However, their cohort contained patients receiving BRAFi monotherapy as well as combined MAPKi and included ~50% of patients who were not treatment nave. == Results == OS was significantly longer in patients receiving anti-PD-1 monotherapy compared to patients receiving combined MAPK inhibitors. Subsequent therapies were comparable among these groups. The difference in OS was less pronounced in patients with high LDH levels and visceral metastatic spread. == Conclusion == First-line treatment with a PD-1 blocking antibody might be associated with longer OS than first-line inhibition of the MAPK pathway in patients with advanced melanoma harboring mutant BRAF. These hypothesis-generating data need to be confirmed or rejected in prospective, randomized trials. == Electronic supplementary material == The online version of this article (10.1007/s00262-019-02311-1) contains supplementary material, which is available to authorized users. Keywords:Melanoma, BRAF, First-line treatment, PD-1, MAPK == Introduction == Approximately, 50% of all melanomas harbor an activating mutation in B-Raf proto-oncogene (BRAF) affecting the codon 600, with consequent activation of the mitogen-activated protein kinase (MAPK) pathway [1]. In patients with advanced BRAFV600E/K-mutated melanomas, inhibition of the MAPK pathway has shown a high response rate and prolongation of overall survival (OS) [2]. Therapeutically, combinations of selective BRAF inhibitors (BRAFi) (vemurafenib or dabrafenib) and MAPK/ERK kinase (MEK) inhibitors (MEKi) (cobimetinib or trametinib) have become a standard of care in these patients [3,4]. Programmed death 1 receptor (PD-1) blockade with monoclonal antibodies (nivolumab, pembrolizumab) has demonstrated an objective response rate (ORR) of ~ 40% and to prolong survival in patients with advanced melanoma [5,6]. Here, the efficacy of this form of therapy was shown both in patients with mutated BRAF and in patients without such an activating mutation [7]. Thus, patients with advanced melanoma harboring mutated BRAFV600E/K can benefit from MAPK inhibitors (MAPKi) as well as PD-1 blockade. However, it remains unclear which, if any, modality should be used as preferred first-line therapy to yield maximum patient benefit. No prospective head-to-head data are currently available to address this everyday challenge in the treatment of patients with BRAF-mutated advanced melanoma. Exploratory analyses of prospective clinical trials as well as retrospective biomarker studies have identified several markers associated with benefit from MAPKi or PD-1 blockade. For instance, elevated lactate dehydrogenase (LDH) is associated with worse outcome both in the context of MAPKi and PD-1 blockade [8,9]. For programmed death ligand 1 (PD-L1) expression, a positive correlation with the ORR of PD-1 blockade and OS has been observed [5,10,11]. Patients considered to be PD-L1 negative, however, still show DUBs-IN-2 clinical responses. For patients receiving MAPKi, controversial data on the predictive value of PD-L1 expression exist [1214]. To date, it remains unclear if any biomarker exists that is predictive for either therapeutic approach that could help to guide the treatment of BRAFV600-mutant melanoma patients regarding first-line therapy and prospective, clinical trials are still underway. To optimize patient benefit, data that may support the use of either PD-1 blockade or MAPKi as first-line therapy in patients with advanced BRAF-mutated melanoma, are urgently needed. With data from prospective clinical trials pending, we conducted a multicenter retrospective analysis to investigate the outcome of DUBs-IN-2 patients undergoing either measure as first-line therapy. == Materials and methods == == Patient cohort == Patients with advanced (unresectable or metastatic) melanoma harboring mutant BRAF (V600E/K) were included in this retrospective analysis. Participating clinical sites provided data of patients who received either dual MAPKi (vemurafenib plus cobimetinib or dabrafenib plus trametinib) or single-agent PD-1 Goat polyclonal to IgG (H+L)(HRPO) blocking antibody (nivolumab or pembrolizumab) as first-line therapy for advanced disease. No further restrictions applied regarding patient selection. The American DUBs-IN-2 Joint Committee on Cancer (AJCC) 2009 classification was used to categorize patients [15]. Demographic, as well as clinical data were collected for all identified patients from patient records. Data were obtained as documented at the start of first-line therapy. Laboratory values were obtained within 4 weeks before start of systemic therapy. Elevated LDH was defined as any value above the local upper limit of normal (ULN). == Definition of end points and data acquisition == OS was calculated from the start of first-line therapy. Patients who were still living were censored at the last documented follow-up. Patients.