Changing Treatment Paradigms for Brain Metastases From Melanoma-Part 2: When and How to Use the New Systemic Agents

Until recently, therapeutic strategies for melanoma brain metastases focused on local treatments: surgery, whole-brain radiation therapy, and stereotactic radiosurgery. Historically, systemic therapy had limited utility. Immunotherapeutic drugs, such as anti–cytotoxic T-lymphocyte–associated antigen 4 and anti–programmed death 1 agents, and agents targeting the BRAF-MEK pathway have revolutionized the systemic treatment of melanoma brain metastases. Recent clinical trials of these agents have shown activity against melanoma brain metastases, and they are increasingly being used in clinical practice. In this article, we provide an overview of the currently available systemic agents, including immunotherapeutic agents and targeted tyrosine kinase inhibitors. We also provide a practical management algorithm to guide the practicing oncologist in the use of both of these new therapies and the more traditional local treatments.

Traditional systemic therapy had a limited role in melanoma brain metastases because of the challenges of drug delivery to the brain resulting from the blood-brain barrier (BBB), with its tight junctions and efflux pumps (P-glycoprotein and multidrug resistance–associated transport proteins).[1] However, the contrast enhancement of brain metastases on MRI indicates that there is a possibility of local disruption of the BBB, potentially providing a window for drug delivery into the malignant lesions.[2]

Chemotherapy

Chemotherapy agents have not shown good activity in melanoma brain metastases. Dacarbazine, which is the approved chemotherapy agent for metastatic melanoma, does not cross the BBB.[3] A number of studies have evaluated the role of alkylating agents with good BBB penetration, such as temozolomide (TMZ), lomustine, and fotemustine, in patients with melanoma brain metastases. In a phase II trial, Agarwala et al enrolled 151 patients with melanoma brain metastases who had received no local radiation therapy for brain metastases to receive TMZ.[4] TMZ use yielded a modest intracranial response rate (IRR) of 6%, a median progression-free survival (PFS) of 4.3 to 5.2 weeks, and a median overall survival (OS) of 3.2 months. Two phase II trials of whole-brain radiation therapy (WBRT) with TMZ[5,6] and one phase II trial of thalidomide and WBRT with TMZ[7] failed to show significantly improved response rates. Lomustine in combination with TMZ showed modest efficacy in a phase I/II study.[8] Intracranial activity of fotemustine was first reported in a phase III trial of fotemustine vs dacarbazine for metastatic melanoma.[9] This led to a randomized phase III trial that compared fotemustine plus WBRT with fotemustine alone in melanoma brain metastases.[10] The response rates were 7.4% for fotemustine alone and 10% for fotemustine plus WBRT. Fotemustine is currently being used in Europe, especially for patients with melanoma brain metastases; however, it has not been approved by the US Food and Drug Administration (FDA) because of associated delayed thrombocytopenia and leukopenia.[11,12]

Targeted Therapy

Mutations of BRAF, NRAS, and KIT are three common, mutually exclusive driver mutations seen in metastatic melanoma.[13,14] Of these three, BRAF mutations are the most common, seen in approximately 40% to 50% of patients with advanced melanoma. The presence of BRAF or NRAS mutations increases the risk of central nervous system (CNS) metastases in patients with advanced melanoma. Prior studies have reported a 24% rate of CNS metastases in BRAF-mutant melanoma and a 23% rate in NRAS-mutant melanoma-compared with a 12% rate in patients who lack these mutations.[15] Dabrafenib and vemurafenib target the BRAF V600 mutation and are FDA-approved for metastatic melanoma.

In a phase I trial of dabrafenib in 10 patients with untreated asymptomatic brain metastases, intracranial response was seen in 8 patients (4 complete responses [CRs], 4 partial responses [PRs]).[16] This led to a phase II trial of dabrafenib in BRAF-mutant melanoma brain metastases (BREAK-MB).[17] This multicenter open-label study accrued 172 patients with BRAF V600E or BRAF V600K mutations who had asymptomatic brain metastases, including at least one measurable lesion. Cohort A consisted of 89 patients who were radiation–naive, and cohort B consisted of 83 patients in whom prior radiation therapy for brain metastases had failed. Patients with BRAF V600E mutations had an IRR of 39% (29/74) in cohort A and 31% (20/65) in cohort B, median PFS of 16.1 weeks in cohort A and 16.6 weeks in cohort B, and median OS of 33.1 weeks in cohort A and 31.4 weeks in cohort B. Patients with BRAF V600K mutations had a lower IRR of 7% (1/15) in cohort A and 22% (4/18) in cohort B. This trial supports the efficacy-with acceptable toxicity-of dabrafenib in patients with BRAF-mutant melanoma brain metastases, especially those with BRAF V600E mutations.

In an open-label study of 24 patients with nonresectable, untreated melanoma brain metastases who harbored BRAF V600 mutations, treatment with vemurafenib resulted in tumor regression in more than 30% of the patients (7/19), and PRs were seen in 3 patients.[18] Median PFS and OS were 3.9 and 5.3 months, respectively, in this study. In a phase II study, 146 patients with BRAF-mutant melanoma brain metastases were treated with vemurafenib.[19] The first cohort included 90 patients with untreated brain metastases, while the second cohort was comprised of 56 patients with previously treated brain metastases. CRs were noted in 2 patients, and there were 14 PRs, for a best objective response rate of 18%. In the patients with previously untreated melanoma brain metastases, the median PFS and OS were 3.7 months and 8.9 months, respectively. Patients with previously treated melanoma brain metastases had similar median PFS and OS: 4.0 months and 9.6 months, respectively.

The feasibility, safety, and effectiveness of combining BRAF inhibitors and radiation therapy have not been evaluated in a prospective setting. There is a concern that there may be an increased incidence of dermatitis with concurrent use of radiation and BRAF inhibitors, specifically in extracranial skin.[20] Rompoti et al reported 5 patients with melanoma brain metastases treated with combined radiation and BRAF inhibition.[21] Two patients underwent stereotactic radiosurgery (SRS) and three received WBRT. Patients treated with SRS did not experience any adverse dermatologic effects, but all three patients treated with WBRT noted grade 1/2 dermatitis. A retrospective analysis evaluated the effectiveness of vemurafenib and radiation in BRAF V600–mutant melanoma brain metastases.[22] All patients received vemurafenib, 6 patients underwent SRS, 2 received WBRT, 1 received SRS and WBRT, and 3 underwent surgery and radiation. Of the 48 index lesions, 36 responded, with 23 demonstrating CRs (48%) and 13 demonstrating PRs (27%). Major limitations of the study were its retrospective nature, the small numbers, and the fact that some of the patients had been pretreated with radiation and systemic therapy, including ipilimumab. Several small retrospective case series have reported outcomes of patients with melanoma brain metastases treated with targeted agents and SRS/WBRT (Table 1). A recent study of 19 patients with BRAF mutations undergoing SRS and concurrent BRAF-directed therapies has shown impressively few local failures (12-month cumulative incidence of 1%).[23] Additional studies of combination therapy are clearly warranted.

Immunotherapy

Melanoma is an immunogenic malignancy,[24] with a high mutational burden that results in large numbers of neoantigens.[25] It has been proposed that the relatively high neoantigen burden makes this malignancy more susceptible to immunotherapy. However, the brain has traditionally been considered an immunologically privileged site due to the presence of the BBB. Recent studies of the intracranial tumor microenvironment, as discussed previously, have suggested otherwise, showing CD8 T cells, CD20-positive cells, T-regulator cells, and programmed death ligand 1 (PD-L1) expression within intracranial tumor.[26]

The intracranial activity of interleukin-2 (IL-2; one of the first immunomodulatory agents) was reported in two retrospective reviews.[27,28] A response rate of 5.6% was seen in 37 patients with untreated brain metastases within a larger group of 1,069 patients with metastatic melanoma and renal cell carcinoma treated with high-dose IL-2.[27] In a second report, 2 of 15 patients with brain metastases treated with high-dose IL-2 demonstrated a CR.[28] No prospective trials have been initiated with high-dose IL-2 because of concerns about cerebral edema and neurotoxicity.

Two pathways that have revolutionized the management of advanced melanoma are those involving cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1)/PD-L1 (Table 2). The CTLA-4 receptor is expressed exclusively on T cells and downregulates the interaction between antigen-presenting cells and T cells. Ipilimumab is a fully human monoclonal antibody that targets CTLA-4.[29] The pivotal phase III trial that compared ipilimumab with or without the gp100 peptide vaccine vs the gp100 vaccine as a single agent allowed enrollment of patients with asymptomatic and/or previously treated melanoma brain metastases.[30] A nonsignificant trend towards better survival in the melanoma brain metastases subgroup was noted among the patients treated with either ipilimumab alone or ipilimumab plus the gp100 vaccine, compared with those treated with the gp100 vaccine alone.[31] In an expanded access program in Italy, 146 patients with melanoma brain metastases received ipilimumab, and a global response rate of 12% was seen.[32] An American expanded access program reported a 1-year OS rate of 20% in 165 patients with melanoma brain metastases treated with ipilimumab.[33] Margolin et al conducted an open-label phase II clinical trial of ipilimumab for melanoma brain metastases.[34] The trial enrolled 72 patients: 51 patients in cohort A (those who were not receiving steroids for cerebral edema) and 21 patients in cohort B (those who were receiving treatment with steroids). According to World Health Organization criteria, the response rate was 18% (9/51) in cohort A, compared with 5% (1/21) in cohort B-and by immune-related response criteria, the response rate was 25% (12/51) in cohort A and 10% (2/21) in cohort B. The median OS was 7.0 months in cohort A and 3.7 months in cohort B. The study concluded that ipilimumab can be used safely in patients with melanoma brain metastases. An Italian phase II trial tested a combination of ipilimumab and fotemustine in patients with advanced melanoma, including patients with asymptomatic brain metastases.[35] A total of 20 patients (out of 83) had asymptomatic melanoma brain metastases, and in these patients, the study reported a median PFS of 3.0 months and a 3-year OS rate of 27.8%.[36] A randomized, three-arm, phase III trial of fotemustine vs fotemustine plus ipilimumab vs ipilimumab plus nivolumab in melanoma with brain metastases (NIBIT-M2) is currently recruiting patients.[37] Several retrospective studies have evaluated the safety of combining ipilimumab and radiation therapy (SRS or WBRT), and prospective trial data are forthcoming.[38-40]

PD-1 receptors are expressed on several types of cells, including T cells and antigen-presenting cells. The interaction of these PD-1 receptors with PD-L1 ligands on tumor cells leads to T-cell exhaustion and downregulation of tumor-specific immune response.[41] Nivolumab and pembrolizumab are two anti–PD-1 antibodies that are currently approved for the treatment of advanced melanoma, and several others are under evaluation. An open-label, single-center, phase II clinical trial is currently enrolling patients with untreated brain metastases from melanoma or non–small-cell lung cancer. In a published early analysis, a response rate of 22% (4 patients) was reported in a total of 18 patients with melanoma brain metastases; the responses were durable.[42] The authors noted a high concordance between systemic and brain metastasis responses. In addition, 11% (2 patients) had stable disease. Intriguingly, all responders lacked a BRAF mutation. Four patients were not evaluable, because of either rapid progression necessitating BRAF-targeted therapy (3 patients) or intralesional hemorrhage (1 patient). Toxicities in the melanoma brain metastases cohort included grade 3 transaminitis (1 patient), as well as grade 1/2 seizures (3 patients) and grade 3 cognitive dysfunction (1 patient) from peritumoral edema.

Combination of Radiation and Systemic Therapy

In vitro models have suggested an improvement in radiotherapeutic response with the use of BRAF inhibition in combination with radiation therapy.[43] Clinical experience with concurrent systemic therapy and SRS has resulted in improved local control rates in some studies; however, this experience has been limited to retrospective institutional clinical series, and not all series have shown benefit (see Table 1). For example, Ly et al[44] reported an improved local control rate for BRAF-mutated lesions treated with SRS concurrently with BRAF inhibitors; however, Wolf et al[45] failed to observe any synergistic benefit with concurrent therapy. Moreover, there may be a critical time window for the effectiveness of combined therapy to be observed. Recent studies have demonstrated improved outcomes when patients are treated with SRS and concurrent systemic therapies: Qian et al[46] demonstrated lower local failure rates when patients were treated with ipilimumab within 4 weeks of SRS; similarly, Kotecha et al[47] demonstrated the lowest local failure rates when patients were treated with BRAF inhibitors within 4 weeks of SRS. Timing of therapy and the selection of specific agents to sequence around SRS delivery requires further study to optimize outcomes while limiting the risk of radiation necrosis.

Leptomeningeal Disease in Melanoma

Leptomeningeal disease is a subset of metastatic disease that has an extraordinarily poor prognosis, with a median survival in melanoma patients of 8 weeks.[48,49] About 5% of malignant leptomeningeal disease originates from melanoma, and up to 23% of melanoma patients develop leptomeningeal disease.[50,51] Primary leptomeningeal melanoma also exists as a separate clinical entity and should be a consideration in the context of a person with multiple congenital melanocytic nevi.[52] Diagnosis of leptomeningeal disease is usually made based on the combination of neurologic symptoms along with corresponding leptomeningeal enhancement on MRI. Although cytology from cerebrospinal fluid is considered to be the gold standard for diagnosis of leptomeningeal disease, the sensitivity of this testing ranges from 50% to 80%, depending on the number of lumbar punctures performed.[53] As with melanoma brain metastases, treatment of melanoma leptomeningeal disease with chemotherapy has low response rates.[54] The clinical course of leptomeningeal disease is more treacherous in melanoma than in other malignancies, given the propensity for melanoma leptomeningeal disease to hemorrhage.[55]

Molecular characterization of melanoma leptomeningeal disease suggests a higher percentage of BRAF mutations compared with the general melanoma population (68% vs 45%), based on a single-center melanoma leptomeningeal disease cohort of 60 patients.[38] Several case reports have been published highlighting CRs and PRs, as well as prolonged ongoing survival beyond 15 to 18 months, with BRAF inhibitors.[54] Prolonged survival has also been reported for immunotherapy approaches, including intrathecal IL-2, adoptive cell therapies with tumor-infiltrating lymphocytes and cytotoxic T lymphocytes, and immune checkpoint inhibitors, compared with historic medians.[54] A single-center study of 38 patients with melanoma leptomeningeal disease who were treated with intrathecal IL-2 reported a median survival of 9.1 months, and the best-responding 15% of patients reached a median survival of over 24 months.[56] Ongoing survival of over 18 months in a patient with melanoma leptomeningeal disease was reported with WBRT followed by ipilimumab; in this case, treatment with ipilimumab resulted in a complete radiologic response.[57] A phase II trial of combination immunotherapy with ipilimumab and nivolumab in melanoma leptomeningeal disease (ClinicalTrials.gov identifier: NCT02939300) has recently opened to accrual. In summary, early data suggest that both targeted therapy and immunotherapy have efficacy in melanoma leptomeningeal disease and can result in durable responses lasting well over a year. Upcoming trials using newer therapies to address melanoma leptomeningeal disease will likely yield significantly improved survival data over the next decade.

An Approach to the Management of Patients With Melanoma Brain Metastases

Appropriate care of patients with melanoma brain metastases begins with diagnosis. In melanoma, the brain is a common site of metastatic spread, both early and late. It is crucial to begin screening patients for brain metastases at the time melanoma is first diagnosed; National Comprehensive Cancer Network guidelines have recently been updated to reflect this changing diagnostic paradigm. The frequency at which to repeat imaging is still not known. A treatment algorithm for patients with melanoma brain metastases has been proposed in the Figure. Enrollment in an appropriate clinical trial is the preferred management for eligible patients with good performance status. When appropriate clinical trials are unavailable or when patients are acutely symptomatic or have hemorrhagic brain metastases, upfront local therapies need to be considered. Surgical resection followed by SRS is suitable for patients with solitary large symptomatic brain metastases, whereas radiation therapy options are preferred for patients with multiple small brain metastases. Although the number of lesions that can be safely and effectively treated with SRS is a moving target, SRS is currently the preferred treatment for patients with 1 to 4 brain metastases and for patients with higher numbers of small-volume metastatic lesions (up to 10 lesions).[58] For patients with numerous lesions or poor performance status, WBRT can be considered. A patient’s BRAF mutation status and presence of extracranial disease must be assessed before initiating systemic treatment (BRAF inhibitors or immunotherapy agents). Upfront systemic treatment may be considered in select patients with small, asymptomatic brain metastases and uncontrolled extracranial disease, reserving local therapy options for more symptomatic patients. Initial reports of combining SRS with either targeted therapy or immunotherapy appear promising, but this approach needs to be systematically investigated in larger studies. Although both BRAF inhibitors and immunotherapy have shown intracranial activity, the ideal sequencing of these agents in BRAF-mutant metastatic melanoma is unclear. In a retrospective study, a longer OS was reported in patients who received ipilimumab prior to BRAF inhibitors, compared with those treated with ipilimumab after BRAF inhibitors; however, the extracranial response rates and median PFS were similar in the two groups.[59] Therefore, treatment decisions should be made with input from a multidisciplinary team that includes radiation oncologists, neurosurgeons, and medical oncologists.

Conclusion

Several therapeutic options now exist for the treatment of melanoma brain metastases. Surgical resection, radiation therapy, targeted therapy, and immunotherapy have all shown some degree of efficacy. Even in cases of leptomeningeal disease, perhaps the worst subset of melanoma brain metastases in terms of survival, treatment with targeted therapy and immunotherapy can induce prolonged survival, compared with historic means.

Nonetheless, despite significant recent improvement in the outcomes of patients with melanoma, brain metastases remain a major determinant of mortality and morbidity in melanoma patients, and those with melanoma brain metastases remain in the worst prognostic category. The vast majority of clinical trials with newer agents exclude patients with melanoma brain metastases; thus, there is still a paucity of data on the effectiveness of new drugs in this context. Understanding the biology of melanoma brain metastases and their clinical response to newer agents-and particularly to combinations of agents and strategies-is crucial to increasing the longevity of the poorest-risk melanoma patients.

Financial Disclosure:Dr. Ahluwalia reports grants and personal fees from Monteris Medical, grants and personal fees from AbbVie, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from AstraZeneca, personal fees from Datar Genetics, personal fees from CBT Pharmaceuticals, personal fees from Kadmon Pharmaceuticals, personal fees from Elsevier, grants and personal fees from Novocure, grants from Novartis, grants and personal fees from Incyte, grants from Pharmacyclics, grants from TRACON Pharmaceuticals, personal fees from prIME Oncology, and personal fees from Caris Life Sciences. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Acknowledgment:Dr. Ahluwalia’s work was supported by the Dean and Diane Miller Family Chair in Neuro-Oncology.

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