A larger study of patients treated with biochemotherapy (dacarbazine, cisplatin, or interferon alpha with or without interleukin 2), high absolute neutrophil count (ANC) was predictive of short OS (Schmidt et al., 2007). In a general cohort of melanoma patients at any stage of disease, NLR was not associated with OS in patients with stage ICIII disease (Gandini et al., 2016). 65 BRAFi patients. In multivariable analysis adjusting for M stage, and disease type (in OS)/gender (in PFS), an NLR value of 5 or above at every timepoint was associated with worse OS (HR 2.03C3.37, p? ?0.001), PFS (HR 1.81C2.51, p? PD184352 (CI-1040) ?0.001), and response to therapy (OR 3.92C9.18, p? ?0.007), in the IPI cohort. In addition, a ?30% increase in NLR above baseline at any timepoint was associated with a worse OS and PFS (HR 1.81 and 1.66, p? ?0.004). In BRAFi patients, NLR was not consistently associated with outcomes. Conclusions A high NLR, whether measured prior to or during treatment with IPI, is associated with worse OS, PFS, and clinical response in patients with advanced melanoma. An increasing NLR from baseline during treatment was correlated with worse OS and PFS in IPI-treated patients. In comparison, as NLR was not associated with outcomes in CD3G BRAFi patients, NLR may have a uniquely predictive value PD184352 (CI-1040) in patients treated with immunotherapy. strong class=”kwd-title” Keywords: Neutrophil to lymphocyte ratio, NLR, Melanoma, Immunotherapy, BRAF inhibitors 1.?Introduction Although advanced melanoma still remains a challenging diagnosis, significant enthusiasm has been generated by new therapeutic agents that have demonstrated increases in survival. Ipilimumab (IPI) is a monoclonal antibody that inhibits cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), thereby acting as a checkpoint inhibitor to enhance native immune function. In randomized trials, IPI produced objective responses in 11% of patients, but some degree of disease control in 29% (Hodi et al., 2010). Moreover, there is a pattern of delayed but often durable response, and long-term survival is possible in patients who respond to treatment (Prieto et al., 2012). In fact, some groups treated with IPI may have 4? year survival rates up to 49.5% (Wolchok et al., 2013a). Despite promising outcomes, immune-related adverse events have been described in a significant proportion of patients who receive the agent. These include diarrhea (30%), colitis (7%), hepatitis (3%), and hypophysitis (2%). In a randomized trial, 2.1% of enrolled patients died as a direct result of treatment (Hodi et al., 2010). The therapeutic effect of ipilimumab led to rapid investigation of other checkpoint blocking agents and antibodies blocking the PD-1 pathway have demonstrated 40C45% response rates with 35%? PD184352 (CI-1040) ?3?year survival and reduced toxicity, compared with ipilimumab (Hamid et al., 2013, Robert et al., 2015a, Hodi et al., 2016). Further, combined checkpoint blockade with ipilimumab?+?nivolumab results in response rates up to 60% in melanoma, albeit with higher rates of toxicity (Wolchok et al., 2013b, Postow et al., 2015). Targeted agents are also important in the treatment of advanced melanoma. BRAF inhibitors (BRAFi), including the agents vemurafenib and dabrafenib, are beneficial in the population of melanoma patients whose tumors harbor a BRAF mutation. In a prospective randomized trial, the response rate to vemurafenib approached 50% and improved overall and progression free survival when compared to dacarbazine, although median progression free survival was only 6?months even with vemurafenib (Chapman et al., 2011). Combined inhibition of BRAF and MEK improves the objective response rate to 64% and improves 12?month overall survival from 65% to 72% when compared with single-agent BRAFI (Robert et al., 2015b, McArthur et al., 2014). Combined BRAF and MEK inhibition is also associated with less dermatologic toxicity (Robert et al., 2015b, Larkin et al., 2014). Therefore, immunotherapy and targeted agents provide important therapeutic options with distinct mechanisms in advanced melanoma, each capable of improving survival. However, not all patients derive benefit, and the personal and financial cost can be significant. In this setting, establishing biomarkers capable of predicting response to these agents would provide an opportunity to identify patients most likely or unlikely to benefit, while allowing a more refined calculation of the risk/benefit ratio. There is a complex interaction between tumors and the innate.