Systemic Therapies for Melanoma Evolve, but More Research is Crucial

Chemotherapy is a terrific clinical tool and is an essential treatment for many types of cancer. But chemotherapeutic agents have historically performed poorly in melanoma. Thus, until recently, management of melanoma brain metastases have focused on surgery, stereotactic radiosurgery, or whole brain radiotherapy.

A recent article in Chinese Clinical Oncology reviewed a number of new systemic therapies—including combination therapies—for treatment of melanoma brain metastases, including kinase inhibitors that have been shown to effectively target BRAF-mutated melanoma cells.

Research on new methods to treat melanoma is crucial, because melanoma is relatively common, and, for patients who develop melanoma brain metastasis, the median survival is 17 to 22 weeks. The incidence of overt brain metastasis at first presentation is approximately 20%, and approximately 50% of stage IV melanoma patients develop brain metastases during the course of their disease. The study authors note, “Recently, incorporation of such patients into clinical trials assessing newer systemic therapies has provided increased therapeutic options, and raises questions regarding the optimal selection and combinations of treatment modalities for brain metastasis.”

The review examined molecular predictors of brain metastases closely associated with gene mutations in BRAF, neuroblastoma rat sarcoma oncogene (NRAS), and phosphatase and tensin homolog (PTEN). Among the key findings of the review:

• Not all patients with melanoma brain metastases require systemic therapy. As one example, the authors cite solitary brain metastasis with the absence of extracranial disease.
• BRAF inhibitors have shown a high rate of intracranial objective responses that parallel extracranial responses and should be considered in BRAF mutated melanoma especially in symptomatic patients with a high disease burden.
• NRAS mutations are less common than BRAF mutations in advanced melanoma. Lack of available targeted therapy for patients who have NRAS mutations confers worse outcomes in comparison with BRAF mutated patients on BRAF inhibitor therapy.
• Clinical trials of therapies specifically targeting NRAS mutations in melanoma have excluded patients with active brain metastases to date, largely because of the need to first determine combinations of therapies with good activity in extracranial metastases
• The PTEN mutations are mutually exclusive with NRAS mutations and are predictive of shorter time to brain metastases.
• In asymptomatic brain metastasis not requiring steroid therapy ipilimumab offers objective responses and survival benefit, similar to that seen with extracranial disease.

Although preliminary trials focused on targeted and immune therapies have shown promise, there is a need for much greater clinical trial evidence of activity, particularly in combinations with each other. “Enrollment into clinical trials is essential to develop evidenced-based practice paradigms for management of this difficult disease, to study mechanisms of intracranial response and resistance to treatment, and to devise better ways of treatment,” the authors note.