BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy

Abstract

Melanoma is an aggressive malignancy that frequently spreads to the brain, resulting in rapid deterioration in both quality and quantity of life. Historically, treatment options for melanoma brain metastases (MBM) have predominantly consisted of surgery and radiotherapy. While these options can help provide local control, the majority of patients still develop intracranial progression. Indeed, novel therapeutic options, including molecularly targeted agents and immunotherapy, have improved outcomes and are now changing the role of radiotherapy. Up to 50% of melanomas contain an activating BRAF mutation, resulting in hyperactive cellular proliferation and survival. Drugs that target BRAF have been introduced for the treatment of metastatic melanoma and offer hope in improving disease outcomes; however, many of these trials either excluded or had a limited amount of patients with MBM. Recent studies have revealed that melanoma cell lines become more radiosensitive following BRAF inhibition, thus providing a potential synergistic mechanism when combining BRAF inhibitor (BRAFi) and radiotherapy. However, neurotoxicity concerns also exist with this combination. This article reviews the efficacy and limitations of BRAFi therapy for MBM, describes current evidence for combining BRAFis with radiation, discusses the rationale and evidence for combination modalities, and highlights emerging clinical trials specifically investigating this combination in MBM.

Molecular and cellular stratagem of brain metastases associated with melanoma (Review)

“…Many clinical trials were addressed to B-Raf pathway inhibition. A phase 2 clinical trial performed between 2011 and 2015 on 146 patients using an inhibitor of B-Raf pathway (vemurafenib) has showed that vemurafenib is an efficient drug for BM with B-raf mutation but not all BM are vemurafenib sensitive (46,47). Therefore, other clinical trials were designed to combine multiple pathway inhibitors or to combine surgical and systemic therapy (e.g., immunotherapy).…”

Ubiquitination of P53 by E3 ligase MKRN2 promotes melanoma cell proliferation

“…Following lung and breast cancer, melanoma is the third most common reason for brain metastases (4). Melanoma spreads to the brain in ≤75% of patients with melanoma (5). Brain metastases cause mortality in 95% of patients with high class (Class III) (6).…”

Post-treatment neutrophil-to-lymphocyte ratio predicts for overall survival in brain metastases treated with stereotactic radiosurgery

“…The incidence of BM is steadily increasing, in part due to increased surveillance and improvements in systemic extracranial therapy [2, 3]. The standard of care for BM continues to evolve given advancements in focal therapies, including stereotactic radiosurgery (SRS), which can offer a high rate of local control without the consequences of whole brain radiotherapy (WBRT) [4].…”