Analysis of statistical power was performed using the powerCT.default0 function of the powerSurvEpi package for R. .032). Immune-related GGT elevation was recorded in 17% (PD-1 group) and 38.5% (Ipi + Nivo group). Of these patients, the majority (81 and 68%, respectively) experienced normal ALT and AST and showed no clinical indicators of hepatotoxicity. Patients who experienced irGGT elevation experienced superior response (PD-1 group: odds ratio [OR] 3.57,p= .00072; Ipi + Nivo group: OR 1.74,p= .12) and OS (PD-1 group: HR 0.37,p= .0016; Ipi + Nivo group: HR 0.33,p= .00050). == Conclusions == The frequency of hepatic irAE is currently underestimated. The addition of the sensitive enzyme ACVRLK7 GGT to the laboratory panel before and during therapy with ICPI allows to detect two to three times more patients developing hepatic or hepatobiliary toxicity than known so far. Immune-related GGT elevations correlate with response and favorable survival. Precis for use in the Table of Contents The frequency of hepatotoxicity under immune checkpoint blockade is currently underestimated. We suggest the addition of gamma-glutamyl transferase to the laboratory panel in checkpoint inhibitor patients for the detection of hepatobiliary toxicity. Keywords:Gamma-glutamyl transferase, Melanoma, Immune checkpoint inhibitors, PD-1, Immune-related adverse events, Hepatotoxicity == Introduction == Immune-related adverse events (irAE) are a common phenomenon in cancer patients receiving immune checkpoint inhibitors (ICPI). In metastatic melanoma, clinically serious grade irAE (grade 3 or higher according to CTCAE criteria) occur in 1016% of patients receiving PD-1 inhibitors [1,2] and in 5556% receiving combined immunotherapy with the CTLA-4 antibody ipilimumab and the PD-1 antibody nivolumab [3,4]. Although irAE constitute a challenge for the clinician, their occurrence is now considered being related with a favorable end result, even in cases when the treatment with ICPI must be quit and corticosteroids are necessary [57]. The prognostic impact of irAE differs between the distinct WRG-28 sites affected by this excessive immune response, with the skin being most clearly associated with favorable prognosis [811]. Hepatic irAE are less frequent compared to cutaneous irAE or diarrhea and colitis, yet they can run complicated and should be handled cautiously to preserve the long-term function of this crucial metabolic organ WRG-28 [1214]. In contrast to cutaneous or endocrine irAE, the prognostic impact of hepatic irAE remains elusive. Liver metastasis is considered an unfavorable prognostic factor in melanoma patients treated with ICPI which is usually associated with lower CD8 + T-cell infiltration at the invasive tumor margin [15]. Moreover, the intracellular enzyme lactate dehydrogenase (LDH), a widely used serum biomarker in metastatic melanoma, increases exceptionally strong in patients with advanced hepatic metastases. Besides its well-known function as a parameter for cholestasis, the biliary enzyme gamma-glutamyl transferase (GGT) plays a fundamental role in the metabolism of glutathione [16]. In contrast to this function as an anti-oxidant enzyme, it has been shown that, under certain conditions, GGT is also able to exert pro-oxidant effects, promoting tumor formation and progression [17]. GGT is mainly expressed around the luminal surface of WRG-28 secretory epithelial cells, especially in epithelial cells of the hepato-biliary tract, the pancreas, and the kidneys [16]. In various malignancies, such as colorectal carcinoma [18,19], urothelial carcinoma [20], endometrial carcinoma [21], renal cell carcinoma [22], as well as others, elevated levels of GGT correlated with impaired survival, higher disease stages, or presence of hepatic metastases. However, in metastatic uveal melanoma, the prognostic role of liver function assessments (LFTs) including GGT in detecting metastasis was contradictory [2326]. In metastatic cutaneous melanoma and in other cancer patients receiving ICPI, it is still unknown, whether LFTs are prognostically relevant. We conducted the present study to evaluate the association between baseline serum levels of GGT and survival of advanced melanoma patients receiving ICPI. The second aim of this study was to characterize GGT serum levels over time during treatment with ICPI. Based on the experience that GGT elevations occur frequently in patients receiving ICPI, our hypothesis before conducting this study was that GGT elevations constitute a hitherto underreported and undescribed hepatic or hepatobiliary irAE. We aimed at evaluating its association with response and survival in melanoma patients receiving either PD-1 antibodies or the combined immunotherapy with CTLA-4 and PD-1 antibodies. == Methods == == Patients == From October 2013 to May 2019, 366 patients with unresectable melanoma were treated with pembrolizumab or nivolumab (referred to as PD-1 group,n= 218 patients) or ipilimumab plus nivolumab (also denoted as Ipi + Nivo group,n= 148 patients) and were enrolled retrospectively in this study. The two cohorts were analyzed separately to account for the major differences of PD-1 monotherapy and the combined PD-1 plus CTLA-4 blockade in respect of efficacy and toxicity profiles [3]. The study was carried out in accordance with the.