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  • br Results The study flow diagram is shown in Fig

    2018-11-07


    Results The study flow diagram is shown in Fig. 1. Baseline characteristics of patients included in the final analysis are shown in Table 1. There were 197 patients treated with IPI and 65 treated with a BRAFi who had pretreatment CBC available. Median time from baseline CBC to first dose of treatment was 0days, with a range of 0–28days. Median follow-up was 54.3months in the IPI group (range 5–109) and 53months in the BRAFi group (range 4–56). In the IPI group, median baseline NLR was 4.4 (range 0.9–87.5) and decreased to 3.2 (range 1–26.8) by week 9 (Table 1). In contrast, NLR remained similar over the course of treatment in the BRAFi group, with a median at baseline and at week 9 of 4.9 (range 1.3–31.9) and 4.6 (range 1.1–26.8), respectively. Univariate associations of NLR with OS and PFS in the IPI group are shown in Table 2. NLR≥5 at all time points, in addition to stage IV M1C disease, mucosal melanoma and Karnofsky performance status score<90 were associated with significantly worse OS and PFS. In multivariate analysis, NLR≥5 at every timepoint was associated with poor OS (HR 2.03–3.37) and PFS (HR 1.81–2.51) (Table 2). Stage IV M1C disease and mucosal melanoma were also associated with worse outcomes. The associations of NLR with outcome remained significant if the median NLR at each timepoint was used as the cutoff to stratify patients. The NLR was then investigated in association with clinical benefit with IPI to see if it atp gamma s was an effective predictive biomarker. In univariate analysis, NLR≥5 at any timepoint, either before or during treatment, was statistically correlated with lack of clinical benefit at 12weeks (Table 3). The association remained in multivariable analysis. NLR was associated with some clinical endpoints in patients treated with BRAFi. While univariate analysis again demonstrated a baseline NLR≥5 was associated with worse OS and PFS, NLR values at follow-up timepoints were not associated with outcome (Table 4). atp gamma s In multivariable analysis, baseline NLR lost statistical association with both OS and PFS. Additionally, the association of NLR with clinical benefit was not significant (Table 5).
    Discussion NLR associates with prognosis in multiple tumor types, as demonstrated by prior reports (Wang et al., 2016; Stotz et al., 2013; Mano et al., 2013; Malietzis et al., 2014; de Martino et al., 2013; Pinato et al., 2014; Perez et al., 2013; Williams et al., 2014; Kelkitli et al., 2014). To our knowledge this is the largest series of patients treated for advanced melanoma with IPI to correlate NLR with both survival outcomes and objective response to therapy, and Linkage disequilibrium is the only series to date that examines the relationship of NLR to outcome in melanoma patients treated with BRAFi. Furthermore, prior reports to date have based their analyses on pretreatment NLR only, while this is the only series to evaluate the meaning of changes in NLR during treatment. Interestingly, we have demonstrated that NLR is highly associated with OS, PFS, and objective response in multivariable analysis for IPI patients, but not for those treated with BRAFi. This suggests a novel interpretation of NLR as a prognostic and potentially predictive biomarker of oncologic outcomes reflecting the unique properties of immunotherapy, but not targeted therapy such as BRAFi. Ferrucci et al. reported on the associations of NLR with OS and PFS in 187 patients with metastatic melanoma treated with IPI (Ferrucci et al., 2015). Consistent with our findings, pretreatment NLR<5 was strongly and independently associated with improved OS and PFS. Objective clinical response to treatment was not reported, and only pretreatment NLR values were assessed. A similar study by Zaragoza et al. included 58 patients with metastatic melanoma treated with IPI (Zaragoza et al., 2016). These authors also chose the pretreatment value in the analysis, and correlated this with OS only. Using a cutoff NLR value of 4, high pretreatment NLR was independently associated with worse OS. Additional studies in small groups of patients consistently demonstrate an association of NLR with OS and PFS (Khoja et al., 2016), and taken together support our finding of a strong association of pretreatment NLR with OS and PFS. The current study adds an additional component to our understanding of NLR by demonstrating that changes in NLR during IPI treatment may also predict OS and PFS. This suggests an important dynamic biomarker, as an increase of the NLR during treatment may be a reason to consider changes in treatment earlier in certain clinical scenarios.