Metastatic melanoma to the brain: prognostic factors after gamma knife radiosurgery. Int J Radiat Oncol Biol Phys 2002;52:1277-87. [Crossref] [PubMed]
41. Paek SH, Audu PB, Sperling MR, et al. Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery 2005;56:1021-34; discussion 1021-34. [PubMed]
42. Corbett K, Sharma A, Pond GR, et al. Central Nervous System-Specific Outcomes of Phase 3 Randomized Clinical Trials in Patients With Advanced Breast Cancer, Lung Cancer, and Melanoma. JAMA Oncol 2021;7:1062-4. [Crossref] [PubMed]
43. Flanigan JC, Jilaveanu LB, Faries M, et al. Melanoma brain metastases: is it time to reassess the bias? Curr Probl Cancer 2011;35:200-10. [Crossref] [PubMed]
44. Tawbi HA, Forsyth PA, Hodi FS, et al. Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204). Neuro Oncol 2021;23:1961-73. [Crossref] [PubMed]
45. Arbour KC, Mezquita L, Long N, et al. Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer. J Clin Oncol 2018;36:2872-8. [Crossref] [PubMed]
46. Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999;5:1365-9. [Crossref] [PubMed]
47. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027-34. [Crossref] [PubMed]
48. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001;2:261-8. [Crossref] [PubMed]
49. Tseng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001;193:839-46. [Crossref] [PubMed]
50. Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003;33:2706-16. [Crossref] [PubMed]
51. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A 2003;100:5336-41. [Crossref] [PubMed]
52. Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature 1987;328:267-70. [Crossref] [PubMed]
53. Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995;3:541-7. [Crossref] [PubMed]
54. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995;270:985-8. [Crossref] [PubMed]
55. Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1:405-13. [Crossref] [PubMed]
56. Brunner MC, Chambers CA, Chan FK, et al. CTLA-4-Mediated inhibition of early events of T cell proliferation. J Immunol 1999;162:5813-20. [PubMed]
57. Freeman GJ, Borriello F, Hodes RJ, et al. Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science 1993;262:907-9. [Crossref] [PubMed]
58. Freeman GJ, Gribben JG, Boussiotis VA, et al. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science 1993;262:909-11. [Crossref] [PubMed]
59. Linsley PS, Clark EA, Ledbetter JA. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci U S A 1990;87:5031-5. [Crossref] [PubMed]
60. Linsley PS, Brady W, Urnes M, et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991;174:561-9. [Crossref] [PubMed]
61. Linsley PS, Greene JL, Brady W, et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994;1:793-801. [Crossref] [PubMed]
62. van der Merwe PA, Bodian DL, Daenke S, et al. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med 1997;185:393-403. [Crossref] [PubMed]
63. Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 2010;207:2175-86. [Crossref] [PubMed]
64. Huang AC, Postow MA, Orlowski RJ, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 2017;545:60-5. [Crossref] [PubMed]
65. Wei SC, Levine JH, Cogdill AP, et al. Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. Cell 2017;170:1120-1133.e17. [Crossref] [PubMed]
66. Wei SC, Anang NAS, Sharma R, et al. Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc Natl Acad Sci U S A 2019;116:22699-709. [Crossref] [PubMed]
67. Shi LZ, Goswami S, Fu T, et al. Blockade of CTLA-4 and PD-1 Enhances Adoptive T-cell Therapy Efficacy in an ICOS-Mediated Manner. Cancer Immunol Res 2019;7:1803-12. [Crossref] [PubMed]
68. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320-30. [Crossref] [PubMed]
69. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015;372:2521-32. [Crossref] [PubMed]
70. Robert C, Ribas A, Schachter J, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol 2019;20:1239-51. [Crossref] [PubMed]
71. Larkin J, Lao CD, Urba WJ, et al. Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma: A Pooled Analysis of 4 Clinical Trials. JAMA Oncol 2015;1:433-40. [Crossref] [PubMed]
72. Ribas A, Hamid O, Daud A, et al. Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. JAMA 2016;315:1600-9. [Crossref] [PubMed]
73. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015;373:23-34. Erratum in: N Engl J Med 2018;379:2185. [Crossref] [PubMed]
74. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2019;381:1535-46. [Crossref] [PubMed]
75. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2017;377:1345-56. [Crossref] [PubMed]
76. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med 2022;386:24-34. [Crossref] [PubMed]
77. Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in previously untreated metastatic or unresectable melanoma: Overall survival and response rates from RELATIVITY-047 (CA224-047). J Clin Oncol 2022;40:360385. [Crossref]
78. Lebbé C, Meyer N, Mortier L, et al. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol 2019;37:867-75. [Crossref] [PubMed]
79. Hodi FS, Oble DA, Drappatz J, et al. CTLA-4 blockade with ipilimumab induces significant clinical benefit in a female with melanoma metastases to the CNS. Nat Clin Pract Oncol 2008;5:557-61. [Crossref] [PubMed]
80. Schartz NE, Farges C, Madelaine I, et al. Complete regression of a previously untreated melanoma brain metastasis with ipilimumab. Melanoma Res 2010;20:247-50. [Crossref] [PubMed]
81. Queirolo P, Spagnolo F, Ascierto PA, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neurooncol 2014;118:109-16. [Crossref] [PubMed]
82. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012;13:459-65. [Crossref] [PubMed]
83. Ascierto PA, Del Vecchio M, Robert C, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2017;18:611-22. [Crossref] [PubMed]
84. Ascierto PA, Del Vecchio M, Mackiewicz A, et al. Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma. J Immunother Cancer 2020;8:e000391. [Crossref] [PubMed]
85. Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 2016;17:976-83. [Crossref] [PubMed]
86. Kluger HM, Chiang V, Mahajan A, et al. Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. J Clin Oncol 2019;37:52-60. [Crossref] [PubMed]
87. Tawbi HA, Forsyth PA, Algazi A, et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med 2018;379:722-30. [Crossref] [PubMed]
88. Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 2018;19:672-81. [Crossref] [PubMed]
89. Long GV, Atkinson V, Lo S, et al. Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets). J Clin Oncol 2021;39:9508. [Crossref]
90. Cancer Genome Atlas Network. Genomic Classification of Cutaneous Melanoma. Cell 2015;161:1681-96. [Crossref] [PubMed]
91. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135-47. [Crossref] [PubMed]
92. Jin SA, Chun SM, Choi YD, et al. BRAF mutations and KIT aberrations and their clinicopathological correlation in 202 Korean melanomas. J Invest Dermatol 2013;133:579-82. [Crossref] [PubMed]
93. Lin YC, Chang YM, Ho JY, et al. C-kit expression of melanocytic neoplasm and association with clinicopathological parameters and anatomic locations in Chinese people. Am J Dermatopathol 2013;35:569-75. [Crossref] [PubMed]
94. Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res 2012;18:3242-9. [Crossref] [PubMed]
95. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011;29:1239-46. [Crossref] [PubMed]
96. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16. [Crossref] [PubMed]
97. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809-19. [Crossref] [PubMed]
98. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:107-14. [Crossref] [PubMed]
99. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010;464:431-5. [Crossref] [PubMed]
100. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010;140:209-21. [Crossref] [PubMed]
101. Poulikakos PI, Zhang C, Bollag G, et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010;464:427-30. [Crossref] [PubMed]
102. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:1694-703. [Crossref] [PubMed]
103. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014;371:1867-76. [Crossref] [PubMed]
104. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877-88. [Crossref] [PubMed]
105. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2018;19:603-15. [Crossref] [PubMed]
106. Lee JM, Mehta UN, Dsouza LH, et al. Long-term stabilization of leptomeningeal disease with whole-brain radiation therapy in a patient with metastatic melanoma treated with vemurafenib: a case report. Melanoma Res 2013;23:175-8. [Crossref] [PubMed]
107. Rochet NM, Kottschade LA, Markovic SN. Vemurafenib for melanoma metastases to the brain. N Engl J Med 2011;365:2439-41. [Crossref] [PubMed]
108. McArthur GA, Maio M, Arance A, et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol 2017;28:634-41. [Crossref] [PubMed]
109. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13:1087-95. [Crossref] [PubMed]
110. Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer 2014;50:611-21. [Crossref] [PubMed]
111. Kushnirsky M, Feun LG, Gultekin SH, et al. Prolonged Complete Response With Combined Dabrafenib and Trametinib After BRAF Inhibitor Failure in BRAF-Mutant Glioblastoma. JCO Precis Oncol 2020;4. ePO. [Crossref] [PubMed]
112. Amaral T, Niessner H, Sinnberg T, et al. An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery-the BUMPER study. Neurooncol Adv 2020;2:vdaa140.
113. Goldinger SM, Valeska Matter A, Urner-Bloch U, et al. Binimetinib in heavily pretreated patients with NRAS-mutant melanoma with brain metastases. Br J Dermatol 2020;182:488-90. [Crossref] [PubMed]
114. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017;18:863-73. [Crossref] [PubMed]
115. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 2010;70:5213-9. [Crossref] [PubMed]
116. Sumimoto H, Imabayashi F, Iwata T, et al. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 2006;203:1651-6. [Crossref] [PubMed]
117. Ott PA, Henry T, Baranda SJ, et al. Inhibition of both BRAF and MEK in BRAF(V600E) mutant melanoma restores compromised dendritic cell (DC) function while having differential direct effects on DC properties. Cancer Immunol Immunother 2013;62:811-22. [Crossref] [PubMed]
118. Hu-Lieskovan S, Mok S, Homet Moreno B, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl Med 2015;7:279ra41. [Crossref] [PubMed]
119. Homet Moreno B, Mok S, Comin-Anduix B, et al. Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma. Oncoimmunology 2015;5:e1052212. [Crossref] [PubMed]
120. Ascierto PA, Ferrucci PF, Fisher R, et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med 2019;25:941-6. [Crossref] [PubMed]
121. Ferrucci PF, Di Giacomo AM, Del Vecchio M, et al. KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma. J Immunother Cancer 2020;8:e001806. [Crossref] [PubMed]
122. Ribas A, Lawrence D, Atkinson V, et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat Med 2019;25:936-40. [Crossref] [PubMed]
123. Sullivan RJ, Hamid O, Gonzalez R, et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med 2019;25:929-35. [Crossref] [PubMed]
124. Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;395:1835-44. [Crossref] [PubMed]
125. Dummer R, Long GV, Robert C, et al. Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma. J Clin Oncol 2022;40:1428-38. [Crossref] [PubMed]
126. Hassel JC, Lee SB, Meiss F, et al. Vemurafenib and ipilimumab: A promising combination? Results of a case series. Oncoimmunology 2015;5:e1101207. [Crossref] [PubMed]
127. Di Giacomo AM, Ascierto PA, Queirolo P, et al. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study. Ann Oncol 2015;26:798-803. [Crossref] [PubMed]
128. Di Giacomo AM, Ascierto PA, Pilla L, et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol 2012;13:879-86. [Crossref] [PubMed]
129. Lee H, Quek C, Silva I, et al. Integrated molecular and immunophenotypic analysis of NK cells in anti-PD-1 treated metastatic melanoma patients. Oncoimmunology 2018;8:e1537581. [Crossref] [PubMed]
130. Lehrer EJ, Peterson J, Brown PD, et al. Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: An international meta-analysis of individual patient data. Radiother Oncol 2019;130:104-12. [Crossref] [PubMed]
131. Sambade MJ, Peters EC, Thomas NE, et al. Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. Radiother Oncol 2011;98:394-9. [Crossref] [PubMed]
132. Khan M, Zheng T, Zhao Z, et al. Efficacy of BRAF Inhibitors in Combination With Stereotactic Radiosurgery for the Treatment of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis. Front Oncol 2021;10:586029. [Crossref] [PubMed]
133. Colaco RJ, Martin P, Kluger HM, et al. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J Neurosurg 2016;125:17-23. [Crossref] [PubMed]
134. Dafni U, Michielin O, Lluesma SM, et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis. Ann Oncol 2019;30:1902-13. [Crossref] [PubMed]
135. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. J Clin Oncol 2021;39:2656-66. [Crossref] [PubMed]
136. Hong JJ, Rosenberg SA, Dudley ME, et al. Successful treatment of melanoma brain metastases with adoptive cell therapy. Clin Cancer Res 2010;16:4892-8. [Crossref] [PubMed]
137. Mehta GU, Malekzadeh P, Shelton T, et al. Outcomes of Adoptive Cell Transfer With Tumor-infiltrating Lymphocytes for Metastatic Melanoma Patients With and Without Brain Metastases. J Immunother 2018;41:241-7. [Crossref] [PubMed]
138. Donia M, Junker N, Ellebaek E, et al. Characterization and comparison of 'standard' and 'young' tumour-infiltrating lymphocytes for adoptive cell therapy at a Danish translational research institution. Scand J Immunol 2012;75:157-67. [Crossref] [PubMed]
139. Eil R, Vodnala SK, Clever D, et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 2016;537:539-43. [Crossref] [PubMed]
140. Geiger R, Rieckmann JC, Wolf T, et al. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. Cell 2016;167:829-842.e13. [Crossref] [PubMed]
141. Sukumar M, Kishton RJ, Restifo NP. Metabolic reprograming of anti-tumor immunity. Curr Opin Immunol 2017;46:14-22. [Crossref] [PubMed]
142. Yang W, Bai Y, Xiong Y, et al. Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 2016;531:651-5. [Crossref] [PubMed]
143. Glitza IC, Smalley KSM, Brastianos PK, et al. Leptomeningeal disease in melanoma patients: An update to treatment, challenges, and future directions. Pigment Cell Melanoma Res 2020;33:527-41. [Crossref] [PubMed]
144. Arasaratnam M, Hong A, Shivalingam B, et al. Leptomeningeal melanoma-A case series in the era of modern systemic therapy. Pigment Cell Melanoma Res 2018;31:120-4. [Crossref] [PubMed]
145. Glitza IC, Ferguson SD, Guha-Thakurta N. Rapid resolution of leptomeningeal disease with targeted therapy in a metastatic melanoma patient. J Neurooncol 2017;133:663-5. [Crossref] [PubMed]
146. Kim DW, Barcena E, Mehta UN, et al. Prolonged survival of a patient with metastatic leptomeningeal melanoma treated with BRAF inhibition-based therapy: a case report. BMC Cancer 2015;15:400. [Crossref] [PubMed]
147. Glitza IC, Rohlfs M, Guha-Thakurta N, et al. Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2. ESMO Open 2018;3:e000283. [Crossref] [PubMed]
148. Qian JM, Martin AM, Martin K, et al. Response rate and local recurrence after concurrent immune checkpoint therapy and radiotherapy for non-small cell lung cancer and melanoma brain metastases. Cancer 2020;126:5274-82. [Crossref] [PubMed]
149. Moyers JT, Chong EG, Peng J, et al. Real world outcomes of combination and timing of immunotherapy with radiotherapy for melanoma with brain metastases. Cancer Med 2021;10:1201-11. [Crossref] [PubMed]
150. Rieth JM, Swami U, Mott SL, et al. Melanoma Brain Metastases in the Era of Targeted Therapy and Checkpoint Inhibitor Therapy. Cancers (Basel) 2021;13:1489. [Crossref] [PubMed]
151. van Zeijl MCT, Ismail RK, de Wreede LC, et al. Real-world outcomes of advanced melanoma patients not represented in phase III trials. Int J Cancer 2020;147:3461-70. [Crossref] [PubMed]
152. Donia M, Ellebaek E, Øllegaard TH, et al. The real-world impact of modern treatments on the survival of patients with metastatic melanoma. Eur J Cancer 2019;108:25-32. [Crossref] [PubMed]