Acta Dermato-Venereologica 98-4CompleteContent | Page 8

406 CLINICAL REPORT Blood Predictive Biomarkers for Nivolumab in Advanced Melanoma Edouard CHASSEUIL 1# , Mélanie SAINT-JEAN 1,2# , Hannah CHASSEUIL 1 , Lucie PEUVREL 2 , Gaëlle QUÉREUX 2 , Jean-Michel NGUYEN 3 , Aurélie GAULTIER 3 , Emilie VAREY 2 , Amir KHAMMARI 2 and Brigitte DRÉNO 2 Department of Dermatology, University of Poitiers, Poitiers, 2 Department of Dermato-Oncology, and 3 SEME, CIC 1413, CRCINA Inserm 1232, CHU Nantes, Nantes, France # These authors contributed equally and should be considered as first authors. 1 Nivolumab response rate is 40% in metastatic mela- noma. Few studies have evaluated pre-treatment bio- markers predictive of response. The aim of this study was to identify potential peripheral blood biomarkers associated with survival in patients with advanced melanoma treated with nivolumab. All advanced me- lanoma cases treated with anti-programmed cell death protein 1 (anti-PD1) over a 3-year period in the Dermato-Oncology Department, Nantes, France were identified. For each case, 9 potential blood biomarkers were identified. Bivariate and multivariate analyses, adjusted for the American Joint Committee on Cancer (AJCC) classification stage, Eastern Cooperative Onco- logy Group (ECOG) performance status, lactate dehy- drogenase (LDH) level and failure to respond to first-li- ne therapy, were used to test the association between biomarkers and overall survival (primary outcome) or progression-free survival (secondary outcome). In- creased monocyte count, leukocyte/lymphocyte ratio and neutrophil/lymphocyte ratio were significantly as- sociated with decreased overall survival after bivariate and multivariate analyses. Increased monocyte count was also significantly associated with decreased pro- gression-free survival. These blood variables are easi- ly measured and could help to predict patient response before the introduction of anti-PD1 therapy. Key words: nivolumab; anti-PD1; melanoma; biomarkers; pre­ dictive. Accepted Dec 20, 2017; Epub ahead of print Dec 20, 2017 Acta Derm Venereol 2018; 98: 406–410. Corr: Brigitte Dréno, Department of Dermato-Oncology, University of Nantes, 1 place Alexis Ricordeau, FR-44093 Cedex 01, Nantes, France. E-mail: [email protected] T he introduction of new therapeutic agents has revo- lutionized the management of metastatic melanoma since 2011. Among these new agents are checkpoint inhibitors: human monoclonal antibodies targeting either programmed cell death protein 1 (PD1) or cytotoxic T- lymphocyte associated protein 4 (CTLA4), key players in immune regulation of tumour progression. PD1 is a T-cell receptor, which, when bound to PD ligand-1 (PDL1) or -2 (PDL2) on tumour cells, causes down-regulation in T-cell-mediated immune response. Nivolumab is one of the 2 anti-PD1 monoclonal antibodies currently available on the market, which constitute the treatment of reference in advanced me- doi: 10.2340/00015555-2872 Acta Derm Venereol 2018; 98: 406–410 lanoma. In 2015, a randomized controlled trial demon- strated increased survival after one year in patients with metastatic melanoma without BRAF mutation treated with nivolumab compared with dacarbazine as first-line therapy (1). Similar results were seen when nivolumab was compared with other chemotherapy agents (dacar- bazine or paclitaxel combined with carboplatin) used as second-line therapy after treatment with BRAF inhibitor or ipilimumab (2). Anti-PD1 response rate is approximately 40%, mea- ning that patient selection is essential. There is a need for prognostic biomarkers, because administering treatment to patient non-responders is costly, exposes them to potential side-effects, and delays the introduc- tion of alternative, potentially more effective, therapies. However, care must be taken to ensure that biomarkers are highly sensitive, in order to avoid the exclusion of patient responders. Easily measurable, validated biomarkers predictive of anti-PD1 response are lacking. Current biomarker pro- positions include increased tumour expression of PDL1 (3) and tumour CD8 T-cell infiltration (4). Histological biomarkers require a tissue biopsy, which is not feasible in all patients because of the risk associated with certain visceral tumour locations and delays in obtaining results. Furthermore, the reliability of histological biomarkers is questionable because tumours are naturally heteroge- neous, and histological samples are not representative of the whole tumour. Moreover, immunohistochemical methods are yet to be validated and homogenized bet- ween the different laboratories (5). The predictive value of PDL1 in melanoma metastasis and the definition of its range of positivity (5%, 10% of cells) are still discussed (5). To date, the most valuable finding is that an absence of PDL1 expression seems to be an argument for using a combination of 2 checkpoint inhibitors, anti-PD1 and anti-CTLA4. Some prognostic blood biomarkers have already been identified for checkpoint therapies. High lactate dehydrogenase (LDH) (6) and high C-reactive protein (CRP) levels prior to anti-PD1 treatment are associated with poor outcomes (7). High lymphocyte count and high eosinophil count prior to first infusion have been shown to be associated with improved overall survival (OS) in metastatic melanoma treated with ipilimumab (anti-CTLA4 monoclonal antibody) (8) and pembro- lizumab (anti-PD1 monoclonal antibody) (9). Inflam- This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2018 Acta Dermato-Venereologica.