Sequencing of New and Old Therapies for Metastatic Melanoma

Abstract

Identification of BRAF driver mutations and agents that block their activity combined with development of immune checkpoint inhibitor therapies have dramatically changed survival and quality of life for patients with metastatic melanoma. Approximately half of patients with metastatic melanoma do not harbor mutations in the BRAF gene and therefore cannot benefit from currently available agents that target this mutation. Additionally, few patients with metastatic melanoma achieve durable disease control with these targeted therapies alone. Conversely, immune-based therapies have the potential to treat melanomas with or without mutations and produce durable responses following discontinuation of therapy, but responses can be delayed. Defining the goals of therapy (rapid response vs durable disease control), establishing the presence of targetable mutations, and considering the toxicities associated with each therapy can inform a treatment strategy. Incorporating both recent therapeutic modalities and older treatment options can provide the greatest potential for durable response. Overall, we recommend using immunotherapies (anti-CTLA4, anti-PD-1, combined anti-CTLA4/anti-PD-1, or interleukin-2) as the backbone of treatment for metastatic melanoma due to their potential for durable response. The targeted therapies and cytotoxic therapies can then be used intermittently to rescue patients from symptomatic disease progression. Of course, available clinical trials should always be considered, whenever possible.

Keywords: BRAF mutation; Cobimetinib; Dabrafenib; Immunotherapy; Ipilimumab; Melanoma; Nivolumab; Pembrolizumab; Targeted therapy; Trametinib; Vemurafenib.