Developments in therapy for brain metastases in melanoma patients

ABSTRACT

Introduction: Cutaneous melanoma brain metastases (MBM) are a major cause of morbidity and mortality. While cytotoxic agents, interferon, or interleukin-2, have been used with some success in extracranial disease, limited efficacy is demonstrated in MBM. The rare patient with long-term survival presented with limited intracranial disease amenable to surgery or radiation therapy. However, the development of targeted therapy and immunotherapy over the last decade has significantly improved overall survival in this formerly devastating presentation of metastatic melanoma.

Areas covered: This article reviews the mechanism of brain metastasis, challenges with treating the central nervous system, historical treatment of MBM, and outcomes in clinical trials with targeted therapy and immunotherapy.

Expert opinion: The MBM patient population now, more than ever, requires a multidisciplinary approach with surgery, radiation therapy, and the use of newer systemic therapies such as immunotherapy agents and targeted therapy agents. MBM has traditionally been excluded from clinical trials for systemic therapy due to poor survival. However, recent data show overall survival rates have significantly improved, supporting the need for inclusion of MBM patients in systemic therapy clinical trials. Understanding the mechanisms of therapeutic activity in the brain, resistance  mechanisms, and the appropriate multi-modality treatment approach requires further investigation. Nevertheless, these therapies continue to give some hope to patients with historically poor survival.

KEYWORDS:

• Melanoma
• brain neoplasms
• metastasis melanoma
• immunotherapy
• targeted therapy

Expert opinion

The role of systemic therapy in the treatment of MBM is evolving. Early recognition and treatment of MBM has been associated with improved neurological symptom-free survival. For oligometastatic, low volume, or single metastatic lesions, SRS should be considered the standard of care as it has near 100% response rates for lesions under 20 mm. Systemic therapy with targeted agentsor immunotherapy agents, clearly have a role where SRS and surgery have limited utility (diffuse MBM) as well as an adjunct to SRS.

Most patients with MBM will also have extracranial metastatic disease, often requiring systemic therapy. This has raised the question as to whether these systemic therapies alone may be enough to treat some patients with MBM without the need for SRS or surgery. Future studies will clarify the role and sequencing/ timing of these systemic therapies in the treatment of MBM that are also amenable to SRS or surgery (NCT 03340129) as definitive therapies or even their ongoing role as adjunct therapies. It is still difficult to predict who will respond to targeted or immunotherapies, and the risk of progression to lesions not amenable to SRS is real. Until these trials are completed, every case should be approached in a multidisciplinary setting considering radiation, systemic and when need surgical therapies is the best pathway for the patient. Regardless, despite the unique nature of MBM and their differences from extracranial metastases, dramatic progress in the fields of SRS, immunotherapy, and targeted therapy has given hope to patients where there was little hope just 10 years ago.

Declaration of interest

JS Zager has received research funding from Novartis, served on the Advisory Board for Array Biopharma/Pfizer and serves on the Speakers Bureau for Array Biopharma/Pfizer JS Zager has also served on advisory boards from Novartis, Merck. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.