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Purpose: The interaction of gut microbiome and immune system is being studied with increasing interest. Disturbing factors, such as antibiotics may impact the immune system via gut and interfere with tumor response to immune checkpoint blockade (ICB)., Methods: In this multicenter retrospective cohort study exclusively treatment-naïve patients with cutaneous or mucosal melanoma treated with first-line anti-PD-1 based ICB for advanced, non-resectable disease between 06/2013 and 09/2018 were included. Progression-free (PFS), and overall survival (OS) according to antibiotic exposure (within 60 days prior to ICB and after the start of ICB vs. no antibiotic exposure) were analyzed. To account for immortal time bias, data from patients with antibiotics during ICB were analyzed separately in the time periods before and after start of antibiotics., Results: Among 578 patients with first-line anti-PD1 based ICB, 7% of patients received antibiotics within 60 days prior to ICB and 19% after starting ICB. Antibiotic exposure prior to ICB was associated with worse PFS (adjusted HR 1.75 [95% CI 1.22-2.52]) and OS (adjusted HR 1.64 [95% CI 1.04-2.58]) by multivariate analysis adjusting for potential confounders. The use of antibiotics after the start of ICB had no effect on either PFS (adjusted HR 1.19; 95% CI 0.89-1.60) or OS (adjusted HR 1.08; 95% CI 0.75-1.57)., Conclusions: Antibiotic exposure within 60 days prior to ICB seems to be associated with worse PFS and OS in melanoma patients receiving first-line anti-PD1 based therapy, whereas antibiotics after the start of ICB do not appear to affect PFS or OS., Competing Interests: Declaration of Competing Interest E.C. received travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, UCB and Almirall outside the submitted work. B.S. Honoraria from MSD, BMS, SUN Pharma, Allmiral, Novartis; Advisory Board for MSD, BMS, Pierre Fabre Pharma, Sanofi; travel support from BMS, Novartis, Pierre Fabre Pharma; Research Funding from Novartis; all outside the submitted work. M.S. received speaker honoraria from Novartis and advisory board honoraria from Sanofi Genzyme. R.G. declares research support from Novartis, Amgen, Sanofi, Merck-Serono, Admiral, SUN Pharma and Kyowa-Kirin; honoraria for lectures from Roche Pharma, Bristol-Myers Scuibb, Novartis, MSD. Almirall, Amgen, Merck-Serono, SUN Pharma, Pierre-Fabre, and Sanofi; advisory honoraria from Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Admiral, Amgen, Pierre-Fabre, Merck-Serono, 4SC, Sun Pharma, Merck-Serono, Sanofi, Delcath and Immunocore. C.L. receives personal fees and travel reimbursement from MSD, BMS, Merck, Sanofi, Almirall Hermal, Kyowa Kirin, Biontech, Pierre Fabre, Novartis and Sun Pharma outside the submitted work. K.K. has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. A.Z.M. received travel support from Novartis, Genzyme, and Bristol-Myers Squibb, outside the submitted work. J.M.P. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis, Sanofi and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos. E.G. received travel support from Pierre-Fabre, outside the submitted work. A.M. received travel support from Novartis, outside the submitted work. A.R. received grants, personal fees, and non-financial support from Novartis; grants and non-financial support from Bristol-Myers Squibb; personal fees and non-financial support from Roche; personal fees from Merck Sharp & Dohme; and non-financial support from Amgen, outside the submitted work. S.U. declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; and meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma; outside the submitted work. D.S. received grants and other support from Bristol-Myers Squibb, personal fees from Bristol-Myers Squibb during the conduct of the study; personal fees from Amgen; personal fees from Boehringer Ingelheim; personal fees from InFlarX; personal fees and other support from Roche; grants, personal fees and other support from Novartis; personal fees from Incyte; personal fees and other support from Regeneron; personal fees from 4SC; personal fees from Sanofi; personal fees from Neracare; personal fees from Pierre-Fabre; personal fees and other support from Merck-EMD; personal fees from Pfizer; personal fees and other support from Philiogen; personal fees from Array, personal fees and other support from MSD Sharp & Dohme, outside the submitted work. E.L. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, Sunpharma, Takeda and travel support from Bristol-Myers Squibb, Pierre- Fabre, Sunpharma and Novartis, outside the submitted work.A.S. L.Z. served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, and Sanofi; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, and Novartis, outside the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The development of leptomeningeal disease (LMD) among melanoma patients is associated with short survival. Unspecific clinical symptoms and imprecise diagnostic criteria often delay diagnosis. Because melanoma patients with LMD have been excluded from most clinical trials, the efficacy of immune checkpoint blockade (ICB) and targeted therapies (TTs) has not been adequately investigated among these patients., Methods: We performed a retrospective study in two tertiary-referral skin cancer centres to evaluate the clinical characteristics, diagnostics, treatments, and overall survival (OS) of melanoma patients with LMD between June 2011 and March 2019., Results: In total, 52 patients were included. The median age at LMD diagnosis was 58 years. Most patients (n = 30, 58%) were men. The median time from the first diagnosis of unresectable disease to the first diagnosis of LMD was 8.5 months (range 0-91.5 months). Most patients (65%, n = 34) were BRAF V600 mutated. Sixteen patients (31%) presented with LMD only, whereas 36 patients (69%) presented with concomitant brain metastases at LMD diagnosis. Eleven patients (21%) showed no evidence of extracranial disease. Forty-four patients (85%) had clinical symptoms at LMD diagnosis. Forty-two patients (81%) had received at least one prior therapy. Forty patients (77%) received at least one treatment after LMD diagnosis, including TT (n = 17), ICB (n = 13), bevacizumab (n = 1), radiotherapy (n = 3), and intrathecal chemotherapy (n = 1); five patients received both TT and ICB. Twelve patients (23%) received no treatment because of rapid progression of LMD. The median OS for the entire cohort was 2.9 months (95% confidence interval [CI] 1.7-4.1). Among patients receiving systemic therapy, OS was 3.7 months (95% CI 2.4-4.9)., Conclusions: Systemic treatment with TT or ICB seems to improve OS among patients with LMD. However, despite new therapy modalities, the prognosis of LMD remains poor., Competing Interests: Conflict of interest statement E.C. received travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis, outside the submitted work. T.K. received travel support from Novartis, Amgen, Celgene, Lilly, and Pierre-Fabre, outside the submitted work. A.Z. received travel support from Novartis, Genzyme, and Bristol-Myers Squibb, outside the submitted work. F.R. received travel support from Pierre-Fabre, Merck Sharp & Dohme, and Novartis, outside the submitted work. S.Kn. received travel support from Bristol-Myers Squibb and Amgen, outside the submitted work. E.G. received travel support from Pierre-Fabre, outside the submitted work. A.R. received grants, personal fees, and non-financial support from Novartis; grants and non-financial support from Bristol-Myers Squibb; personal fees and non-financial support from Roche; personal fees from Merck Sharp & Dohme; and non-financial support from Amgen, outside the submitted work. S.U. received grants, personal fees, and non-financial support from Novartis; grants and non-financial support from Bristol-Myers Squibb; personal fees and non-financial support from Roche; personal fees from Merck Sharp & Dohme; and non-financial support from Amgen, outside the submitted work. D.S. received grants and other support from Bristol-Myers Squibb, personal fees from Bristol-Myers Squibb during the conduct of the study; personal fees from Amgen; personal fees from Boehringer Ingelheim; personal fees from InFlarX; personal fees and other support from Roche; grants, personal fees and other support from Novartis; personal fees from Incyte; personal fees and other support from Regeneron; personal fees from 4SC; personal fees from Sanofi; personal fees from NeraCare; personal fees from Pierre-Fabre; personal fees and other support from Merck-EMD; personal fees from Pfizer; personal fees and other support from Philiogen; personal fees from Array, personal fees and other support from MSD Sharp & Dohme, outside the submitted work. E.L.: served as consultant or/and has received honoraria from Amgen, Actelion, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Janssen, Medac, Sanofi, and Sun Pharma; and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sun Pharma, and Novartis, outside the submitted work. M.G. reports work as a consultant/independent contractor with Roche Pharma, Janssen, Novartis, AbbVie Inc, Novocure Inc, and Daiichi-Sankyo; honorarium from Novartis, UCB Inc, TEVA Pharmaceuticals, Bayer Corp, Novocure Inc, Medac, Merck Sharp & Dohme Corp, and Kyowa Kirin Group; grants from Novocure and Medac and travel fees from Novocure Inc and Medac, outside the submitted work. L.Z. served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, and Sanofi; research funding to institution from Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, and Novartis, outside the submitted work. Other authors declare no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Anti-[programmed cell death protein 1 (PD-1)] antibodies nivolumab and pembrolizumab were approved for adjuvant treatment of melanoma as they demonstrated improved relapse-free survival. Currently, combined anti-PD-1 plus anti-[cytotoxic T-lymphocyte-associated protein 4 (CTLA4)] blockade is being investigated in adjuvant and neoadjuvant trials. Sarcoidosis-like reactions have been described for immune checkpoint inhibitors and are most likely drug-induced. The reported rate of sarcoidosis/sarcoidosis-like reactions within clinical melanoma trials is <2%. We observed that a remarkably higher number of melanoma patients (10/45 patients, 22%) treated with immune checkpoint inhibitor (ICI) within an adjuvant clinical trial-developed drug induced sarcoidosis-like reaction (DISR) mimicking metastasis., Case Presentation: Of 45 stage III melanoma patients who were treated at our institute with adjuvant ICI (either nivolumab alone or in combination with ipilimumab) within a two-armed, blinded clinical trial, ten developed a DISR. Three of the ten patients were men, median age was 52 years (range, 32-70 years). DISRs were asymptomatic and generally detected radiographically at first radiographic imaging after the start of therapy (median time, 2.8 months) and described as a differential diagnosis to tumour progression. In one patient, DISR was only apparent 13.1 months after start of therapy and 4 weeks after the end of ICI treatment. DISR presented as mediastinal/hilar lymphadenopathy in 8/10 patients (as only site or in addition to lung, skin and/or bone involvement), one patient had only lung and cutaneous, one patient only cutaneous DISR. Biopsies from lymph nodes, skin and bone were taken in 8/10 patients, and histology confirmed sarcoidosis-like reactions (SLRs). As patients were asymptomatic, no treatment for DISR was required, and study treatment was stopped for DISR in only one patient due to bone involvement. DISRs have resolved or are in remission in all patients. At a median follow-up time of 15.3 months (range, 12-17.6 months), two patients experienced melanoma relapse., Conclusions: In most cases, sarcoidosis could only be differentiated from melanoma progression on biopsy. Treating physicians as well as radiologists have to be aware of the potentially higher rate of DISR in patients receiving adjuvant ICI. A thorough interdisciplinary workup is required to discriminate from true melanoma progression and to decide on continuation of adjuvant ICI treatment., Competing Interests: Conflict of interest statement E.C.: reports travel support from Bristol-Myers Squibb, MSD SHARP & DOHME and Novartis.T.K.: reports travel support from Novartis, Amgen, Celgene, Lilly and Pierre-Fabre. L.Z.: served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Sanofi, and travel support from MSD, BMS, Amgen, Pierre Fabre and Novartis. E.H.: reports no conflict of interest. S.U.: reports grants, personal fees and non-financial support from Novartis, grants and non-financial support from BMS, personal fees and non-financial support from Roche, personal fees from MSD Sharp & Dohme, non-financial support from Amgen, outside the submitted work. E.G.: reports travel support from Pierre-Fabre. A.R.: reports grants, personal fees and non-financial support from Novartis, grants and non-financial support from Bristol-Myers Squibb, personal fees and non-financial support from Roche, personal fees from MSD Sharp & Dohme, non-financial support from Amgen, outside the submitted work . F.B.: reports personal fees and non-financial support from Boehringer Ingelheim and Roche Pharma, personal fees from Galapagos, outside the submitted work. T.E.W: reports no conflict of interest. J.W.: reports no conflict of interest. D.T.: reports no conflict of interest. D.S: reports grants and other from BMS, personal fees from BMS, during the conduct of the study; personal fees from Amgen, personal fees from Boehringer Ingelheim, personal fees from InFlarX, personal fees and other from Roche, grants, personal fees and other from Novartis, personal fees from Incyte, personal fees and other from Regeneron, personal fees from 4SC, personal fees from Sanofi, personal fees from Neracare, personal fees from Pierre Fabre, personal fees and other from Merck-EMD, personal fees from Pfizer, personal fees and other from Philiogen, personal fees from Array, personal fees and other from MSD, outside the submitted work. E.L.: served as consultant or/and has received honoraria from Amgen, Actelion, Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Janssen, Medac, and travel support from Amgen, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Amgen, Pierre Fabre, Sunpharma and Novartis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)