OBJECTIVE: To examine the current controversies and discuss consensus 
recommendations regarding treatment sequencing and the role of BRAF inhibitor at 
disease progression.
DATA SOURCE: An English-language literature search of MEDLINE/PubMed (1966-May 
2014), using the keywords advanced melanoma, ipilimumab, cytotoxic T-lymphocyte 
antigen 4, dabrafenib, vemurafenib, BRAF inhibitor, trametinib, MEK inhibitor, 
and treatment sequencing was conducted. Data were also obtained from package 
inserts, meeting abstracts, and clinical registries.
STUDY SELECTION AND DATA EXTRACTION: All relevant published articles and 
abstracts on ipilimumab, vemurafenib, dabrafenib, and trametinib were reviewed. 
Clinical trial registries and meeting abstracts were used for ongoing studies.
DATA SYNTHESIS: The availability of new agents has made therapy selection more 
complex. Immunotherapy supporters reason that immunotherapy offers the best 
chance for long-term benefit and does not compromise the antitumor activity of 
subsequent BRAF inhibitors. Targeted therapy advocates rely on the high 
probability and rapid onset of response to BRAF inhibitors. Currently, there is 
insufficient evidence regarding the role of BRAF inhibitor at disease 
progression.
CONCLUSIONS: Therapy should be individualized based on patient- and 
disease-specific factors. Immunotherapy represents the best option for durable 
remission; however, targeted therapy is more appropriate for patients who are 
symptomatic or have rapidly growing tumors. The novel therapies have also 
demonstrated meaningful intracranial activity; thus, the presence of brain 
metastases should be taken into consideration in selecting therapy. Limited data 
exist about the continuation of BRAF inhibitors after therapeutic failure. 
Active research is ongoing to define the best option for patients with BRAF 
inhibitor refractory disease.