Melanoma is an aggressive disease that accounts for approximately 75% of skin cancer-related deaths.,Historically, treatment options for patients with advanced stage melanoma have been limited by modest response rates and failure to improve overall survival.,The treatment landscape for advanced stage melanoma was revolutionized in 2011 with the approval of ipilimumab and vemurafenib, both of which improved overall survival in phase III clinical trials.,More recently, the targeted inhibitors dabrafenib and trametinib have demonstrated similar therapeutic profiles.,To (a) discuss emerging treatment options for advanced melanoma, specifically ilpilimumab, vemurafenib, dabrafenib, and trametinib, in the context of their mechanisms of action and their potential for long-term improvement in patient outcome, and (b) to consider the impact of these agents on the current treatment landscape.,A literature search was conducted to collect data from clinical trials involving ipilimumab, vemurafenib, dabrafenib, and trametinib.,Emphasis was placed on outcome measures related to long-term clinical benefit.,Ipilimumab, a fully human monoclonal antibody, exploits the natural ability of the immune system to eradicate primary cancer cells.,It inhibits the binding of cytotoxic T-lymphocyte antigen-4 to its ligands, thereby potentiating T-cell response and antitumor immunity.,In a phase III clinical trial, ipilimumab at 3 mg/kg improved overall survival in previously treated patients with metastatic melanoma.,Components of the mitogen-activated protein kinase (MAPK) pathway are particularly relevant in melanoma and have been targeted by small molecular inhibitors.,Vemurafenib and dabrafenib inhibit the BRAF V600 mutation, which prevents oncogenic activities such as uncheck proliferation and evasion of immune response.,Data from phase III clinical trials suggest that both vemurafenib and dabrafenib improve patient outcomes, with vemurafenib showing an overall survival benefit and dabrafenib showing improved median progression-free survival.,The targeted-therapy approach in melanoma continued to gain momentum with the development of trametinib, which inhibits the MEK protein, the only known substrate of the BRAF V600 protein.,Inhibition of MEK leads to decreased cell signaling and proliferation in cancer cells.,In phase III trials, trametinib demonstrated significant improvement in median progression-free survival and median overall survival compared with chemotherapy treatment, making this treatment a valuable addition to the current armamentarium.,The adverse events associated with these new treatments are generally tolerable and mild to moderate in severity; however, care should be taken when selecting a therapy, since the specific adverse events associated with these treatments are unique, and serious events have been reported.,The immunotherapy ipilimumab and the MAPK-targeted inhibitors vemurafenib, dabrafenib, and trametinib have forever changed the treatment landscape for melanoma.,Indeed, these new therapies have demonstrated long-term improvement in patient outcome, a benefit not afforded by traditional therapeutics.,Important research continues on the molecular basis of melanoma, and new targets are likely to emerge.,Other areas of work include optimization of sequencing and/or combination of current treatments, which may increase the number of patients who experience clinical benefit.
Immune checkpoint inhibitors1 result in impressive clinical responses2-5 but optimal results will require combination with each other6 and other therapies.,This raises fundamental questions about mechanisms of non-redundancy and resistance.,Here, we report major tumor regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation (RT) and reproduced this effect in mouse models.,Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common.,Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion.,Accordingly, optimal response in melanoma and other cancer types requires RT, anti-CTLA4, and anti-PD-L1/PD-1.,Anti-CTLA4 predominantly inhibits T regulatory cells (Tregs) to increase the CD8 T cell to Treg (CD8/Treg) ratio.,RT enhances the diversity of the T cell receptor (TCR) repertoire of intratumoral T cells.,Together, anti-CTLA4 promotes expansion of T cells, while RT shapes the TCR repertoire of the expanded peripheral clones.,Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligo-clonal T cell expansion.,Similar to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed.,Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4-based therapy, and the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response and immunity through distinct mechanisms.