Melanoma brain metastasis: overview of current management and emerging targeted therapies

Abstract

The high rate of brain metastasis in patients with advanced melanoma has been a clinical challenge for oncologists. Despite considerable progress made in the management of advanced melanoma over the past two decades, improvement in overall survival has been elusive. This is due to the high incidence of CNS metastases, which progress relentlessly and which are only anecdotally responsive to systemic therapies. Surgery, stereotactic radiosurgery and whole-brain radiotherapy with or without cytotoxic chemotherapy remain the mainstay of treatment. However, new drugs have been developed based on our improved understanding of the molecular signaling mechanisms responsible for host immune tolerance and for melanoma growth. In 2011, the US FDA approved two agents, one antagonizing each of these processes, for the treatment of advanced melanoma. The first is ipilimumab, an anti-CTLA-4 monoclonal antibody that enhances cellular immunity and reduces tolerance to tumor-associated antigens. The second is vemurafenib, an inhibitor that blocks the abnormal signaling for melanoma cellular growth in tumors that carry the BRAF^V600E mutation. Both drugs have anecdotal clinical activity for brain metastasis and are being evaluated in clinical trial settings. Additional clinical trials of newer agents involving these pathways are also showing promise. Therefore, targeted therapies must be incorporated into the multimodality management of melanoma brain metastasis.

Keywords::

• brain metastasis
• immunotherapy
• melanoma
• targeted therapy

Figure 1. The Ras/Raf/MEK/ERK pathway is an important signaling pathway for cell growth and differentiation.

(A) Protein signaling cascade commences with the onset of Raf activation by activated growth factor receptors, leading to the induction of specific gene transcription. Homeostatic control is regulated by feedback mechanisms along each chain on the pathway. (B) Mutations in the BRAF gene results in the presence of the constitutively activated form of BRAF and the persistent activation of ERK signaling that stimulate the proliferation and survival of melanoma cells.

Figure 2. Vemurafenib.

The large molecular weight at 489.9 and the polar chlorophenyl and sulfonic acid groups may prevent this molecule from readily crossing the blood–brain barrier.

Propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2.4-difluorophenyl}-amide: C₂₃H₁₈ClF₂N₃O₃S: Mr = 489.9.

Adapted from [69].

Patients with advanced melanoma have a high propensity of developing melanoma brain metastases [1,2]. However, the treatment of these metastases has not changed in the past two decades. Neuro-oncologists and neurosurgeons have achieved limited success using conventional treatments that include radiotherapy, either local treatment with stereotactic radiosurgery or global therapy with whole-brain radiotherapy (WBRT), with or without antecedent surgical resection. These treatment approaches have limitations because melanoma is typically radioresistant and multiple brain metastases are often found at the time of neurological presentation [3]. However, two treatments have recently become available for advanced melanoma. Ipilimumab (Yervoy™), which received US FDA approval on 25 March 2011 [101], is a humanized monoclonal antibody against the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) receptor, thereby allowing the persistent and increased activation of immune response against metastatic melanomas. Later, the FDA also approved vemurafenib (Zelboraf^®) on 17 August 2011 [102] for the treatment of BRAF^V600E-mutated malignant melanoma. Vemurafenib is a small-molecule inhibitor of the serine threonine kinase BRAF capable of correcting the abnormal activation of the MAPK pathway. It has significant activity against tumor cells harboring the mutated BRAF^V600E protein. Although definitive data are lacking at present, these two therapeutic strategies may offer an alternative to the management of metastatic melanoma in the brain and the rest of the CNS.

Genetic mutations in melanoma

DNA damage of melanocytes from ultraviolet radiation is the basis for the oncogenesis of melanoma. Similar to other epithelial malignancies, there are cumulative somatic mutations detected as the tumor evolves from benign nevus to invasive melanoma [4,5]. Notably, loss of the germ-line mutation CDKN2A/p16^INK4a has been linked to the development of inherited melanoma [6]. As this mutation is also found in 10–25% of sporadic melanoma, mutated CDKN2A/p16^INK4a appears to be a key initiator of melanoma oncogenesis [6]. In addition, a number of somatic mutations are found in melanomas (Table 1) and the accumulation of such mutations is likely to enable the subsequent tumorigenic progression of benign melanotic nevus to dysplastic nevus and then superficial spreading melanoma. Furthermore, there is a high frequency of BRAF mutations, in the order of 26–70% [5], found in invasive melanoma. In particular, the activating mutation BRAF^V600E is linked to the efficacy of vemurafenib for metastatic melanoma [7,8]. Last, the final steps of melanoma tumorigenesis probably also involve the co-option of the microenvironment near the tumor, including evading the immune system, in order to allow growth, proliferation and eventual metastasis of melanoma cells [9]. It is unclear at this time how differences among patients’ genetic and immunological background influence the efficacy of new immunotherapy and targeted drugs.

The growing problem of melanoma brain metastasis

The cumulative incidence of melanoma brain metastasis is <10% according to a large series [10,11]. However, brain involvement increases substantially to 45–50% in those having advanced melanoma and 75% at autopsy [12,13]. This is because melanoma micrometastases [14,15] are common in the brain and patients can harbor numerous metastases in the brain without neurological deficits. Furthermore, while melanoma can present in the brain as the first site of metastasis, it is more common for brain metastasis to present later in the course of disease, most often acting as a harbinger of terminal disease with a median survival of approximately 4 months after detection. While surgery and radiotherapy interventions can prolong the disease-free interval when solitary, large metastases in the brain are found early in the course of melanoma metastasis, these treatments provide only short-term, but nevertheless important palliation. Additionally, symptomatic leptomeningeal spread of metastatic melanoma, which occurs in 1–5% of melanoma patients [16], is not as common as parenchymal brain metastases, but carries a poor prognosis and continues to be an area of unmet need. Therefore, the application of efficacious treatments for advanced melanoma that concomitantly cross the blood–brain barrier remains the best strategy to control brain metastasis.

The role of surgery & radiotherapy for melanoma brain metastasis

Surgical resection and radiotherapy have been the conventional treatment for brain metastasis from melanoma [17–19]. Although it has been shown in randomized trials that resection of a solitary brain metastasis followed by whole-brain cranial irradiation would improve patient survival [20,21], this strategy may not be relevant to melanoma because of the high frequency of multiple and miliary brain metastases and their radioresistance. Furthermore, most patients enrolled in prior randomized studies had lung cancer and those with melanoma comprised only 2–8% of the cohort [20,21]. However, a retrospective analysis by Raizer et al. demonstrated that there is a lower hazard rate of death in patients who had neurosurgical resection incorporated as part of their overall disease management [22]. Therefore, patient selection for neurosurgical intervention, which is primarily directed at symptom management, is essential to achieving a good outcome. For example, removal of a large brain metastasis of ≥4 cm in diameter may relieve elevated intracranial pressure and reverse neurological impairment by alleviating mass effect across the midline due to brain shift or subfalcine herniation, herniation of the uncus of the temporal lobe causing compression of the brainstem and posterior cerebral artery or hydrocephalus secondary to blockage of cerebrospinal fluid outflow. For patients with smaller and few metastases (less than six), neurosurgical evacuation of a hemorrhagic tumor may be indicated because this would alleviate neurological deficits as the mass effect from blood does not typically respond to dexamethasone. Last, tumors that are near sensitive areas of brain, such as the language areas, sensorimotor homunculus and visual cortex, or those that cause intractable seizures, should also be strongly considered for resection. The overarching goal of neurosurgical intervention should be directed at preservation of neurological function so that patients can later receive systemic treatment for their advanced melanoma.

Melanoma cells have low responsiveness to radiation in vitro and this correspond to the low efficacy of WBRT [23,24]. After WBRT, the median survival of patients with melanoma brain metastasis is only 14 weeks [25,26]. However, Smalley et al. demonstrated that adjuvant WBRT given after resection of a solitary melanoma brain metastasis resulted in a lower relapse rate than those who were just observed, 12 versus 85%, respectively [27]. However, past clinical trials have shown that escalating the radiation dose per fraction, adding temozolomide as radiosensitizer, or combining temozolomide and thalidomide to WBRT did not result in prolonged survival [28–30]. The Graded Prognostic Assessment, in which a score is calculated based on the Karnofsky performance status and the number of brain metastases, may offer a better estimate of survival with median survivals vary between 15 and 57 months in the worst and best prognostic groups, respectively [31]. In sum, the available data indicate that WBRT has limited efficacy against patients with multiple melanoma brain metastases but WBRT can benefit those who have minimal residual disease after resection of a solitary brain metastasis.

Stereotactic radiosurgery is another modality of treatment that delivers highly conformal radiation to a metastasis target in a high dose per fraction fashion [32]. In general, the local control rate is in the order of 90% for brain metastasis from systemic malignancy [32]. However, retrospective studies have shown that the 1-year local control rate is only 63–75% for melanoma [33]. Tumor size seems to be an important determinant of local control, with 1-year local control of 75 versus 42% in tumors ≤2 versus >2 cm³, respectively [34]. Furthermore, the prospective RTOG 9508 trial [35] and retrospective data from Sperduto et al. using the Grade Prognostic Assessment [36] both showed that radiosurgery plus WBRT is better than WBRT alone. In addition, Sperduto et al. showed that radiosurgery alone is better than WBRT and this benefit is predominantly found in patients with good performance status and limited number of brain metastases [36]. Although randomized prospective data demonstrating benefit for melanoma brain metastases are still lacking, radiosurgery alone is definitely less invasive and carries fewer comorbidities than neurosurgical resection.

Conventional chemotherapies

Chemotherapy has limited efficacy against metastatic melanoma to the brain. Temozolomide, at a dose of 150 mg/m²/day × 5 days, only had an objective response rate of 3–5% [37,38]. When temozolomide is combined with WBRT, the objective response rates improved to 9–44% [39,40], while the objective response rates for temozolomide plus thalidomide was 0–12% [41], temozolomide plus thalidomide and WBRT was 8% [28], and temozolomide plus sorafenib was 21.7% [42]. The nitrosourea fotemustine offers a higher response rate, in the order of 25–28% [43], but it is not available in the USA. Although patients treated with paclitaxel have a 12–14% response rate [44], its penetrance across the blood–brain barrier is rather limited. New immunotherapy and small-molecule serine threonine kinase inhibitors, as well as those that are currently in clinical trial testing, are beginning to show promise for the prevention and treatment of brain metastases while exhibiting tolerable side effects.

Ipilimumab (BMS-734016) immunotherapy

Ipilimumab immunotherapy was granted FDA approval on 25 March 2011 [101] for use against metastatic melanoma. It works by blocking the CTLA-4 antigen on the T-cell surface and resulting in the persistent and heightened activation of anti-tumor adaptive immunity [45]. In Phase I and II dose-finding studies, ipilimumab appears to have a linear dose–response relationship (overall response rate: 11.1% at 10 mg/kg, 4.2% at 3 mg/kg and 0% at 0.3 mg/kg) that is also accompanied by a linear dose–toxicity effect (adverse event at any grade: 70.4% at 10 mg/kg, 64.8% at 3 mg/kg and 26.4% at 0.3 mg/kg) [46]. Like other biological agents, ipilimumab did not have a maximum tolerated dose or a significant number of adverse events at grade 3 or 4. The most common immune-mediated toxicity was associated with the highest dose used (10 mg/kg), resulting in diarrhea that occurred at a rate of 16% [47]. In Phase III trials ipilimumab has been shown to have efficacy in the prolongation of overall survival of patients with metastatic melanoma. In the trial comparing ipilimumab at a dose of 3 mg/kg plus gp100 vaccine versus gp100 vaccine alone and ipilimumab alone, patients treated with ipilimumab plus gp100 had a median survival of 10.0 versus 6.4 months for those treated with gp100 alone, while those had ipilimumab alone had 10.1 months, with no statistical difference between the ipilimumab groups [48]. In another trial of patients with untreated metastatic melanoma, ipilimumab plus dacarbazine combination was better than dacarbazine alone and the median survival was 11.2 versus 9.1 months, respectively [49]. The respective proportions of patients who were alive were 47.3 versus 36.3% at 1 year, 28.5 versus 17.9% at 2 years, and 20.8 versus 12.2% at 3 years [49]. Therefore, the data indicate that ipilimumab has an acceptable toxicity profile and significant efficacy in the prolongation of patient survival.

While ipilimumab cannot cross the blood–brain barrier, activated T cells can migrate into the brain and exert an anti-tumor effect. However, data on its efficacy against melanoma brain metastases are limited. Only one prior trial enrolled patients with known brain metastases and the inclusion criteria required them to be treated and to have achieved radiologic stability prior to enrollment [49]. Nevertheless, anecdotal reports have indicated that ipilimumab may have efficacy against metastatic melanoma in the brain and the spinal cord. Hodi et al. reported a case of a woman with melanoma that had metastasized to the brain and spinal cord from an unknown primary [50]. After initial treatment with neurosurgical resection of a symptomatic metastasis, adjuvant radiosurgery to other brain metastases, external beam irradiation to spinal metastases and adjuvant temozolomide, she received ipilimumab at the time of disease progression in the brain. Although a new brain metastasis was found during the maintenance phase of ipilimumab treatment, surgical removal of the metastasis demonstrated predominantly CD8⁺ cytotoxic T cells but few FoxP3⁺ Tregs, suggesting a fulminant immune response against this brain metastasis rather than tumor progression. Her melanomas remained stable for 7 months and she lived for 2 years from the time of initial diagnosis. In a separate analysis of clinical response in the Phase III trial of ipilimumab plus gp100 versus gp100 or ipilimumab alone, Downey et al. reported one complete response and two partial responses that were associated with ipilimumab treatment out of ten patients with brain metastases who were previously treated with adjuvant radiotherapy [51]. Last, Schartz et al. reported a patient with multiple melanoma brain metastases who had a complete response after ipilimumab treatment alone [52]. Therefore, these anecdotal cases suggest that CD8⁺ cytotoxic T cells can travel into the immunologically privileged CNS and mount an antimelanoma immune response. Similar to the variable kinetics of response to ipilimumab in systemic melanoma [53], the response heterogeneity seen in the population with brain metastasis probably has to do with the background immunogenicity and immunoediting capability of the individual melanoma brain metastases, as well as the host’s ability to recognize melanoma antigens. However, the efficacy of ipilimumab against leptomeningeal metastasis remains unknown.

In order to adequately evaluate the efficacy of ipilimumab against active melanoma brain metastases, a separate Phase II multi-institutional trial is being conducted in melanoma patients with active brain metastases. This trial is using a high-dose regimen that was not FDA approved at the time of this review; specifically, 10 mg/kg every 3 weeks for four doses followed by the same dose every 12 weeks. The primary end point is ‘disease control rate’, specifically the total complete responses, partial responses, and stable disease at 12 weeks. In the preliminary report [54], arm A (51 patients) consisted of asymptomatic patients not requiring steroids and arm B (21 patients) consisted of patients requiring steroids for symptomatic brain metastases. About three-quarters of the patients had received prior systemic therapy (78.4% in arm A and 71.4% in arm B) and approximately 40% had received prior radiotherapy (39.2% in arm A and 42.9% in arm B). Disease control with ipilimumab at 12 weeks was achieved in 23.5% of brain metastases, 27.5% of nonbrain metastases and 17.6% of total tumor burden in arm A. Not surprisingly, the values were lower in arm B: 9.5, 4.8 and 4.8%, respectively. Grade 3 immune-mediated adverse reactions were reported in 21.6% of patients in arm A (including diarrhea, rash, adrenal insufficiency and hypophysitis) and 9.5% of patients in arm B (including diarrhea, rash, increased alanine aminotransferase or aspartate aminotransferase). One death in arm A from septic shock was considered drug-related. With a third of the patients not yet evaluable, and by using either modified WHO criteria or immune-related response criteria, there were eight partial responses in brain metastases in arm A and one in arm B, some of which were durable responses. These preliminary data point to the encouraging efficacy of ipilimumab against active melanoma brain metastases.

Other immunotherapies in development

While there is as yet no published controlled data on iplimumab activity against melanoma metastases in the CNS, the following new agents (not inclusive) are being tested alone or in combination with ipilimumab and other agents in order to further augment cellular immune responses against melanoma. Anti-PD-1 (also known as MDX 1106/BMS-936558/ONO-4538) is a fully human monoclonal IgG4 antibody directed against another negative immunoregulator programmed death-1 (PD-1; or programmed cell death-1 [PCD-1]), a transmembrane protein receptor and member of the immunoglobulin superfamily. Activated PD-1 negatively regulates T-cell activation and effector function through the suppression of PI3K/Akt pathway activation, which provides the necessary signaling for cellular survival [55–57]. In early clinical trials, anti-PD-1 antibody has induced partial responses in melanoma patients and they experienced less severe immune-related toxicity than ipilimumab [58]. In a recent report, 104 patients with heavily pretreated advanced melanoma, but with brain metastasis stabilized by other means, received anti-PD-1 at 1, 3 or 10 mg/kg every 2 weeks followed by cohort expansion, resulted in 25% (26 out of 104) objective responses of systemic melanomas and many were durable [59]. Two other anti-PD-1 antibodies, CT011 and MK-3475, are also in development [60,61]. Given the favorable response and toxicity profiles, anti-PD-1 antibody could have efficacy against melanoma brain metastases but more clinical data are needed.

Other immunomodulatory monoclonal antibodies currently being tested including BMS-663513[62]. This is an agonist human monoclonal antibody that targets CD137 (a member of the TNF receptor family), which acts as a costimulatory molecule for CD8⁺ and CD4⁺ T cells. In a Phase I trial, there were three partial responses among 54 enrolled melanoma patients without brain metastasis. A second agonist humanized monoclonal antibody against CD134 (OX40, a member of the TNF receptor superfamily of receptors) that results in secondary costimulatory signaling, is being tested in Phase I trials [63,64]. Last, lymphocyte activation gene-3 (LAG-3) is a cell-surface molecule that maintains tolerance to self and tumor antigens. Naive CD8⁺ T cells express low levels of LAG-3, and expression increases upon antigen stimulation. In vivo antibody blockade of LAG-3 or genetic ablation of the Lag-3 gene results in increased accumulation and effector function of antigen-specific CD8⁺ T cells within organs and tumors [65,66]. In one study, combining LAG-3 blockade with specific anti-tumor vaccination resulted in a significant increase in activated CD8⁺ T cells in the tumor and disruption of the tumor parenchyma, supporting that LAG-3 blockade may have potential as an anti-melanoma treatment [65]. These novel strategies of immunomodulatory treatments for systemic malignant melanoma may hold promise in the prevention and/or treatment of melanoma brain metastasis.

Vemurafenib for BRAF^V600E

Vemurafenib received FDA approval on 17 August 2011 [102] for the treatment of BRAF^V600E-positive malignant melanoma. Vemurafenib is a small-molecule serine threonine kinase inhibitor of BRAF and its action blocks the mutated BRAF^V600E and its abnormal activation of the MAP kinase pathway (Figure 1) [67,68]. BRAF is estimated to be mutated in over 40% of advanced melanomas and 90% of the mutations involve a valine-to-glutamic acid substitution at residue 600 (V600E) [67,69]. In the initial Phase I testing of the drug, the overall response rate was 76% (37 out of 49 patients with mutated BRAF^V600E responded) and 34 (69%) had a partial response while three (6%) had a complete response [8]. This impressive result led to a pivotal Phase III trial comparing vemurafenib plus dacarbazine versus dacarbazine alone showing that overall survival at 6 months was 84 versus 64%, and the median progression-free survival was 5.3 versus 1.6 months, respectively [7]. The clinical data indicate that vemurafenib is efficacious against malignant melanoma.

The efficacy of vemurafenib against brain metastasis from melanoma is unknown. This is because past clinical trials excluded patients with active brain metastases [7,8]. However, the physiochemical property of vemurafenib (Figure 2) suggests that it may have difficulty crossing the blood–brain barrier. This is because drug penetrance into the CNS depends on its size, preferably <300 in molecular weight, and its lipid solubility, preferably >1 in the octanol:water partition coefficient. Vemurafenib has a molecular weight of 489.9 [67] and its large size makes it difficult to passively diffuse across the blood–brain barrier. Furthermore, the molecular structure of the drug, which has the polar sulfonic acid and chlorophenyl groups at either end making it hydrophilic and hydroscopic [67,69], also limits its ability to cross the blood–brain barrier. However, additional pharmacokinetic data, by measuring drug levels in the cerebrospinal fluid or extracellular fluid from the brain parenchyma by microdialysis, would be needed in order to determine the extent of CNS penetration.

Despite these unfavorable chemical properties, there have been anecdotal reports of vemurafenib efficacy against melanoma brain metastases. An open-label single-arm trial evaluated the safety and efficacy of 960 mg of vemurafenib taken twice daily in patients with BRAF^V600E-positive metastatic melanoma and unresectable CNS metastases that required corticosteroids for symptom control [70]. Preliminary results were presented for seven out of a planned 20 total patients enrolled in the trial. Median number of brain metastases per patient was nine (range: 3–18), which were previously treated with whole-brain radiation in six and another type of radiotherapy in one [70]. Four patients had received one prior systemic therapy while three others had three or more treatments for their metastases in the body [70]. Of the five patients with staging data available after 1–4 months of vemurafenib therapy, one had a confirmed partial response in the brain and body, one had a minor response in the brain and body, and three achieved stable disease. Adverse events possibly related to vemurafenib were only of grade 1 or 2 vomiting, liver enzyme elevation, arthralgia, cough, facial paresis, fatigue, cutaneous herpes zoster eruption, muscle spasm, nausea, peripheral edema, oral herpes, maculopapular rash and sinusitis [70].

A case report described the use of vemurafenib in a 16-year-old woman with rapidly progressive and hemorrhagic CNS metastases from BRAF^V600E mutation-positive melanoma despite prior high-dose IL-2, ipilimumab and stereotactic radiosurgery [71]. At baseline she was receiving dexamethasone as the largest of several lesions was 5 cm with associated vasogenic edema. She had an excellent response while being dosed at 960 mg twice daily, and after 6 months an MRI showed reduction in all brain metastases [71].

Other BRAF^V600E inhibitors

Dabrafenib (GSK2118436) is another orally bioavailable and specific inhibitor of mutated BRAF^V600E protein currently in development. It has the lowest IC₅₀ against BRAF^V600E among its competitors and may have a more favorable chemical profile for penetrating the CNS compared with vemurafenib. In a Phase I/II trial presented at the ESMO 2010 meeting in Milan (Italy), dabrafenib shrank the previously untreated brain metastases in seven out of ten patients [72]. The overall reductions ranged from 20 to 100% of brain metastases that were 3 mm or larger in diameter before treatment [72]. Furthermore, preliminary results of another Phase I–II study with this agent were also reported in which 57 melanoma patients with activating mutation of BRAF received dabrafenib, including ten out of 16 at the planned Phase II dose, where 27 objective responses were observed including activity against previously untreated brain metastases [73]. These data suggest that dabrafenib may be more effective than vemurafenib or ipilimumab for patients with advanced melanoma with brain metastases.

Other agents targeting BRAF and the MAP kinase pathway include RAF-265, which is a potent inhibitor of RAF with a highly selective profile and inhibits all three isoforms of RAF, as well as mutant BRAF, with high potency. RAF265 is now being investigated in Phase I and II clinical trials in melanoma [74]. Moreover, XL281 is a specific inhibitor of RAF kinases, including the mutant form of BRAF, and has completed Phase I testing so far [75].

Quelling resistance to BRAF inhibitors

The median time to progression for vemurafenib is only 6 months. Hence, a lot of work is being done to understand and thwart the induction of vemurafenib resistance. Efforts are centered around developing stronger inhibitors, that is, dabrafenib (GSK2118436), that bind tighter to the kinase domains or that bind to nearby conserved domains that can obstruct the ATP-binding pockets, while others are aimed at developing pan-Raf inhibitors such as RAF-265 that might also inhibit CRAF implicated in the pathway to developing skin cancers and keratoacanthomas. Investigators are also testing combinations of other agents with Raf inhibitors in order to block signaling pathways that are downstream from Raf (i.e., MEK), parallel to Raf (i.e., PI3K) or upstream from Raf (i.e., EGF receptor) [74]. Concomitant blockade of such redundant or bypass pathways may prevent the development of resistant cells and enhance the efficacy of targeted therapies.

Expert commentary

The era of personalized cancer therapy against melanoma has begun with the introduction of vemurafenib. This is based on the principle of applying a drug that specifically targets an activating mutation on which the tumor cells depend for their growth and proliferation. The initial response rate to vemurafenib was impressive and 70–80% of treated patients having the BRAF^V600E mutation had an objective response [7]. However, resistant disease eventually develops due to the selection pressure imposed on the tumor cells by the medication and the eventual escape by these cells via other signal transduction survival pathways. It is noteworthy that resistance to vemurafenib occurred rather quickly in melanoma patients and the median progression-free survival was only 5.3 months [7]. Therefore, treatment of metastatic melanoma may require the inhibition of several targets by multiple drugs that are applied sequentially or in a combinatorial fashion. The combined approach may be less desirable due to a potential increase in off-target effects resulting in greater clinical toxicities. Furthermore, the development cost of each drug is already high and the combined cost of developing a set of drugs that only benefit a small subset of melanoma patients may be prohibitive. Therefore, cost–benefit analysis may become a necessary endeavor in the future drug development process.

Cancer immunotherapy can result in durable responses because it activates the patient’s intrinsic immune system to destroy melanoma metastases. Because of the heterogeneous immunological profiles among individual patients, ipilimumab efficacy as measured by response, as well as the kinetics of such response, was found to be different among patients [49,50,54]. However, those who experienced a benefit had durable systemic responses and the complete response seen in some often lasted for years. It is also noteworthy that ipilimumab can effect anti-melanoma responses in the CNS [51–53]. It remains to be determined whether or not there is synergistic efficacy when targeted therapy is combined with immunotherapy for metastatic melanoma to the CNS and other systemic organs.

Five-year view

Five years from now, there will most likely be additional targeted therapies and immunotherapies for metastatic melanoma. Because of the high rate of metastasis to the CNS, the treatment of brain, spinal cord and leptomeningeal metastases will become an even more pressing issue in the management of patients with advanced melanoma. The critical issues will include the design of small molecule inhibitors that have a high penetrance across the blood–brain barrier as well as immunotherapies that can drive more anti-melanoma cytotoxic T cells into the CNS.

Table 1. Known genetic mutations in melanomas.

Progression of melanoma	Gene mutation	Frequency of mutation (%)
Benign nevus	CDKN2A16/p16	21
Dysplastic nevus (superficial spreading)	APAF-1PKB/AKTMYC amplificationAPC promoter 1A hypermethylationPTEN deletion/mutation, loss of heterozygosityP53 loss/mutationN-RASGRM3CHRM3GPR98	1060–702517231030161028
Invasive melanoma	BRAF	26–70

These mutations are thought to make the oncogenesis of melanoma possible. However, the development of metastatic tumors may require additional genetic and epigenetic events.

Key issues

• – The efficacy of ipilimumab and vemurafenib against melanoma brain metastasis is unknown.

• – Ipilimumab can most likely induce an anti-melanoma immune response in the CNS, based on the anecdotal reports of response in patients with melanoma brain metastases and the cytotoxic CD8⁺ T cells that were found in resected specimens.

• – Separate clinical trials would be needed in order to evaluate the extent of benefit from ipilimumab and vemurafenib against metastatic melanoma in the CNS.

• – For the small-molecule inhibitor vemurafenib, serum and cerebrospinal fluid pharmacokinetic studies would be needed in order to assess the extent of CNS penetration.

• – The cost associated with specific targeted therapy in serial and combinatorial personalized cancer therapies should be studied further.

Acknowledgements

The authors thank Nkengafeh Asong and Edwin Lok for their assistance with this review.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.