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Simple Summary  Pembrolizumab, a monoclonal antibody targeting programmed cell death 1, improves the survival of patients with advanced melanoma. This study aimed to investigate the association of baseline clinical characteristics, laboratory and imaging variables, and gene expression profiling scores on tumor tissue analysis of advanced melanoma patients who were treated with pembrolizumab, with survival using univariate and multivariate analysis. Baseline organ function (reflected by the presence of active brain metastases, number of metastatically affected organs, albumin) and systemic inflammatory/immunologic status (reflected by albumin, C-reactive protein, absolute lymphocyte count, neutrophil-to-lymphocyte ratio) are the most important clinical and/or laboratory parameters predictive of survival. Novel biomarkers include the baseline presence of  BRAF V600   or  NRAS Q61/G12/G13   mutant circulating tumor DNA and baseline total metabolic tumor volume assessed by whole-body  18 F-FDG-PET/CT. Gene expression profiling scores by the NanoString PanCancer IO360 panel were not conclusive in our patient population.    Abstract  Background: Pembrolizumab improves the survival of patients with advanced melanoma. A comprehensive analysis of baseline variables that predict the benefit of pembrolizumab monotherapy has not been conducted. Methods: Survival data of patients with advanced melanoma who were treated with pembrolizumab in a single university hospital were collected. A multivariate Cox regression analysis was performed to correlate baseline clinical, laboratory, and radiologic characteristics and NanoString IO360 gene expression profiling (GEP) with survival. Results: 183 patients were included (stage IV 85.2%, WHO performance status ≥1 31.1%; pembrolizumab first-line 25.7%), of whom 112 underwent baseline  18 F-FDG-PET/CT imaging, 58 had circulating tumor DNA (ctDNA) assessments, and GEP was available in 27 patients. Active brain metastases, a higher number of metastatic sites, lower albumin and absolute lymphocyte count (ALC), higher C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio, higher total metabolic tumor volume (TMTV), and higher ctDNA levels were associated with worse survival. Elevated lactate dehydrogenase (LDH) ≥ 2ULN (upper limit of normal), CRP ≥ 10ULN, or ALC &lt; 750/mm 3  delineate a subpopulation where treatment with pembrolizumab is futile. A TMTV ≥ 80 mL encompassed 17/21 patients with LDH ≥ 2ULN, CRP ≥ 10ULN, or ALC &lt; 750/mm 3 . No significant associations were observed between baseline GEP scores and survival. Conclusion: Multiple baseline variables correlate with survival on pembrolizumab. TMTV is a more comprehensive baseline biomarker than CRP, LDH, or ALC in predicting the futility of pembrolizumab.

cancers

A Comprehensive Analysis of Baseline Clinical Characteristics and Biomarkers Associated with Outcome in Advanced Melanoma Patients Treated with Pembrolizumab