S Ugurel1, D Schadendorf2, K Horny3, A Sucker2, S Schramm4, J Utikal5, C Pföhler6, R Herbst7, B Schilling8, C Blank9, J C Becker3, A Paschen2, L Zimmer2, E Livingstone2, P A Horn4, V Rebmann4. 1. Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Consortium of Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: selma.ugurel@uk-essen.de. 2. Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Consortium of Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 3. Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Consortium of Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Translational Skin Cancer Research, German Consortium of Translational Cancer Research (DKTK), Essen, Germany. 4. Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 5. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. 6. Department of Dermatology, Saarland University Medical Center, Homburg/Saar, Germany. 7. Department of Dermatology, Helios Klinikum Erfurt, Erfurt, Germany. 8. Department of Dermatology, University Hospital Würzburg, Würzburg, Germany. 9. Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Abstract
BACKGROUND: Programmed cell death protein 1 (PD-1) checkpoint inhibition has recently advanced to one of the most effective treatment strategies in melanoma. Nevertheless, a considerable proportion of patients show upfront therapy resistance and baseline predictive biomarkers of treatment outcome are scarce. In this study we quantified PD-1 and programmed death-ligand 1 (PD-L1) in baseline sera from melanoma patients in relation to therapy response and survival. PATIENTS AND METHODS: Sera taken at therapy baseline from a total of 222 metastatic melanoma patients (two retrospectively selected monocentric discovery cohorts, n = 130; one prospectively collected multicentric validation cohort, n = 92) and from 38 healthy controls were analyzed for PD-1 and PD-L1 concentration by sandwich enzyme-linked immunosorbent assay. RESULTS: Melanoma patients showed higher serum concentrations of PD-1 (P = 0.0054) and PD-L1 (P < 0.0001) than healthy controls. Elevated serum PD-1 and PD-L1 levels at treatment baseline were associated with an impaired best overall response (BOR) to anti-PD-1 (P = 0.014, P = 0.041), but not to BRAF inhibition therapy. Baseline PD-1 and PD-L1 serum levels correlated with progression-free (PFS; P = 0.0081, P = 0.053) and overall survival (OS; P = 0.055, P = 0.0062) in patients who received anti-PD-1 therapy, but not in patients treated with BRAF inhibitors. By combining both markers, we obtained a strong discrimination between favorable and poor outcome of anti-PD-1 therapy, with elevated baseline serum levels of PD-1 and/or PD-L1 associated with an impaired BOR (P = 0.037), PFS (P = 0.048), and OS (P = 0.0098). This PD-1/PD-L1 combination serum biomarker was confirmed in an independent multicenter validation set of serum samples prospectively collected at baseline of PD-1 inhibition (BOR, P = 0.019; PFS, P = 0.038; OS, P = 0.022). Multivariable Cox regression demonstrated serum PD-1/PD-L1 as an independent predictor of PFS (P = 0.010) and OS (P = 0.003) in patients treated with PD-1 inhibitors. CONCLUSION: Our findings indicate PD-1 and PD-L1 as useful serum biomarkers to predict the outcome of PD-1 inhibition therapy in melanoma patients and to select patients for PD-1-based versus BRAF-based therapy strategies.
BACKGROUND: Programmed cell death protein 1 (PD-1) checkpoint inhibition has recently advanced to one of the most effective treatment strategies in melanoma. Nevertheless, a considerable proportion of patients show upfront therapy resistance and baseline predictive biomarkers of treatment outcome are scarce. In this study we quantified PD-1 and programmed death-ligand 1 (PD-L1) in baseline sera from melanoma patients in relation to therapy response and survival. PATIENTS AND METHODS: Sera taken at therapy baseline from a total of 222 metastatic melanoma patients (two retrospectively selected monocentric discovery cohorts, n = 130; one prospectively collected multicentric validation cohort, n = 92) and from 38 healthy controls were analyzed for PD-1 and PD-L1 concentration by sandwich enzyme-linked immunosorbent assay. RESULTS: Melanoma patients showed higher serum concentrations of PD-1 (P = 0.0054) and PD-L1 (P < 0.0001) than healthy controls. Elevated serum PD-1 and PD-L1 levels at treatment baseline were associated with an impaired best overall response (BOR) to anti-PD-1 (P = 0.014, P = 0.041), but not to BRAF inhibition therapy. Baseline PD-1 and PD-L1 serum levels correlated with progression-free (PFS; P = 0.0081, P = 0.053) and overall survival (OS; P = 0.055, P = 0.0062) in patients who received anti-PD-1 therapy, but not in patients treated with BRAF inhibitors. By combining both markers, we obtained a strong discrimination between favorable and poor outcome of anti-PD-1 therapy, with elevated baseline serum levels of PD-1 and/or PD-L1 associated with an impaired BOR (P = 0.037), PFS (P = 0.048), and OS (P = 0.0098). This PD-1/PD-L1 combination serum biomarker was confirmed in an independent multicenter validation set of serum samples prospectively collected at baseline of PD-1 inhibition (BOR, P = 0.019; PFS, P = 0.038; OS, P = 0.022). Multivariable Cox regression demonstrated serum PD-1/PD-L1 as an independent predictor of PFS (P = 0.010) and OS (P = 0.003) in patients treated with PD-1 inhibitors. CONCLUSION: Our findings indicate PD-1 and PD-L1 as useful serum biomarkers to predict the outcome of PD-1 inhibition therapy in melanoma patients and to select patients for PD-1-based versus BRAF-based therapy strategies.
Authors: Oliver Hoffmann; Sebastian Wormland; Ann-Kathrin Bittner; Monika Collenburg; Peter A Horn; Rainer Kimmig; Sabine Kasimir-Bauer; Vera Rebmann Journal: J Cancer Res Clin Oncol Date: 2022-04-02 Impact factor: 4.553
Authors: Arrush Choudhary; D Marshall Brinkley; Sepideh Besharati; Wouter C Meijers; James B Atkinson; Kaushik Amancherla; Qingfeng Zhu; Shi Huang; Lee S Nguyen; Joe-Elie Salem; Enrico Ammirati; JoAnn Lindenfeld; Robert A Anders; Javid Moslehi Journal: Circ Heart Fail Date: 2021-09-24 Impact factor: 10.447