Targeted and Immunotherapies in BRAF Mutant Melanoma

Where We Stand and What to Expect

X. Bai; K.T. Flaherty


The British Journal of Dermatology. 2021;185(2):253-262. 

In This Article

Abstract and Introduction


The therapeutic landscape for melanoma has evolved drastically in the past decade. Currently, immune checkpoint inhibitors and small-molecule inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway are the two mainstay therapies for BRAF V600 mutant advanced melanoma. Although MAPK dependence has been variably demonstrated in melanomas lacking BRAF V600 mutations, definitive evidence of benefit with MAPK inhibitors has not been demonstrated. Thus, in the BRAF V600 'wild-type' setting, immune checkpoint inhibitors are the standalone option(s). In the BRAF V600 mutant setting, there is no definitive evidence prioritizing one therapeutic modality over another. Herein, we review the updated data of the pivotal phase III randomized controlled trials that established the standard-of-care first-line treatment for advanced melanoma, as it provides insights into long-term benefit, which is a major factor in therapy selection. We discuss the clinical considerations for choosing between these therapies in the front-line setting and beyond, specifically for patients with BRAF V600 mutant melanoma based on currently available evidence. We have previously proposed a time-dependent resistance paradigm in which future therapeutic development strategies can be rooted. We also discuss how these Food and Drug Administration (FDA)-approved therapeutic modalities are being pursued earlier in the course of disease management, namely in adjuvant and neoadjuvant settings. FDA-approved interlesional oncolytic virotherapy in the modern era is also briefly discussed.


Melanoma is the deadliest form of skin cancer. As recently as a decade ago, advanced melanoma was one of the more common cancers for which systemic therapy offered no appreciable impact on outcomes.[1] However, mortality has been decreasing in recent years, despite its increasing incidence.[2–4] This great success is largely a consequence of the widespread adoption of novel systemic therapies for advanced melanoma, namely targeted therapies [mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi)] and immunotherapies [immune checkpoint inhibitors (ICIs)], which are both rooted in a deep understanding of the molecular make-up of this disease and tumour–immune interactions.[5,6] Melanoma is unique in its high prevalence of BRAFV600 hotspot mutation,[7] and particularly high somatic mutation burden vs. other tumour types.[6]

Regarding front-line therapy of advanced melanoma, current U.S. Food and Drug Administration (FDA)-approved MAPKi include three BRAF/MAPK/mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor combinations: dabrafenib/trametinib (D/T); vemurafenib/cobimetinib (V/C); and encorafenib/binimetinib (E/B). ICIs include pembrolizumab (pembro), nivolumab (nivo) and ipilimumab/nivo (ipi/nivo). The majority of patients suffer from de novo or acquired resistance to ICIs and MAPK, respectively. These therapies were evaluated largely in first-line clinical trials, against historically standard treatments, and without widespread availability of the same agents for attempted salvage therapy. To date, there have been no head-to-head comparison trials to inform overall or subpopulation-specific priority in treatment selection. Herein, we review the most recent updates of phase III trials, and discuss the first- and subsequent-line treatment options, with a focus on melanoma bearing BRAF V600 somatic mutations where treatment selection is the most pressing issue. We propose a novel time-dependent perspective on the emergence of resistance and suggest new options for future therapeutic development strategies. We also cover how these FDA-approved drugs have been and are being investigated in adjuvant and neoadjuvant settings.