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Most patients with advanced basal cell carcinomas (BCCs) may not benefit sufficiently from standard treatment comprising surgery and radiation. Vismodegib, an oral selective hedgehog pathway inhibitor, is approved for treatment of patients with locally advanced BCC inappropriate for surgery or radiotherapy, or for patients with symptomatic metastatic BCC. In order to enhance understanding of the effectiveness, safety and utilization of vismodegib in clinical practice in Germany, a non-interventional study, JONAS, was conducted. A total of 53 patients with locally advanced BCC who initiated treatment with vismodegib between 2016 and 2018 were included in the study, which was embedded in the German ADOReg skin cancer registry. Duration of response, the primary endpoint, was 12.4 months, progression-free survival 32.2 months and overall response rate 77.4%. Most adverse events were mild to moderate. Overall, results confirmed previous findings, demonstrating favourable responses and manageable safety of vismodegib in patients with locally advanced BCC in clinical practice.

Background: β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial., Methods: Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47-0.68). β-blocker use was defined as oral administration of any β-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of β-blockers and RFS., Results: Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70-1.31). The HRs of RFS associated with β-blocker use were 0.67 (95% CI 0.38-1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80-1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18-0.65) among β-blocker users and 0.59 (95% CI 0.48-0.71) among those not using β-blockers., Conclusions: This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37., Competing Interests: Conflict of interest statement Alexander Eggermont Consulting fees: Agenus, Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, Galecto, GSK, IO Biotech, ISA Pharmaceuticals, Merck/MSD, Nektar, Novartis, Pfizer, SAiRoPA, Sellas, SkylineDx, TigaTx, TTxDiscovery. Payment or honoraria: Biocad, BMS, Merck/MSD. Participation on a Data Safety Monitoring Board or Advisory Board: GSK, Novartis and Pfizer. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences German Cancer Aid. Stock or stock options: SkylineDx and SAiRoPA. Rutger Koornstra Grants or contracts from any entity: Roche. Leonel Hernandez-Aya Grants or contracts from any entity: Bristol Myers Squibb, Regeneron Pharmaceuticals, Immunocore, Merck, Polynoma, Corvus Pharmaceuticals, Roche, Genentech, Merck Serono, Amgen, MedImmune, Takeda Pharmaceuticals, Moderna Therapeutics. Consulting fees: Massive Bio, Bristol Myers Squibb - Advisory Board. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sanofi, Regeneron Pharmaceuticals - Speakers bureau. Support for attending meetings and/or travel: Sanofi, Regeneron Pharmaceuticals, Bristol Myers Squibb. Anna Maria di Giacomo Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Pierre Fabre, Sanofi. Support for attending meetings and/or travel: BMS, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Pierre Fabre, Sanofi, GSK, Novartis. Alfonsus J.M. van den Eertwegh Grants or contracts from any entity: Roche, Sanofi, Bristol Myers Squibb. Consulting fees: Bristol Myers Squibb. Support for attending meetings and/or travel: MSD Oncology, Roche, Pfizer, Sanofi. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre. Jean-Jacques Grob Consulting fees: Bristol Myers Squibb, MSD Oncology, Roche/Genentech, Novartis, Amgen, Pierre Fabre, Sun Pharma, Merck KGaA, Sanofi, Pfizer, Roche. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis - Speakers bureau. Support for attending meetings and/or travel: BMS, MSD Oncology, Novartis, Pierre Fabre. Ralf Gutzmer Grants or contracts from any entity: Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma Industries, Sanofi. Consulting fees: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Genentech, Novartis, Merck Serono, Almirall, Amgen, Sun Pharma Industries, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, Bayer AG, Immunocore. Support for attending meetings and/or travel: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Industries. Rahima Jamal Grants or contracts from any entity: Merck Sharp & Dohme, Bristol Myers Squibb. Caroline Robert Consulting fees: ROCHE, NOVARTIS, PIERRE FABRE, MSD, BMS, SANOFI, PFIZER, AstraZeneca. Oliver John Kennedy None declared. Paul Lorigan Grants or contracts from any entity: BMS, Pierre Fabre. Consulting fees: BMS, Merck, GSK. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Pierre Fabre, Novartis, MSD, BMS. Support for attending meetings and/or travel: BMS, Support to attend ASCO, MSD - Support to attend ASCO. Mario Mandalà Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, NOVARTIS, PIERRE FABRE, SANOFI. Participation on a Data. Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre - Advisory Boards. Michal Kicinski All support for the present manuscript: Merck - Merck is the sponsor of the study (money paid to my institution). Grants or contracts from any entity: Pierre Fabre - Sponsor and provider of an academic grant for different melanoma studies (money paid to my institution), BMS - Sponsor and provider of an academic grant for different melanoma studies (money paid to my institution). Stefan Suciu All support for the present manuscript: Merck - Merck is the sponsor of the study (money paid to my institution). Grants or contracts from any entity: BMS, Pierre-Fabre - Sponsor and provider of academic grants to other EORTC melanoma studies; payments were made to my institution. Sara Valpione None declared. Sara Gandini None declared. Christian Blank Grants or contracts from any entity: BMS, Novartis, NanoString, and 4SC. Consulting fees: BMS, MSD, Roche, Novartis, Lilly, Pfizer, GSK, GenMab and Pierre Fabre - Payments were made to my institution, Third Rock Venture - Payments were made to me. Stock or stock options: Unity Cars – Stocks, Immagene BV – Co-founder. Alexander C.J. van Akkooi Grants or contracts from any entity: Amgen, Merck-Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC. Georgina V Long Consulting fees: GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, Specialised Therapeutics Australia Pty Ltd. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb - Personal 1 h lecture of my own slides, Pierre Fabre, Personal 1 h lecture of my own slides. Participation on a Data: Safety Monitoring Board or Advisory Board: See consulting fees, All for advisory boards. Victoria Atkinson Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre- Speakers bureaus fees. Support for attending meetings and/or travel: BMS, Travel support. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards. Stephane Dalle Grants or contracts from any entity: Bristol Myers Squibb, Merck Sharp & Dohme - My Institution. Support for attending meetings and/or travel: Bristol Myers Squibb, Pierre Fabre, Merck Sharp & Dohme. Other financial or non-financial interests: Sanofi Pasteur - My wife is an employee of Sanofi Pasteur. Andrew M. Haydon Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis, Merck - Honoraria for lectures, presentations, speakers bureaus. Participation on a Data Safety Monitoring Board or Advisory Board: Novartis, Pierre Fabre, Merck Sharp & Dohme - Advisory Boards. Andrey Meshcheryakov Grants or contracts from any entity: Sanofi, AstraZeneca, Merck Sharp & Dohme - My institution, me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Honoraria for lectures, presentations, speakers bureaus. Support for attending meetings and/or travel: BIOCAD, SERVIER, Merck Sharp & Dohme, Sanofi-Aventis, Merck - Attending meetings and/or travel. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Advisory Board. Adnan Khattak None declared. Matteo S. Carlino Payment or honoraria for lectures, presentations, speakers bureauads, manuscript writing or educational events: Bristol Myers Squibb, MSD, Novartis - Honoraria for lectures, presentations, speakers bureaus. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, IDEAYA Biosciences, Sanofi, Merck Serono, Regeneron Pharmaceuticals, QBiotics, Nektar, Eisai - Advisory Board. Shahneen Sandhu Grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, Merck Sharp & Dohme, Merck Serono, Genentech, AstraZeneca - Funding to the institution. Consulting fees: Amgen, Merck Sharp & Dohme, Merck Serono, AstraZeneca, Bristol Myer Squibb - Funding to the institution. James Larkin Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare research, Royal College of General Practitioners, VJOncology, Agence Unik, Bristol Myers Squibb - Honoraria for lectures, presentations. Participation on a Data Safety Monitoring Board or Advisory Board: Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, MCA, Inselgruppe, Pfizer, Goldman Sachs, MSD - Advisory Board. Susana Puig Grants or contracts from any entity: Almirall - To My Institution, ISDIN - To My Institution, La Roche Posay - To My Institution. Consulting fees: ISDIN, Almirall, La Rohe Posay - To Me, Sanofy, Sunpharma - To Me, Pfizer, Roche, Regeneron - To Me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche Posay - To Me, Pfizer, Roche, Regeneron - To Me, BMS, Sunpharma - TO ME. Support for attending meetings and/or travel: Almirall - TO ME. Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Sanofy - To Me, Sunpharma, Almirall - To Me, ISDIN, Pfzer, Novartis - TO ME. Paolo A. Ascierto Grants or contracts from any entity: Bristol Myers Squibb, Roche, Genentech, Array BioPharma - To my institution. Consulting fees: Bristol Myers Squibb, Roche, Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma Industries, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron Pharmaceuticals - To me. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, Roche, Genentech, Merck - Advisory Board. Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma Industries, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron Pharmaceuticals - To me. Piotr Rutkowski Grants or contracts from any entity: Novartis, Roche, Bristol Myers Squibb - My institution. Consulting fees: Bristol Myers Squibb, MSD, Novartis, Roche, Eli Lilly, Pfizer, Pierre. Fabre - Advisory Role - Personal fees. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, Amgen - Advisory boards, To me, Pfizer, Novartis, Eli Lilly - speakers bureaus. Participation on a Data Safety Monitoring Board or Advisory Board: See above - Advisory Board. Dirk Schadendorf Grants or contracts from any entit: Bristol Myers Squibb, Novartis, Roche, MSD Oncology, Array BioPharma/Pfizer. Consulting fees: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharna, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, Sandoz. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA - speakers bureaus. Support for attending meetings and/or travel: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi/Regeneron. Participation on a Data Safety Monitoring Board or Advisory Board: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar - Advisory Board., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Currently, there are no robust biomarkers that predict immunotherapy outcomes in metastatic melanoma. We sought to build multivariable predictive models for response and survival to anti-programmed cell death protein 1 (anti-PD-1) monotherapy or in combination with anticytotoxic T-cell lymphocyte-4 (ipilimumab [IPI]; anti-PD-1 ± IPI) by including routine clinical data available at the point of treatment initiation., Methods: One thousand six hundred forty-four patients with metastatic melanoma treated with anti-PD-1 ± IPI at 16 centers from Australia, the United States, and Europe were included. Demographics, disease characteristics, and baseline blood parameters were analyzed. The end points of this study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The final predictive models for ORR, PFS, and OS were determined through penalized regression methodology (least absolute shrinkage and selection operator method) to select the most significant predictors for all three outcomes (discovery cohort, N = 633). Each model was validated internally and externally in two independent cohorts (validation-1 [N = 419] and validation-2 [N = 592]) and nomograms were created., Results: The final model for predicting ORR (area under the curve [AUC] = 0.71) in immunotherapy-treated patients included the following clinical parameters: Eastern Cooperative Oncology Group Performance Status, presence/absence of liver and lung metastases, serum lactate dehydrogenase, blood neutrophil-lymphocyte ratio, therapy (monotherapy/combination), and line of treatment. The final predictive models for PFS (AUC = 0.68) and OS (AUC = 0.77) included the same variables as those in the ORR model (except for presence/absence of lung metastases), and included presence/absence of brain metastases and blood hemoglobin. Nomogram calculators were developed from the clinical models to predict outcomes for patients with metastatic melanoma treated with anti-PD-1 ± IPI., Conclusion: Newly developed combinations of routinely collected baseline clinical factors predict the response and survival outcomes of patients with metastatic melanoma treated with immunotherapy and may serve as valuable tools for clinical decision making., Competing Interests: Inês Pires da SilvaConsulting or Advisory Role: MSDSpeakers' Bureau: Roche, Novartis, Bristol Myers SquibbTravel, Accommodations, Expenses: Roche, Bristol Myers Squibb Jennifer L. McQuadeHonoraria: Merck, Bristol Myers Squibb, RocheConsulting or Advisory Role: Bristol Myers Squibb, Roche Pharma AGTravel, Accommodations, Expenses: Merck Selma UgurelHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Merck SeronoConsulting or Advisory Role: Bristol Myers Squibb, Roche, Merck SeronoResearch Funding: Bristol Myers Squibb (Inst), Merck Serono (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Pierre Fabre Rudolf HerbstEmployment: Helios Kliniken Jochen UtikalStock and Other Ownership Interests: BioNTech, Moderna Therapeutics, Pfizer, Merck, SanofiHonoraria: Bristol Myers Squibb, Novartis, MSD Oncology, Roche, Pierre Fabre, SanofiConsulting or Advisory Role: Bristol Myers Squibb, Roche, MSD Oncology, Novartis, Pierre Fabre, Amgen, SanofiResearch Funding: Apogenix (Inst), Noxxon Pharma (Inst), Elsalys Biotech (Inst), TILT Biotherapeutics (Inst)Travel, Accommodations, Expenses: MSD Oncology, Roche, Novartis, Pierre Fabre, Bristol Myers Squibb, Amgen, Sanofi Claudia PföhlerHonoraria: Bristol Myers Squibb, Novartis, Roche, MSD, Merck Serono, Sun Pharma, Amgen, AbbVieConsulting or Advisory Role: Bristol Myers Squibb Foundation, Novartis, MSD, Roche, Sanofi, Allergy Therapeutics, Merck SeronoTravel, Accommodations, Expenses: Bristol Myers Squibb, Novartis, MSD, Roche, Pierre Fabre, Celgene, AbbVie, Merck Serono Patrick TerheydenHonoraria: Bristol Myers Squibb, Novartis, Roche, CureVac, Merck Serono, MSD OncologyConsulting or Advisory Role: Bristol Myers Squibb, Novartis, Pierre Fabre, Roche, Sanofi, Merck KGaA, 4SC, AlmirallTravel, Accommodations, Expenses: Bristol Myers Squibb, Pierre Fabre Michael WeichenthalHonoraria: Merck Sharp & Dohme, Roche, Novartis, Bristol Myers Squibb, SanofiConsulting or Advisory Role: Merck Sharp & Dohme, Roche, Novartis, Bristol Myers Squibb, Sun Pharma, Sanofi, Pierre FabreResearch Funding: Merck Sharp & Dohme (Inst), Millennium (Inst), Bristol Myers Squibb (Inst), Johnson & Johnson (Inst), Novartis (Inst) Ralf GutzmerHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Merck Serono, Almirall Hermal GmbH, Amgen, Sun Pharma, Pierre Fabre, Sanofi/Regeneron, ImmunocoreConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Almirall Hermal GmbH, 4SC, Amgen, Pierre Fabre, Merck Serono, Sun Pharma, Sanofi, ImmunocoreResearch Funding: Pfizer (Inst), Novartis (Inst), Johnson & Johnson (Inst), Amgen (Inst), Merck Serono (Inst), Sun Pharma (Inst), Sanofi (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Peter MohrHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Amgen, Pierre Fabre, Merck, SanofiConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Roche, Merck, Pierre Fabre, SanofiSpeakers' Bureau: Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Amgen, SanofiResearch Funding: Merck Sharp & Dohme (Inst), Bristol Myers Squibb (Inst), Novartis (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Amgen, Roche, Sun Pharma, Sanofi Jessica L. SmithHonoraria: Pierre FabreTravel, Accommodations, Expenses: MSD Oncology Richard A. ScolyerEmployment: Royal Prince Alfred HospitalHonoraria: GlaxoSmithKline, Harvard Medical School, Wake Forest School of MedicineConsulting or Advisory Role: Bristol Myers Squibb GesmbH (Austria), Bristol Myers Squibb SA (Switzerland), GlaxoSmithKline, Merck Sharp & Dohme, NeraCare GmbH, Novartis Australia, Amgen, Myriad Genetics, MSD Sharp & Dohme (Australia) Pty Limited, Novartis, QBiotics, Provectus Biopharmaceuticals Australia, Evaxion BioTech A/S, Novartis Pharmaceuticals Australia Pty Limited, RocheResearch Funding: The Ainsworth Foundation (Inst), National Health and Medical Research Council, Melanoma Research Alliance (MRA) GrantTravel, Accommodations, Expenses: Bristol Myers Squibb, Novartis AustraliaUncompensated Relationships: Melanoma Institute Australia Ana M. AranceConsulting or Advisory Role: BMS, Roche, Novartis, Pierre Fabre, MSD, Merck, SanofiSpeakers' Bureau: Pierre Fabre, Novartis, MSD, BMS, Roche, Merck, SanofiResearch Funding: Pierre Fabre, Novartis, Roche, BMS, MSD, Merck, Sanofi, AmgenTravel, Accommodations, Expenses: BMS, MSD, Novartis, Pierre Fabre, Roche, Merck, Sanofi Lisa PickeringConsulting or Advisory Role: Pfizer, Ipsen, BMS, Eisai, MSD Oncology, NovartisSpeakers' Bureau: Pfizer, BMSResearch Funding: NIHR (Inst), Rosetrees Trust (Inst), Kidney and melanoma cancer fund of RMH charity (Inst) James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais Paul LoriganHonoraria: Novartis, Pierre Fabre, Merck, BMS, MSD, NeraCare GmbH, Amgen, Roche, Oncology Education, NektarConsulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Novartis, NektarSpeakers' Bureau: Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Pierre FabreResearch Funding: BMS, Pierre FabreTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bristol Myers Squibb Christian U. BlankStock and Other Ownership Interests: Uniti Cars, ImmageneConsulting or Advisory Role: Roche/Genentech (Inst), MSD Oncology (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), AstraZeneca (Inst), Lilly (Inst), Pierre Fabre (Inst), GenMab (Inst), Third Rock VenturesResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), NanoString Technologies (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb Dirk SchadendorfHonoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, SandozConsulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, NektarSpeakers' Bureau: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaAResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi/Regeneron Michael A. DaviesConsulting or Advisory Role: Genentech/Roche, Novartis, Bristol Myers Squibb, NanoString Technologies, Array BioPharma, Apexigen, ABM Therapeutics, Pfizer, EisaiResearch Funding: GlaxoSmithKline (Inst), Genentech/Roche (Inst), AstraZeneca (Inst), Merck (Inst), Oncothyreon (Inst), Myriad Genetics (Inst), Sanofi (Inst), Pfizer (Inst) Matteo S. CarlinoHonoraria: Bristol Myers Squibb, MSD, NovartisConsulting or Advisory Role: Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, IDEAYA Biosciences, Sanofi, Merck Serono, Regeneron, QBiotics, Nektar, Eisai, OncoSec Douglas B. JohnsonConsulting or Advisory Role: Bristol Myers Squibb, Merck, Novartis, Janssen, Iovance Biotherapeutics, Catalyst Pharmaceuticals, Oncosec, Pfizer, Mosaic ImmunoEngineering, TargovaxResearch Funding: Incyte, Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Intellectual property and patents pending surrounding use of MHC-II and response to immune therapy Georgina V. LongHonoraria: BMS, Pierre FabreConsulting or Advisory Role: Aduro Biotech, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Hexal, Highlight Therapeutics, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, QBiotics, Regeneron, SkylineDx, Specialised Therapeutics, Array BioPharma, Evaxion Biotech A/S, Evaxion Biotech A/S, SkylineDX B.V Alexander M. MenziesConsulting or Advisory Role: MSD Oncology, Novartis, Pierre Fabre, Bristol Myers Squibb, Roche, QBioticsNo other potential conflicts of interest were reported.

Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman's rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0-35.4) months, the rwPFS was 3.9 months (95%CI 3.5-4.9), the rwTtNT was 10.7 months (95%CI 9.0-12.9), and the rwToT was 6.2 months (95%CI 5.1-6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints.

Introduction: Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown., Methods: Patients with metastatic melanoma treated with chemotherapy after progression on immunotherapy with checkpoint inhibitors were identified retrospectively from 24 melanoma centres. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety were examined., Results: In total, 463 patients were treated between 2007 and 2017. Fifty-six per cent had received PD-1-based therapy before chemotherapy. Chemotherapy regimens included carboplatin + paclitaxel (32%), dacarbazine (25%), temozolomide (15%), taxanes (9%, nab-paclitaxel 4%), fotemustine (6%) and others (13%). Median duration of therapy was 7.9 weeks (0-108). Responses included 0.4% complete response (CR), 12% partial response (PR), 21% stable disease (SD) and 67% progressive disease (PD). Median PFS was 2.6 months (2.2, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3), respectively. Twelve-month PFS was 12% (95% CI 2-15%). In patients who had received anti-PD-1 before chemotherapy, the ORR was 11%, and median PFS was 2.5 months (2.1, 2.8). The highest activity was achieved with single-agent taxanes (N = 40), with ORR 25% and median PFS 3.9 months (2.1, 6.2). Median OS from chemotherapy start was 7.1 months (6.5, 8.0). Subsequent treatment with checkpoint inhibitors achieved a response rate of 16% with a median PFS of 19.1 months (2.0-43.1 months). No unexpected toxicities were observed., Conclusion: Chemotherapy has a low response rate and short PFS in patients with metastatic melanoma who have failed checkpoint inhibitor therapy, although activity varied between regimens. Chemotherapy has a limited role in the management of metastatic melanoma., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SMG has past advisory board relationships and travel grant support from MSD, BMS, Novartis and Roche. She received research time support from the University of Zurich and medAlumni. KBB received travel grant support from Novartis and honoraria from MSD. SL has no conflicts of interest to declare. AF has occasional advisory board relationships with Novartis, Roche, MSD and receives travel grant support from Novartis, Roche, BMS. MM has no conflicts of interest to declare. LZ served as a consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sun Pharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sun Pharma, Sanofi and Novartis, outside the submitted work. CK declares travel support from Roche. RD has intermittent advisory board relationships and receives honoraria from Roche, Novartis, BMS, MSD, Amgen, Takeda, Pierre Fabre and Sun Pharma. He receives research funding from Roche, BMS, Novartis, MSD and Amgen. ZE on prior advisory boards for Pfizer, Novartis, Genentech, Regeneron, Array, Eisai, OncoSec, Signatura, Sun Pharma; Research funding from Novartis and Pfizer. EB: Consulting as an advisory board member for Nektar and BMS. Clinical trial support from Lilly, Novartis, Partners therapeutics, Genentech and BVD. PA has advisory board relationships with BMS, Roche-Genentech, MSD, Array, Novartis, Amgen, Merck Serono, Pierre-Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, Sindax, Astra Zeneca and receives research funding from BMS, Roche, Genentech, Array. RG: Research support (to institution): Pfizer, Johnson & Johnson, Novartis, SUN, Amgen, Sanofi, Merck-Serono. Honoraria for lectures (personally): Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, SUN, Pierre-Fabre, Sanofi. Honoraria for advisory boards: Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, 4SC, SUN, Merck-Serono and Sanofi. EAR has no conflicts of interest to declare. CH has no conflicts of interest to declare. DBJ has advisory board relationships with Array Biopharma, BMS, Catalyst, Iovance, Jansen, Merck, Novartis and Oncosec and receives research funding from BMS and Incyte. AG: speaker's honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, GSK, Novartis, Merck, MSD Sharp & Dohme, Pfizer and Roche. PK has occasional advisory board relationships with BMS, Roche, Amgen, Novartis, MSD and receives travel grant support from BMS and MSD. NB has no conflicts of interest to declare. JVC has no conflicts of interest to declare. KCK 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. MAW has an advisory role for Array Biopharma. JC has served as a consultant and has received honoraria from Sanofi-Genzyme and Bristol-Myers Squibb. VA has advisory board role for BMS, MSD, Novartis, Roche, Pierre Fabre, Nektar, Q Biotics; speakers fees from BMS, MSD, Novartis, Pierre Fabre, Limbic and travel support from BMS. JLS: honoraria from Bristol-Myers Squibb, MSD and Pierre Fabre. OM has intermittent advisory board relationships and receives honoraria from Roche, Novartis, BMS, MSD, Amgen, Pierre Fabre. He receives research funding from Roche, BMS, Novartis, MSD and Amgen. GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V., Specialised Therapeutics Australia Pty Ltd. JCH has research support from BMS, advisory board relationship with Pierre Fabre, Sanofi, Sun Pharma and MSD; receives speakers honoraria from BMS, MSD, Novartis, Roche, Sanofi and Almirall and travel support from Pierre Fabre. BW receives research funding from BMS und MSD. LEH has no COI nor funding to disclose. DS: Dr. Schadendorf reports grants, personal fees and other from BMS, during the conduct of the study; personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from Novartis, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grants, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees from Sanofi/Regeneron, non-financial support from Merck, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, outside the submitted work. GM receives reimbursement of clinical trial costs to his institution from Roche-Genentech and Array Biopharma/Pfizer. PAO reports research funding from and has advised Neon Therapeutics, Bristol-Meyers Squibb, Merck, CytomX, Pfizer, Novartis, Celldex, Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences, Xencor, Oncorus and Roche/Genentech. CB has advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures; has research funding (incl IIS funding) from BMS, MSD, 4SC, Novartis, NanoString; and has stock ownership from Uniti Cars, co-founder Immagene BV. CR has occasional advisory board relationships and receives honoraria from BMS, MSD, GSK, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi. RJS reports grant support from Merck and Amgen, as well as personal fees for consulting/advisory board membership for AstraZeneca, Bristol-Myers Squibb, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, Replimune. AH reports grant support and personal fees from Amgen, BMS, Eisai, Immunocore, MerckPfizer, MSD/Merck, Novartis Pharma, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme and from SeaGen outside the submitted work. MSC: consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, OncoSec, Pierre-Fabre, QBiotics, Regeneron, Roche, Merck and Sanofi and received honoraria from BMS, MSD and Novartis. CG: Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted work. MAD: is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (1 P50 CA221703-02 and 1U54CA224070-03), the American Cancer Society and the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. He has been a consultant to Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai and ABM Therapeutics, and he has been the PI of research grants to MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. AMM: Advisory board fees from BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups ( p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1-23.8) versus 9.4 months (cohort B, 95% CI: 6.1-14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.

Background: Around 50% of cutaneous melanomas harbour therapeutically targetable BRAF V600 mutations. Reliable clinical biomarkers predicting duration of response to BRAF-targeted therapies are still lacking. Recent in vitro studies demonstrated that BRAF-MEK inhibitor therapy response is associated with tumour TERT promoter mutation status. We assessed this potential association in a clinical setting., Methods: The study cohort comprised 232 patients with metastatic or unresectable BRAF V600-mutated melanoma receiving combined BRAF/MEK inhibitor treatment, including a single-centre retrospective discovery cohort (N = 120) and a prospectively collected multicenter validation cohort (N = 112). Patients were excluded if they received BRAF or MEK inhibitors in an adjuvant setting, as monotherapy, or in combination with immunotherapy. Kaplan-Meier and univariate/multivariate Cox regression analyses were performed as appropriate., Results: median age at first diagnosis was 54 years (range 16-84 years). The majority of patients were men 147/232 (63.4%). Most tumours harboured TERT promoter mutations (72%, N = 167). A survival advantage was observed in both progression-free survival (PFS) and overall survival (OS) for patients with TERT promoter-mutant versus wild-type tumours in both the discovery cohort (mPFS of 9.6 months [N = 87] vs 5.0 months [N = 33]; hazard ratio [HR] = 0.56 [95% confidence interval {CI} 0.33-0.96] and mOS of 33.6 months vs 15.0 months; HR = 0.47 [95%CI 0.32-0.70]) as well as the validation cohort (mPFS of 7.3 months [N = 80] vs 5.8 months [N = 32]; HR = 0.67 [95%CI 0.41-1.10] and mOS of 51.1 months vs 15.0 months; HR = 0.33 [95%CI 0.18-0.63]). In the pooled cohort of TERT promoter-mutant (N = 167) versus wild-type (N = 65) tumours, respectively, PFS was 8.9 versus 5.5 months, (HR = 0.62; 95%CI 0.45-0.87; P = 0.004), and OS was 33.6 versus 17.0 months, (HR = 0.51; 95%CI 0.35-0.75, P = 0.0001)., Conclusions: In patients with melanoma receiving BRAF/MEK-targeted therapies, TERT promoter mutations are associated with longer survival. If validated in larger studies, TERT promoter mutation status should be included as a predictive biomarker in treatment algorithms for advanced melanoma., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.M.T. reported no relevant conflicts of interest. J.M. declares travel support from Bristol Myers Squibb, Novartis and Sun Pharmaceutical Industries, outside the submitted work. A.Z. declares travel support from Novartis, Sanofi Genzyme and Bristol-Myers Squibb, outside the submitted work. R.M. reported no relevant conflicts of interest. E.C. reported no relevant conflicts of interest. G.L. declares travel support from Sun Pharma, outside the submitted work. P.J. reported no relevant conflicts of interest. R.H. declares speakers and advisory board honoraria from BMS, MSD, Novartis, Pierre Fabre, Roche and SUN-Pharma, outside the submitted work. P.T. declares honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin and Biofrontera; travel support from Bristol-Myers Squibb and Pierre-Fabre, outside the submitted work. J.U. declares advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche and Sanofi, outside the submitted work. C.P. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Sun Pharma, Pierre Fabre, AbbVie, Kyona Kirin and Amgen and received travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sun Pharma and Novartis, outside the submitted work. J.Ul declares travel support: Medac, Sun Pharma; consulting: Bristol-Myers Squibb, Sun Pharma; lectures: Bristol-Myers Squibb, MSD, Merck, Novartis, Roche, Sanofi, Sun Pharma; grants: Novartis, outside the submitted work. A.K. reported no relevant conflicts of interest. P.M. declares research support (to institution): Bristol-Myers Squibb, Novartis, MSD. Honoraria for lectures (personally): Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, Pierre-Fabre, Sanofi. Honoraria for advisory boards: Bayersdorf, Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, SUN, Merck-Serono, Sanofi, outside the submitted work. R.G. invited speaker: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Advisory board: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, Merck Serono, Pfizer, Immunocore. Research grants: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi. Travel/meeting support: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre, outside the submitted work. F.M. declares travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche, outside the submitted work. E.D. reported no relevant conflicts of interest. M.W. reported no relevant conflicts of interest. J.K. reported no relevant conflicts of interest. I.M. reported no relevant conflicts of interest. A.S. reported no relevant conflicts of interest. A.P. reported no relevant conflicts of interest. E.L. served as a consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sun Pharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sun Pharma and Novartis, outside the submitted work. L.Z. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sun Pharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sanofi, Sun Pharma and Novartis, outside the submitted work.E.H. reported no relevant conflicts of interest. 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, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme, outside the submitted work. D.S. reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sun Pharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. K.G.: No relevant conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Immunogenicity of SARS-CoV-2 vaccines is modestly impaired in cancer patients due to a generally weakened immune system. Immune checkpoint inhibitors (ICI) are expected to enhance immune response. This has already been described to be the case in influenza vaccines, and first data about COVID-19 vaccines show a trend in this direction., Aim: We aimed to investigate the immune response of patients with melanoma under ICI therapy after COVID-19 vaccination., Patients and Methods: In the Skin Cancer Center Hanover (Germany), we recruited 60 patients with advanced melanoma who either received ICI therapy during or before the vaccination period. Serological blood analysis was performed using quantitative ELISA for Anti-SARS-CoV-2 spike protein 1 IgG antibodies., Results: We did not observe an enhanced humoral immune response in patients under active or past ICI therapy after COVID-19 vaccination. Nevertheless, there is a tendency of higher antibody levels when ICI therapy was received within the last 6 months before vaccination. Subgroup analysis revealed that patients in our study population under ongoing targeted therapy during vaccination period had significantly higher median antibody levels than patients without any active antitumor treatment., Conclusion: Melanoma patients under ICI therapy show comparable antibody response after SARS-CoV-2 vaccination to healthy health care professionals. This finding is independent of the timing of ICI therapy., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Based on its viral-associated or UV-associated carcinogenesis, Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Thus, clinically evident MCC occurs either in immuno-compromised patients or based on tumor-intrinsic immune escape mechanisms. This notion may explain that although advanced MCC can be effectively restrained by treatment with PD-1/PD-L1 immune checkpoint inhibitors (ICIs), a considerable percentage of patients does not benefit from ICI therapy. Biomarkers predicting ICI treatment response are currently not available., Methods: The present multicenter retrospective study investigated clinical and molecular characteristics in 114 patients with unresectable MCC at baseline before treatment with ICI for their association with therapy response (best overall response, BOR). In a subset of 21 patients, pretreatment tumor tissue was analyzed for activation, differentiation and spatial distribution of tumor infiltrating lymphocytes (TIL)., Results: Of the 114 patients, n=74 (65%) achieved disease control (BOR=complete response/partial response/stable disease) on ICI. A Bayesian cumulative ordinal regression model revealed absence of immunosuppression and a limited number of tumor-involved organ systems was highly associated with a favorable therapy response. Unimpaired overall performance status, high age, normal serum lactate dehydrogenase and normal serum C reactive protein were moderately associated with disease control. While neither tumor Merkel cell polyomavirus nor tumor PD-L1 status showed a correlation with therapy response, treatment with anti-PD-1 antibodies was associated with a higher probability of disease control than treatment with anti-PD-L1 antibodies. Multiplexed immunohistochemistry demonstrated the predominance of CD8 + effector and central memory T cells (T CM ) in close proximity to tumor cells in patients with a favorable therapy response., Conclusions: Our findings indicate the absence of immunosuppression, a limited number of tumor-affected organs, and a predominance of CD8 + T CM among TIL, as baseline parameters associated with a favorable response to PD-1/PD-L1 ICI therapy of advanced MCC. These factors should be considered when making treatment decisions in MCC patients., Competing Interests: Competing interests: SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme. LZ 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: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, and Novartis, outside the submitted work. PT declares invited speaker's honoraria from Bristol-Myers Squibb, Novartis, MSD, Pierre-Fabre, CureVac, Roche, Kyowa Kirin, Biofrontera, advisory board honoraria from Bristol-Myers Squibb, Novartis, Pierre-Fabre, Merck Serono, Sanofi, Roche, Kyowa Kirin, and travel support from Bristol-Myers Squibb, and Pierre-Fabre. UL declares advisory board honoraria from MSD, Roche, Sanofi, Novartis, Sun Pharma, Almirall Hermal. TE declares consulting fees from BMS, Novartis, Roche, Pierre Fabre, Sanofi; board membership and payment for lectures in speakers bureau from Pierre Fabre, MSD, Roche, BMS, Novartis and Sanofi. CL reports advisory board honoraria from MSD, BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Kyowa Kirin, Almiral Hermal, Biontech, Merc; speakers fee from MSD, BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Merck; travel reimbusment from MSD, BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Kyowa Kirin, Almiral Hermal, Biontech and Merck. JCH declares research support from Bristol Myers Squibb; advisory board honoraria from Pierre Fabre, Sanofi, Sun Pharma and Merck Sharp & Dome; speakers honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Sanofi and Almirall and travel support from Pierre Fabre. TG reports receiving speakers and/or advisory board honoraria from BMS, Sanofi-Grenzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen Lilly, Pfizer, Pierre Fabre; speakers and/or advisory board honoraria from BMS, Sanofi-Grenzyme, MSD, Novartis, Pharma, Roche, Abbvie, Almirall, Janssen Lillly, Pfizer, Pierre Fabre. SH declares advisory boards honoraria from Pierre Fabre, MSD, BMS, Novartis, Sanofi. PM reports board membership and payment for lectures in speakers bureau from Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi. P. Mohr reports research support (to institution): Bristol-MyersSquibb, Novartis, MSD. Honoraria for lectures (personally): Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi, Amgen, SUN-Pharma, Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, Pierre-Fabre, Sanofi. Honoraria for advisory boards: Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi, Beiersdorf, Almiral-Hermal, AmgenBayersdorf, Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, SUN-Pharma, SUN, Merck-Serono, Sanofi. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, AMGEN, SUNPHARMA, Allergy Therapeutics and LEO. LMH served as consultant and/or has received honoraria from Amgen, BMS, Curevac, MSD, Novartis, Pierre-Fabre, Roche, Sanofi and Sun Pharma, outside the submitted work. Research funding to institution: Novartis. R. Gutzmer reports research support from Pfizer, Johnson & Johnson, Novartis, Amgen, MerckSerono, SUN Pharma; honoraria for lectures from Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, SUN, Pierre-Fabre, Sanofi, SUN Pharma, Bayer; honoraria for advice from Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, 4SC, Incyte, SUN Pharma, Sanofi, Pfizer. JSU is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. H-US is an employee of Targos Molecular Pathology Inc. and reports research support from Novartis Oncology and received honoraria from MSD, BMS, Roche Pharma, Novartis Oncology, AstraZeneca, Eisai, Takeda, Molecular Health, outside of the submitted work. DS reports personal fees from Amgen, GSK, BMS, Novartis, Roche, Merck, Astra Zeneca, Merck-Serono, Pfizer, Incyte, Array Pierre Fabre, Sanofi Genzyme, Regeneron, 4Sc, InFlaRx, Neracare, Ultimovacs, SunPharma, Philogen, Immunocore, Sandoz-Hexal outside the submitted work. JCB is receiving speaker's bureau honoraria from Amgen, Pfizer, MerckSerono, Recordati and Sanofi; is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group receives research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: NF1-mutated tumours represent a small subset (10-15%) of melanomas, not sufficiently analysed in large clinical cohorts. This study investigated the largest multicentre collection of NF1-mutated melanomas to date., Methods: This study analysed a multicentre tumour tissue sample cohort from 266 patients with NF1-mutated melanoma. Targeted next-generation sequencing of the TERT promoter and 29 relevant melanoma genes was performed. Survival was compared with NF1 wild-type cohorts from the Tissue Registry in Melanoma project (n = 432)., Results: Most NF1-mutated melanoma arose in the head-and-neck region of patients >60 years. NF1 alterations were frequently inactivating, primarily non-sense, less frequently truncating mutations. Non-inactivating NF1 mutations more frequently co-occurred with activating BRAF and RAS mutations. NF1-mutated tumours had higher numbers of gene mutations and UV signature C>T and CC>TT transitions than BRAF, RAS and triple wild-type melanomas. NF1-mutated acral and mucosal melanomas harboured a different mutation signature and were frequent in women (69% and 83%, respectively), differing from non-acral cutaneous NF1-mutated melanomas (men 73%, women 27%). Overall survival in stage IV disease was comparable for patients with NF1-mutated or wild-type melanoma. However, in patients receiving first-line immune checkpoint inhibitor treatment, better median overall survival (mOS) was observed for NF1-mutated than wild-type tumours (mOS = not reached vs mOS = 25.82, p = 0.0154, n = 80 and 432, respectively)., Conclusions: Cutaneous, acral and mucosal NF1-mutated melanomas vary in clinical and genetic characteristics and demonstrate a favourable outcome on immune checkpoint inhibition therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The BOLT study for sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received sonidegib 200 mg once daily., Methods: This phase 2, double-blind study randomized patients 1:2 to sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria., Results: Per mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3-68.3%) and 71.2% (58.7-81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]). Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8-72.4%) and 74.2% (62.0-84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE)., Conclusions: Overall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria., Trial Registration: BOLT registration: ClinicalTrials.gov ( NCT01327053 ) on March 30, 2011., (© 2021. The Author(s).)

The chemokine CCL18 is produced in cells of the myelomonocytic lineage and represents one of the most highly expressed chemokines in lesional skin and serum of atopic dermatitis patients. We investigated the role of histamine in CCL18 production in human monocyte-derived M2 macrophages differentiated in the presence of M-CSF and activated with IL-4, IL-13 or with IL-10. Since expression and regulation of histamine H1 receptor (H1R), H2R and H4R by IL-4 and IL-13 on human M2 macrophages were described, we analyzed expression of the histamine receptors in response to IL-10 stimulation by quantitative RT-PCR. IL-10 upregulated H2R and downregulated H4R mRNA expression by trend in M2 macrophages. IL-10, but in a more pronounced manner, IL-4 and IL-13, also upregulated CCL18. Histamine increased the cytokine-induced upregulation of CCL18 mRNA expression by stimulating the H2R. This effect was stronger in IL-10-stimulated M2 macrophages where the upregulation of CCL18 was confirmed at the protein level by ELISA using selective histamine receptor agonist and antagonists. The histamine-induced CCL18 upregulation in IL-10-activated M2 macrophages was almost similar in cells obtained from atopic dermatitis patients compared to cells from healthy control persons. In summary, our data stress a new function of histamine showing upregulation of the Th2 cells attracting chemokine CCL18 in human, activated M2 macrophages. This may have an impact on the course of atopic dermatitis and for the development of new therapeutic interventions.

Introduction: Immune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia., Methods: This multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, treatment, and outcomes of melanoma patients with grade 4 neutropenia (<500 neutrophils/µl blood) treated with ICI between 2014 and 2020. Some of these patients received metamizole in addition to ICI (ICI+/met+). Bone marrow biopsies (BMB) of these patients were compared to BMB from non-ICI treated patients with metamizole-induced grade 4 neutropenia (ICI-/met+)., Results: In total, 10 patients (median age at neutropenia onset: 66 years; seven men) with neutropenia were identified, equating to an incidence of 0.14%. Median onset of neutropenia was 6.4 weeks after starting ICI (range 1.4-49.1 weeks). Six patients showed inflammatory symptoms, including fever (n=3), erysipelas (n=1), pharyngeal abscess (n=1), and mucositis (n=1). Neutropenia was diagnosed in all patients by a differential blood count and additionally performed procedures including BMB (n=5). Nine of 10 patients received granulocyte colony-stimulating factors (G-CSF) to treat their grade 4 neutropenia. Four patients received systemic steroids (including two in combination with G-CSF, and one in combination with G-CSF and additional ciclosporin A). Four patients were treated with one or more antibiotic treatment lines, two with antimycotic treatment, and one with additional antiviral therapy. Five patients received metamizole concomitantly with ICI. One fatal outcome was reported. BMB indicated a numerically lower CD4+ to CD8+ T cells ratio in patients with irNeutropenia than in those with metamizole-induced neutropenia., Conclusion: Grade 4 neutropenia is a rare but potentially life-threatening side effect of ICI treatment. Most cases were sufficiently managed using G-CSF; however, adequate empiric antibiotic, antiviral, and antimycotic treatments should be administered if neutropenic infections are suspected. Immunosuppression using corticosteroids may be considered after other causes of neutropenia have been excluded., Competing Interests: AZ received travel support from Novartis, Sanofi Genzyme, and Bristol-Myers Squibb, outside the submitted work. RK has received speaker fees by NG-Akademie GmbH and Hollister Incorporated, outside the submitted work. MS is an honoraria and/or travel grants from Abbvie, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pfizer and Sanofi-Aventis. AG: Speaker´s honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, GSK, Novartis, Merck, MSD Sharp & Dohme, Pfizer and Roche. BB received speaker fees for BMS, MSD, Novartis. Travel accomodation: BMS, Pierre Fabre. MS is an honoria for advisory board for Sanofi/Regneron and speaker fees für Novartis Pharma AG. GM has received speaker fees from PharmaMar, outside the submitted work. DJ received advisory board honoraria from BMS, Catalyst, Iovance, Jansen, Merck, Novartis, Oncosec, and Pfizer, and research funding from BMS and Incyte. LS is an honoraria for advisory boards & speaker fees from BMS. CaL received Advisory board: Roche, Novartis, BMS, MSD, SunPharma, Biontech, Kyowa Kirin, Sanofi, Pierre Fabre, Merck; Speakers fee: Roche, Novartis, BMS, MSD, SunPharma, Biontech, Kyowa Kirin, Sanofi, Pierre Fabre, Merck; Travel reimbursement: Roche, Novartis, BMS, MSD, SunPharma, Biontech, Kyowa Kirin, Sanofi, Pierre Fabre, Merck. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, Pierre Fabre, SUNPHARMA and LEO. GL is a consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Evaxion Biotech A/S, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V., Specialised Therapeutics Australia Pty Ltd. AM is an honoraria for advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. MC is a consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck and Sanofi, and received honoraria from BMS, MSD, and Novartis. CeL received Honoraria: Roche; BMS; Novartis; Amgen; MSD; Pierre Fabre; Pfizer; Incyte; Consulting or Advisory Role: BMS; MSD; Novartis; Amgen; Roche; Merck Serono; Sanofi; Pierre Fabre; Speakers’ Bureau: Roche; BMS; Novartis; Amgen; MSD; Research Funding: Roche; BMS; Travel, Accommodations, Expenses: BMS; MSD; Novartis; Sanofi; Pierre Fabre; Other Relationship: Avantis Medical Systems (board). MT received grants and personal fees from MSD, Ono Pharmaceutical, BMS, Bayer, Eisai, Novartis, Pfizer, Rakuten Medical, Merck Biopharma, personal fees from LOXO, Celgene, Amgen, outside the submitted work. PB received research funding from BeiGene, BMS, MSD and Takeda; advisory board honoraria from Takeda; speakers honoraria from BMS and travel support from Celgene, all outside the submitted work. TEi received speaker fees from Novartis, Pierre Fabre, MSD, Sanofi Genzyme, Alirall Hermal and Bristol-Myers Squibb, outside the submitted work. KK 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. RG: Invited speaker: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Advisory board: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, MerckSerono, Pfizer, Immunocore. Research grants: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi. Travel/meeting support: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre, outside the submitted work. CB received advisory board honoraria and/or speaker´s fees from Amgen, BMS, Immunocore, Merck, MSD, Novartis, Pierre Fabre, Regeneron, Roche, and Sanofi-Aventis. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. JB is receiving speaker’s bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group receives research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis. EL served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Pierre Fabre, Sanofi, Sunpharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. JH received research support from BMS; advisory board honoraria from Pierre Fabre, Sanofi, Sun Pharma and MSD; speakers honoraria from GSK, Amgen, BMS, MSD, Novartis, Roche, Sanofi and Almirall and travel support from Pierre Fabre and 4SC. DS reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from SunPharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. LH reports Consultancy, speaker fees, travel grants or research funding: BMS, MSD, Merck, Roche, Amgen, Curevac, Novartis, Sanofi, Pierre Fabre. Clinical studies: BMS, MSD, Merck, Roche, Amgen, GSK, Curevac and Novartis. LZ reports being a consultant and/or receiving honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; research funding to institution from Novartis; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zaremba, Kramer, De Temple, Bertram, Salzmann, Gesierich, Reinhardt, Baroudjian, Sachse, Mechtersheimer, Johnson, Weppler, Spain, Loquai, Dudda, Pföhler, Hepner, Long, Menzies, Carlino, Lebbé, Enokida, Tahara, Bröckelmann, Eigentler, Kähler, Gutzmer, Berking, Ugurel, Stadtler, Sucker, Becker, Livingstone, Meier, Hassel, Schadendorf, Hanoun, Heinzerling and Zimmer.)

Background: Organ transplant recipients show a high incidence for the formation of cutaneous squamous cell carcinoma (cSCC), while sirolimus appears to reduce the risk. GRO-α is a chemokine, which is overexpressed in many tumor entities and associated with malignant transformation. However, little is known about the expression and function of GRO-α in human cSCC., Objective: Our aim was to investigate the relevance of the GRO-α (CXCL-1)/ CXCR2 axis in human cSCC and the potential impact of sirolimus., Methods: We analyzed the GRO-α expression in human keratinocytes, different cSCC cell lines as well as cSCC tissue and investigated its effect on cell proliferation and migration. Additionally, we incubated cells with sirolimus and measured the expression of GRO-α and its receptor CXCR2., Results: We showed that both constitutive as well as induced GRO-α expression is higher in in cSCC cell lines compared to keratinocytes and that GRO-α protein is detectable in human cSCC tissue. By GRO-α exposure and shRNA knock down, we identified GRO-α as a driving factor in proliferation and migration. Moreover, in a dermis equivalent GRO-α knocked down cSCC cell lines displayed a reduced capacity in tumor nest formation. Incubation with sirolimus significantly inhibited GRO-α expression in keratinocytes as well as tumor cell lines. Moreover, sirolimus decreased the expression of the corresponding receptor CXCR2., Conclusion: Taken together, our results suggest that the GRO-α/CXCR2 axis plays a role in human keratinocyte carcinogenesis and might represent a molecular mechanism for the preventive effect of mTOR inhibitors in cSCC development., Competing Interests: Declaration of Competing Interest Katrin Schaper-Gerhardt received research grant from Pfizer. Imke Satzger has received payments for serving on scientific advisory boards for Roche and Bristol-Myers Squibb, and grant support from Roche, Pfizer, and Novartis. Ralf Gutzmer served as consultant for BristolMyers Squibb, Roche Pharma, MerckSharpDohme, Novartis, GlaxoSmithKline, Amgen, Almirall Hermal, LEO, Pfizer, Incyte, Pierre-Fabre, Sun Pharma. Ralf Gutzmer received honoraria for lectures from BristolMyers Squibb, Roche Pharma, MerckSharpDohme, Novartis, Amgen, Merck Serono, Almirall-Hermal, Pierre-Fabre, Sanofi, SUN Pharma, Bayer. Ralf Gutzmer received travel support from BristolMyers Squibb, Merck Serono, SUN Pharma, Roche Pharma. Ralf Gutzmer received research grants from Pfizer, Novartis, Johnson&Johnson, Sanofi, Merck Serono, Amgen, SUN Pharma. The other authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in the USA, EU, Switzerland, and Australia and metastatic basal cell carcinoma (mBCC) in Switzerland and Australia in patients not amenable to surgery or radiotherapy. Vismodegib is approved to treat patients with mBCC, recurrent laBCC, or those not candidates for surgery or radiation. There is no head-to-head trial comparing Hedgehog inhibitors. We describe time to onset and severity of adverse events (AEs) in two studies reporting cumulative AE incidence every treatment cycle: the sonidegib phase 2 BOLT study and the expanded-access, open-label vismodegib study., Methods: This analysis included patients with histologically confirmed laBCC or mBCC from BOLT who received sonidegib 200 mg once daily (QD) and patients from the vismodegib study who received vismodegib 150 mg QD. Cumulative occurrence of AEs and median time to AE onset were calculated on 30-day cycles for sonidegib and 28-day cycles for vismodegib. AEs were graded for severity using the Common Terminology Criteria for Adverse Events. Only common (at least 15% incidence) AEs were analyzed in this study., Results: Over 18 treatment cycles, the most common all-grade AEs for sonidegib and vismodegib were muscle spasm (54.4% vs 70.6%; P = 0.0236), alopecia (49.4% vs 58.0%; no significant difference [NS]), and dysgeusia (43.0% vs 70.6%; P = 0.0003); incidences of diarrhea, nausea, fatigue, and weight decrease were 31.6% vs 25.2% (NS), 39.2% vs 19.3% (P = 0.0032), 32.9% vs 19.3% (P = 0.0429), and 30.4% vs 16.0% (P = 0.0217), respectively. Sonidegib-treated patients had more delayed median time to onset for all AEs than vismodegib-treated patients, except fatigue and weight decrease (NS). Most AEs reported were grade ≤ 2., Conclusion: This post hoc analysis suggests lower overall incidence and slower onset of certain AEs in patients treated with sonidegib compared with vismodegib. In the absence of head-to-head comparisons, the relevance of these findings needs further studies to provide conclusive evidence., (© 2021. The Author(s).)

Background: PD-1-based immune checkpoint blockade (ICB) is a highly effective therapy in metastatic melanoma. However, 40-60% of patients are primarily resistant, with valid predictive biomarkers currently missing. This study investigated the digitally quantified tumor PD-L1 expression for ICB therapy outcome prediction., Patients and Methods: Tumor tissues taken prior to PD-1-based ICB for unresectable metastatic disease were collected within the prospective multicenter Tissue Registry in Melanoma (TRIM). PD-L1 expression (clone 28-8; cut-off=5%) was determined by digital and physician quantification, and correlated with therapy outcome (best overall response, BOR; progression-free survival, PFS; overall survival, OS)., Results: Tissue samples from 156 patients were analyzed (anti-PD-1, n=115; anti-CTLA-4+anti-PD-1, n=41). Patients with PD-L1-positive tumors showed an improved response compared to patients with PD-L1-negative tumors, by digital (BOR 50.5% versus 32.2%; p=0.026) and physician (BOR 54.2% versus 36.6%; p=0.032) quantification. Tumor PD-L1 positivity was associated with a prolonged PFS and OS by either digital (PFS, 9.9 versus 4.6 months, p=0.021; OS, not reached versus 13.0 months, p=0.001) or physician (PFS, 10.6 versus 5.6 months, p=0.051; OS, not reached versus 15.6 months, p=0.011) quantification. Multivariable Cox regression revealed digital (PFS, HR=0.57, p=0.007; OS, HR=0.44, p=0.001) and physician (OS, HR=0.54, p=0.016) PD-L1 quantification as independent predictors of survival upon PD-1-based ICB. The combination of both methods identified a patient subgroup with particularly favorable therapy outcome (PFS, HR=0.53, p=0.011; OS, HR=0.47, p=0.008)., Conclusion: Pre-treatment tumor PD-L1 positivity predicted a favorable outcome of PD-1-based ICB in melanoma. Herein, digital quantification was not inferior to physician quantification, and should be further validated for clinical use., Competing Interests: J-MP served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis and received travel support from Bristol-Myers Squibb, Novartis and Therakos. PT declares Invited Speaker´s honoraria from Bristol-Myers Squibb, Novartis, MSD, Pierre-Fabre, CureVac, Roche, Kyowa Kirin, Biofrontera, Advisory Board honoraria from Bristol-Myers Squibb, Novartis, Pierre-Fabre, Merck Serono, Sanofi, Roche, Kyowa Kirin, and Travel support from Bristol-Myers Squibb, and Pierre-Fabre. JoU is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. ClP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, AMGEN, SUNPHARMA, Allergy Therapeutics and LEO. LZ 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: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, and Novartis, outside the submitted work. EL served as consultant and/or has received honoraria from Amgen, Actelion, Roche, Bris-tol-Myers Squibb, Merck Sharp & Dohme, Novartis, Janssen, Medac, Sanofi, Sunpharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. JB is receiving speaker’s bureau honoraria from Amgen, Pfizer, MerckSerono, Recordati and Sanofi, is a paid consultant/advisory board member/DSMB member for 4SC, Almirall, Boehringer Ingelheim, ICON, InProTher, MerckSerono, Pfizer, and Sanofi/Regeneron. His group receives research grants from Merck Serono, HTG, IQVIA, and Alcedis. GL has received travel support from Sun Pharma. AR reported grants from Novartis, Bristol Myers Squibb, and Adtec; personal fees from Merck Sharp & Dohme; and nonfinancial support from Amgen, Roche, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, and Teva. DS 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. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Bristol Myers Squibb. The funder had the following involvement with the study: Financing of test material., (Copyright © 2021 Placke, Soun, Bottek, Herbst, Terheyden, Utikal, Pföhler, Ulrich, Kreuter, Pfeiffer, Mohr, Gutzmer, Meier, Dippel, Weichenthal, Zimmer, Livingstone, Becker, Lodde, Sucker, Griewank, Horn, Hadaschik, Roesch, Schadendorf, Engel and Ugurel.)

Background: Basal cell carcinoma (BCC) can arise by the uncontrolled proliferation of cells from multiple epidermal compartments due to aberrant activation of the Hedgehog (Hh) signalling pathway. Vismodegib, a small-molecule inhibitor of this pathway, is approved for treatment of patients with locally advanced (la) BCC inappropriate for surgery or radiotherapy or patients with symptomatic metastatic (m) BCC., Objectives: The aim of this non-interventional study was to assess effectiveness with a special focus on duration of response (DOR), safety and utilization of vismodegib for treatment of laBCC in daily practice in Germany., Methods: This non-interventional study (NIS) observed treatment of laBCC with vismodegib according to the German label in clinical practice. All available patients who had received at least one dose of vismodegib between commercial availability of vismodegib in Germany (02 August 2013) and 3 years before end of study (31 March 2016) could be included and were documented retrospectively and/or prospectively for up to 3 years. Primary effectiveness variable was DOR. Assessment of tumour response was carried out by the treating physicians. Exploratory variables included utilization of vismodegib, decision makers for therapy and method of tumour response evaluation. All statistical analyses were descriptive., Results: Between September 2015 and March 2019, 66 patients were observed at 26 German centres. The objective response rate (ORR) was 74.2% and the disease control rate (DCR) was 90.9%. The median DOR was 15.9 months (95% CI: 9.2; 25.7; n = 49 patients with response). The median progression-free survival (PFS) was 19.1 months and the median time to response (TTR) 2.7 months. A total of 340 adverse events were reported in 63 (95.5%) patients; no new safety signals were identified., Conclusions: The NIS NIELS shows effectiveness and safety of vismodegib in patients with laBCC. It confirms the transferability of the results of the pivotal trial into routine clinical practice., (© 2021 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB., Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan-Meier method. Log-rank tests, χ 2 tests, and t-tests were performed to detect significant differences between both cohorts., Results: The median OS of the overall population was 16 months (95% CI 13.4-23.7) and the median PFS, 2.8 months (95% CI 2.5-3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts., Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.

Background: In COLUMBUS, treatment with encorafenib plus binimetinib in patients with advanced BRAF-mutant melanoma showed improved progression-free and overall survival with favourable tolerability compared to vemurafenib treatment. Here, results on health-related quality of life (HRQoL) are presented., Methods: COLUMBUS was a two-part, open-label, randomised, phase III study in patients with BRAF-mutant melanoma. In PART-I, 577 patients were randomised (1:1:1) to encorafenib plus binimetinib, encorafenib or vemurafenib. The primary objective was to assess progression-free survival. As a secondary objective, HRQoL was assessed by the EQ-5D, the EORTC QLQ-C30 and the FACT-M questionnaires. Furthermore, time to definitive 10% deterioration was estimated with a Kaplan-Meier analysis and differences in mean scores between groups were calculated with a mixed-effect model for repeated measures. Hospitalisation rate and the impact of hospitalisation on HRQoL were also assessed., Results: Patients receiving the combination treatment showed improvement of their FACT-M and EORTC QLQ-C30 global health status scores, compared to those receiving vemurafenib (post-baseline score differences: 3.03 [p < 0.0001] for FACT M and 5.28 [p = 0.0042] for EORTC QLQ-C30), indicative of a meaningful change in patient's status. Furthermore, a delay in the deterioration of QoL was observed in non-hospitalised patients compared to hospitalised patients (hazard ratio [95% CI]: 1.16 [0.80; 1.68] for EORTC QLQ-C30 and 1.27 [0.81; 1.99] for FACT-M) and a risk reduction of 10% deterioration, favoured the combination in both groups., Conclusion: The improved efficacy of encorafenib plus binimetinib compared to vemurafenib, translates into a positive impact on the perceived health status as assessed by the HRQoL questionnaires. The study is registered with ClinicalTrials.gov, number NCT01909453 and EudraCT number 2013-001176-38., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients., Methods: In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately., Results: Median follow-up time was 30.5 (range 0.8-154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40-0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45-1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%., Conclusion: Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.Z.: received travel support from Novartis, Sanofi Genzyme, and Bristol Myers Squibb, outside the submitted work. M.P.: No relevant conflicts of interest. J.C.H.: received honoraria from talks: BMS, MSD, Roche, Novartis, Sun Pharma, Almirall, Sanofi, honoraria from adboards: Sun Pharma, Sanofi, Pierre Fabre, scientific grant: BMS. V.G.: received honoraria from Bristol Myers Squibb (BMS) and reports travel support from Novartis, Pierre Fabre Pharmaceuticals, BMS, Merck Sharp & Dohme (MSD), Sanofi Genzyme and SUN Pharmaceutical Industries outside the submitted work. Z.F.: No relevant conflicts of interest. C.L.: served as consult and and/or has received honoraria and or received travel support from Roche, Novartis, Pierre Fabre, MDS, Merck, BMS, Sanofi, Sun Pharma, Biontech, Kyowa Kirin, Almirall Hermal outside the submitted work. D. R.-S. has received honoraria for talks from Roche and Pierre Fabre and has received travel grants from Novartis, Pierre Fabre and Sanofi Genzyme. R. G.: received honoraria: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre Fabr; consultant or advisory role: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre Fabre, Merck Serono, Bayer, Pfizer; Funding: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck Serono, SUN Pharma, Sanofi; travel, accommodations, expenses: Roche, BMS, SUN, Merck Serono, Pierre Fabre. J. U. is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. Se.H.: served as consultant and/or has received honoraria from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Sun Pharma outside the submitted work. L.R.: No relevant conflicts of interest. K.C.K.: served as consultant and/or has received honoraria from Amgen, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sun Pharma and travel support from Amgen, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Sun pharma and Novartis, outside the submitted work. C.W.: served as consultant and/or has received honoraria from Amgen, Roche, Bristol Myers Squibb, Kyowa Kirin, Merck Sharp & Dohme, Novartis, Sanofi, Takeda and travel support from Amgen, Bristol Myers Squibb, Curevac, Pierre Fabre and Novartis, outside the submitted work. A.M.: has received speaker or consultant fees from AbbVie, Almirall, Novartis, Bristol Myers Squibb, Pfizer, and Roche, outside of the submitted work; A.M. is employed by Novartis; the work described in this publication was completed prior to his employment at Novartis. K. M.T.: served as consultant and/or has received honoraria from Bristol Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Sanofi, Sun Pharma, LEO, Galderma, and Candela and travel support from Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, and Candela, outside the submitted work. T.W.: received honoraria and travel support from Amgen, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, outside the submitted work. C.P.: received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, Sanofi ‘Genzyme, Sun Pharma, Amgen and LEO. A. R.: reports non-financial support from Amgen, non-financial support from Roche, personal fees and non-financial support from Merck/MSD, grants and non-financial support from Novartis, grants and non-financial support from BMS, non-financial support from TEVA, grants from Adtec, 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, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme. 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 Sun Pharma and travel support from MSD, BMS, Amgen, Pierre Fabre, Sun Pharma, Sanofi and Novartis, outside the submitted work. N.S.: No relevant conflicts of interest. A.S.: No relevant conflicts of interest. F.K.: No relevant conflicts of interest. L.H.: served as consultant and/or has received honoraria from Amgen, Roche, Bristol Myers Squibb, Curevac, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sun Pharma and a research grant from Novartis, outside the submitted work. Fri.M.: has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. Fra.M.: served as consultant and/or has received honoraria from Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme and travel support from Novartis, Sun Pharma and Bristol Myers Squibb, outside the submitted work. M.S.: participated in advisory boards of Bristol Myers Squibb, Novartis, MSD, Roche, Pierre Fabre, Kyowa Kirin, Immunocore and Sanofi Genzyme. M.S. received travel accommodation and expenses by Novartis, Pierre Fabre, and Sun Pharma, outside the submitted work. B.S.: received personal honoraria from Bristol Myers Squibb, Merck Sharpe & Dome, Novartis, Pfizer/EMD Serono, Pierre Fabre and Roche; has an advisory role for Bristol Myers Squibb, Merck Sharpe & Dome, Novartis, Pierre Fabre and Roche; and has received research funding from Bristol Myers Squibb, Merck Sharpe & Dome, and Pierre Fabre, all paid to the institute. Su.H.: No relevant conflicts of interest. D.S: reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sun Pharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. E.L.: served as consultant and/or has received honoraria from Amgen, Actelion, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Janssen, Medac, Sanofi, Sun Pharma and travel support from Amgen, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Sun Pharma and Novartis, outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Patients with stage IIC malignant melanoma are recommended to undergo cross-sectional imaging for initial staging. PET/CT is superior to other methods regarding its diagnostic accuracy of the tumor spread in stage III. So far there is no meaningful data on the nationwide availability, usage and cost recovery of this imaging technique., Patients and Methods: Questionnaires on the healthcare situation in 2018 were sent to all German dermatology clinics and PET/CT centers in March and April 2019., Results: 61.2 % of the dermatology clinics (71/115) and 48.2 % of the PET/CT centers (77/160) took part in the survey. A total of 22,645 patients with malignant melanoma were seen in these clinics in 2018. 16.8 % of the patients with stage IIC melanoma received a PET/CT for primary staging. The costs of this examination were covered for all statutory and privately insured patients in 40 % and 68 % of dermatology clinics (20/50 and 34/50), respectively. 68.0 % (34/50) of all dermatology clinics reported relevant changes of treatment according to PET/CT findings. Long examination periods by the health insurance companies and the time required to submit the application were the most common reasons for dermatology clinics to reject a request for PET/CT. Relevant incidental findings were reported in 90.2 % (47/51) of all PET/CT centers., Conclusions: There are clear differences in the nationwide availability and cost coverage of PET/CT in primary staging for stage IIC melanoma. For these reasons, a two-tiered healthcare system may be assumed., (© 2021 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Cancer patients represent a vulnerable cohort during the Sars-CoV-2 pandemic. Oncological societies have generated a plethora of recommendations, but precise instructions about routine oncological procedures remain scarce. Here, we report on local COVID-19 protection measures established in an interdisciplinary approach at a tertiary care center during the first wave of the pandemia in Germany. Following these measures, no additional morbidity or mortality during oncological procedures was observed, and no nosocomial infections were registered. However, Validation of our measures is outstanding and regional SARS-CoV-2 prevalence was low. However, specific oncological measures might be important to ensure optimal oncological results, especially for advanced cancer stages during this and future pandemia. In the future, communication about these measures might be crucial to a cancer patient´s assigned network to reduce the danger of excess mortality within the second wave of the COVID-19 pandemic.

Purpose: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting., Methods: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated., Results: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures., Conclusion: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

Background: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy., Methods: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants., Findings: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths., Interpretation: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy., Funding: Regeneron Pharmaceuticals and Sanofi., Competing Interests: Declaration of interests AJS reports advisory board or steering committee roles with Janssen, Regeneron Pharmaceuticals, Roche, and Sanofi; and research support from Abbvie, Bristol Myers Squibb, Genesis Pharma, and Novartis. AS reports advisory roles with Regeneron Pharmaceuticals and Roche. KP reports advisory board roles with Abbvie, LEO Pharma, Janssen, Almirall, Eli Lilly, Galderma, Novartis, Pierre Fabre, Sun Pharma, and Sanofi, outside the submitted work. OB has advisory board roles with Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Ultimovacs. KDL reports grants from the University of Colorado; and grants and personal fees from Regeneron Pharmaceuticals. ALSC reports advisory roles with Regeneron Pharmaceuticals and Merck; and research funding from Regeneron Pharmaceuticals, Merck, Novartis, and Galderma. SD reports that their spouse is an employee of Sanofi. LL reports institutional grants and personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Debiopharm International SA, Eisai, Novartis, and Roche; institutional grants from Celgene International, Exelixis, Hoffmann-La Roche, IRX Therapeutics, Medpace, Merck-Serono, and Pfizer; and personal fees from Sobi, Ipsen, Incyte Biosciences Italy SRL, Doxa Pharma, Amgen, Nanobiotics SA, GlaxoSmithKline, AccMed, Medical Science Fundation G. Lorenzini, Associazione Sinapsi, Think 2 IT, Aiom Servizi, Prime Oncology, WMA Congress Education, Fasi, DueCi Promotion SRL, MI&T, Net Congress & Education, PRMA Consulting, Kura Oncology, Health & Life SRL, and Immuno-Oncology Hub. CR reports grants and personal fees advisory board roles with Bristol Myers Squibb, Pierre Fabre, Novartis, Amgen, Merck, Roche, Merck Sharp & Dohme, Sanofi, Biothera, and Ultimovacs. CU reports advisory board and speaker roles for Roche, Sanofi, Regeneron Pharmaceuticals, and Sun Pharma. AH reports institutional funding and personal fees from Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Merck & Co, Philogen, Pierre Fabre, Provectus, Regeneron Pharmaceuticals, Roche, Sanofi Genzyme, and Novartis; and consultancy fees from OncoSec, Almirall Hermal, and Sun Pharma. MRM reports advisory roles with and travel fees from Regeneron Pharmaceuticals and Sun Pharmaceuticals; advisory role with Rakuten Medical; and research funding from Regeneron Pharmaceuticals and PellePharm. RD has intermittent, project focused consultant and advisory roles with Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron Pharmaceuticals, Alligator, MaxiVAX SA, and touchIME outside the submitted work. SL, S-YY, KM, EC, VJ, NF, EO, FS, DMW, and TB are employees and shareholders of Regeneron Pharmaceuticals. CL reports personal fees from Roche, Sun Pharma, Bristol Myers Squibb, Merck Sharp & Dohme, Merck, Novartis, Pierre Fabre, Kyowa Kirin, Almiral Hermal, and Biontech. ZE reports advisory board fees from Regeneron Pharmaceuticals, Novartis, Array, Genentech, and SunPharma; and grants from Novartis. RG reports documentation fees to institution from Regeneron Pharmaceuticals; personal fees and non-financial support from Amgen, Bristol Myers Squibb, Roche Pharma, Merck Serono, Pierre Fabre, Sanofi, and Regeneron Pharmaceuticals; grants, personal fees, and non-financial support from Novartis; grants and personal fees from Pfizer; grants from Johnson & Johnson; and personal fees from Merck Sharp & Dohme, Almirall Hermal, SUN Pharma, 4SC, and Bayer. JU reports grants and personal fees from Sanofi, Bristol Myers Squibb, Novartis, and Merck Sharp & Dohme; and personal fees from Roche, medac, and Sun Pharma. SPu reports personal fees and non-financial support from Sanofi; other (clinical trials) from Regeneron Pharmaceuticals; grants from Avene; non-financial support from Abbie; grants, personal fees, and non-financial support from ISDIN, La Roche-Posay, and Roche; grants and personal fees from Sun Pharma; non-financial support from Eli Lilly and Merck Sharp & Dohme; personal fees, non-financial support, and other (related to clinical trials) from Pfizer; grants, personal fees, and other from Leo Pharma and Almirall; personal fees and other (related to clinical trials) from Ojer Pharma; personal fees from Pierre Fabre; and non-financial support from MAVIG, FotoFinder, and 3Gen. GDY is an employee of, shareholder in, and a member of the Board of Directors at Regeneron Pharmaceuticals. GT is an employee of, patent holder, and shareholder of Regeneron Pharmaceuticals. IL and MGF are employees of, have patents pending, and are shareholders of Regeneron Pharmaceuticals. SPr, MK, NB-S, AFO, IB, and VDG declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Ipilimumab has shown long-term overall survival (OS) in patients with advanced melanoma in clinical trials, but robust real-world evidence is lacking. We present long-term outcomes from the IMAGE study (NCT01511913) in patients receiving ipilimumab and/or non-ipilimumab (any approved treatment other than ipilimumab) systemic therapies., Methods: IMAGE was a multinational, prospective, observational study assessing adult patients with advanced melanoma treated with ipilimumab or non-ipilimumab systemic therapies between June 2012 and March 2015 with ≥3 years of follow-up. Adjusted OS curves based on multivariate Cox regression models included covariate effects. Safety and patient-reported outcomes were assessed., Results: Among 1356 patients, 1094 (81%) received ipilimumab and 262 (19%) received non-ipilimumab index therapy (systemic therapy [chemotherapy, anti-programmed death 1 antibodies, or BRAF ± MEK inhibitors], radiotherapy, and radiosurgery). In the overall population, median age was 64 years, 60% were male, 78% were from Europe, and 78% had received previous treatment for advanced melanoma. In the ipilimumab-treated cohort, 780 (71%) patients did not receive subsequent therapy (IPI-noOther) and 314 (29%) received subsequent non-ipilimumab therapy (IPI-Other) on study. In the non-ipilimumab-treated cohort, 205 (78%) patients remained on or received other subsequent non-ipilimumab therapy (Other-Other) and 57 (22%) received subsequent ipilimumab therapy (Other-IPI) on study. Among 1151 patients who received ipilimumab at any time during the study (IPI-noOther, IPI-Other, and Other-IPI), 296 (26%) reported CTCAE grade ≥ 3 treatment-related adverse events, most occurring in year 1. Ipilimumab-treated and non-ipilimumab-treated patients who switched therapy (IPI-Other and Other-IPI) had longer OS than those who did not switch (IPI-noOther and Other-Other). Patients with prior therapy who did not switch therapy (IPI-noOther and Other-Other) showed similar OS. In treatment-naive patients, those in the IPI-noOther group tended to have longer OS than those in the Other-Other group. Patient-reported outcomes were similar between treatment cohorts., Conclusions: With long-term follow-up (≥ 3 years), safety and OS in this real-world population of patients treated with ipilimumab 3 mg/kg were consistent with those reported in clinical trials. Patient-reported quality of life was maintained over the study period. OS analysis across both pretreated and treatment-naive patients suggested a beneficial role of ipilimumab early in treatment., Trial Registration: ClinicalTrials.gov , NCT01511913. Registered January 19, 2012 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01511913.

Background: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome., Methods: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS)., Results: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema., Conclusions: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment., Competing Interests: KK 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. RG received honoraria for lectures and advisory boards, research support and meeting support from Almirall Hermal, Amgen, Astra Zeneca, Bristol Myers Squibb, Leo, Merck Serono, Merck Sharp and Dohme, Pierre Fabre, Roche, Sanofi Genzyme, Regeneron, Sun Pharma, Takeda, Pfizer, Novartis, Johnson&Johnson, 4SC, and Incyte. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre, and research funding from Novartis and Roche. LZ has served as consultant and/or has received honoraria from Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre Fabre, and Sanofi, and received travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Amgen, Pierre Fabre, and Novartis. MH has received consultant and/or speaker honoraria form Bristol Myers Squibb, Novartis, Merck Sharp and Dohme, Sanofi, Roche and travel support from Novartis, and Bristol Myers Squibb. AG reports speakers honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, and Roche, advisory board honoraria from Bristol Myers Squibb, Novartis, Merck Sharp and Dohme, Pierre Fabre, Pfizer, Roche and Sanofi Genzyme, and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, and Roche. K-MT received honoraria for lectures and advisory boards from Bristol-Myers Squibb, Roche, Novartis, Merck Sharp and Dohme, Pierre Fabre, LEO, Galderma, AbbVie, La Roche-Posay and Candela, and travel support from Bristol-Myers Squibb, Roche, Novartis, Merck Sharp and Dohme, Pierre Fabre, LEO, and Candela. JU is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. JH reports speakers honoraria from Bristol Myers Squibb, Novartis, Merck Sharp and Dohme, and Roche, advisory board honoraria from Merck Sharp and Dohme, Pierre Fabre, Sunpharma and Sanofi Genzyme, and travel support from Bristol Myers Squibb, and Pierre Fabre. CL declares speakers and advisory board honoraria and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis, Roche, Amgen, Pierre Fabre, and Sun Pharma. CP received speaker or consultant honoraria and travel support from Novartis, Bristol Myers Squibb, Roche, Merck Serono, Merck Sharp and Dohme, Celgene, AbbVie, and LEO. LH received grants from Novartis, and has received speaker or consultant fees personal fees from Amgen, Bristol Myers Squibb, Merck Sharp and Dohme, Roche, Curevac, Pierre Fabre, Roche, Novartis, and Sanofi. MK has received grants from Bristol Myers Squibb, Merck Sharp and Dohme, Leo, Novartis, and Roche. DG declares speakers and advisory honoraria as well as travel support from Bristol Myers Squibb, Novartis, Pierre Fabre, Sanofi Genzyme, Amgen, Galderma, Janssen, and Roche. DS declares advisory board and speakers honoraria from Roche, Novartis, Bristol-Myers-Squibb, MSD, Merck-Serono, Sanofi, Nektar, Amgen, Hexal, InFlaRx, Array, Pierre Fabre, Immunocore, Philogen Sun Pharma, Regeneron, and Ultimovacs, as well as grant and travel support from Roche, Novartis, Bristol-Myers-Squibb, MSD, Merck-Serono, and Sanofi. SU declares research support from Bristol Myers Squibb, and Merck Serono, speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp, and Dohme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kähler, Gutzmer, Meier, Zimmer, Heppt, Gesierich, Thoms, Utikal, Hassel, Loquai, Pföhler, Heinzerling, Kaatz, Göppner, Pflugfelder, Bohne, Satzger, Reinhardt, Placke, Schadendorf and Ugurel.)

Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74-80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68-80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24-38), and fear of adverse events (21.1%, 95% CI 16-28) and impaired quality of life (11.9%, 95% CI 7-16). Of all BRAF -mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47-59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results., Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37., Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73])., Interpretation: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests AMME reports being the study chair of the EORTC 18071/CA-029 phase 3 clinical trial (Bristol Myers Squibb [BMS]) and of the EORTC 1325/KEYNOTE-054 phase 3 trial (Merck Sharp & Dohme), and has worked in a consulting or advisory role and received honoraria from Biocad, Biotech, BioInvent, BMS, CatalYm, GlaxoSmithKline (GSK), IO Biotech, ISA Pharmaceuticals, Merck, Novartis, Regeneron Pharmaceuticals, Sellas, and SkylineDx. CUB reports receiving grants from BMS, NanoString Technologies, Novartis, and Third Rock Ventures and personal fees from AstraZeneca, BMS, GenMab, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, and Roche during the conduct of the study; he owns stocks in Unity Cars, and is co-founder of Immagene BV. MM reports receiving grants from BMS, MSD, and Roche Novartis and has worked in a consulting or advisory role for BMS, MSD, and Pierre Fabre. GVL has worked in a consulting or advisory role and received honoraria from Aduro Biotech, Amgen, Array BioPharma, Boehringer Ingelheim, BMS, Highlight Therapeutics, MSD, Novartis, Pierre Fabre, QBiotics, Regeneron Pharmaceuticals, and SkylineDX. VGA has worked in a consulting or advisory role and received speaking fees or travel support, or both, from BMS, Merck, MSD, Nektar, Novartis, OncoSec, Pierre Fabre, and Roche. SD reports receiving grants from BMS and MSD. AMH reports receiving personal fees from BMS, MSD, and Novartis. AM has worked in a consulting or advisory role and received honoraria from Amgen, AstraZeneca, Aventis, Bayer, BIOCAD, BMS, Eisai, Eli Lilly, Merck, Sanofi, SERVIER, and Takeda Pharmaceuticals. AK reports grants and personal fees from MSD. MSC has worked in a consulting role and received honoraria from BMS, Eisia, IDEAYA Biosciences, Merck Serano, MSD, Novartis, Oncosec, Pierre Fabre, Q biotics, Roche, and Sanofi. SSa reports receiving grants from Amgen, AstraZeneca, BMS, Endocyte, and MSD. JL reports receiving grants from Achilles Therapeutics, AVEO Pharmaceuticals, BMS, Covance, Genentech/Roche, Immunocore, MSD, Nektar, Novartis, Pharmacyclics, and Pfizer and has worked in a consulting role and received honoraria from Achilles Therapeutics, AstraZeneca, Boston Biomedical, BMS, Covance, Eisai, EUSA Pharma, Genentech/Roche, GSK, Immunocore, Imugene, Incyte, iOnctura, Ipsen, Kymab, Merck Serono, MSD, Nektar, Novartis, Pfizer, Pierre Fabre, Secarna Pharmaceuticals, and Vitaccess. SP received grants from Abbie, Almirall, AMLO Biosciences, Castle Biosciences, La Roche Posay, Leo Pharma, Melagenix, and Sun Pharma, has worked in a consulting role and received honoraria from Almirall, ISDIN, La Roche-Posay, Leo Pharma, Regeneron, Sanofi, and Sun Pharma, and speaker's bureau from Bioderma, BMS, La Roche Posay, Pierre Fabre, Roche, and Sanofi. PAA received grants and research funds from Array BioPharma, BMS, and Genentech/Roche and has worked in a consulting role and received honoraria from 4SC, Array BioPharma, AstraZeneca, BMS, Genentech/Roche Genmab, Idera Pharmaceutials, Immunocore, Incyte, MedImmune, Merck Serono, MSD, NewLink Genetics, Novartis, Pierre Fabre, Sandoz, Sanofi, Sun Pharma, Syndax Pharmaceuticals, and Ultimovacs. PR has worked in a consulting or advisory role and received honoraria from Blueprint Medicines, BMS, MSD, Novartis, Pfizer, and Pierre Fabre. DS has worked in a consulting role and received honoraria from 4SC, Array BioPharma, AstraZeneca, Incyte, Pierre Fabre, and Pfizer. RK has worked in a consulting role and received honoraria from BMS, MSD, Novartis, Pierre Fabre, and Roche. LH-A reports that his institution received fees to conduct clinical trials from Merck, Amgen, BMS, Corvus, Genentech, Immunocore, Merck-EMD, Novartis, Polynoma, Regeneron, and Roche. AMDG has worked in a consulting or advisory role and received fees from BMS, GSK, Pierre Fabre, and Sanofi. AJMvdE has worked in a consulting or advisory role and received fees from BMS, MSD, Merck, Sanofi, Roche, Novartis, Eisai, Ipsen, Pfizer, and Pierre Fabre and grants from BMS, Sanofi, and Roche. J-JG has worked in a consulting or advisory role or received speaker fees, and received fees from Amgen, BMS, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi. RG has worked in an advisory role and received fees from 4SC, Almirall, Amgen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and Sun Pharma and received grants from Amgen, Johnson & Johnson, Novartis, and Pfizer. RJ reports receiving grants and patient fees from MSD during the conduct of the study and receiving grants from BMS and Iovance and fees to conduct clinical trials for his institutions from Roche, GSK, AstraZeneca, and Novartis. PCL has worked in a consulting or advisory role and his institution received honoraria and grants from 4SC, Amgen, BMS, Merck, and Novartis. ACJvA reports receiving grants from 4SC, Amgen, BMS, Merck, MSD, Novartis, Pfizer, and Sanofi. CK and NI are employees and shareholders of Merck. MK and SSu report receiving grants from Merck during the conduct of the study. CR has worked in a consulting or advisory role and received honoraria from Amgen, Biothera, BMS, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Ultimovacs. SM declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint., Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing., Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant., Interpretation: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests AMME reports non-financial support from BMS and Merck & Co during the conduct of the study; personal fees from Biocad, BioInvent, Bristol Myers Squibb (BMS), CatalYm, GSK, IO Biotech, ISA pharmaceuticals, Merck, Novartis, Regeneron, Sellas, SkylineDx, Novartis, and Pfizer, outside the submitted work. AMH reports personal fees from Merck Sharp and Dohme (MSD); and personal fees from Novartis and BMS, outside the submitted work. AJMvdE reports grants and personal fees from BMS; grants from Roche and Idera; and personal fees from MSD, Amgen, Pierre Fabre, and Novartis, outside the submitted work. AM reports personal fees from Lilly Pharma, AstraZeneca Pharmaceuticals, Merck, BMS, and Sanofi-Aventis Group, outside the submitted work AMDG reports advisor or consultant roles from BMS, Pierre Fabre, Sanofi, and MSD, outside the submitted work. ACJvA reports grants and personal fees from Amgen and Merck-Pfizer; and personal fees from BMS, Novartis, MSD-Merck, Sanofi, Sirius Medical, and 4SC, outside the submitted work. CUB reports grants and personal fees from BMS and Novartis; personal fees from Roche, MSD, Pfizer, Lilly, Pierre Fabre, and GenMAb; grants from NanoString and Third Rock Ventures; stock ownership of Unity Cars; and is a cofounder of Immagene, outside the submitted work. CR participated in advisory boards for Roche, Pierre Fabre, Merck, Novartis, Amgen, BMS, Novartis, MSD, Sanofi, Biothera, and Ultimovacs. DS reports personal fees consulting or advisory role, honorarium, speakers bureau, travel, accommodations, and expenses from MSD during the conduct of the study; personal fees and non-financial support from Roche/Genentech, Merck Serono, and Merck; grants, personal fees, non-financial support, consulting or advisory role, honoraria, speakers bureau, travel, accommodations, expenses, and research funding from Novartis and Amgen; grants, personal fees, consulting or advisory role, honoraria, speakers bureau, travel, accommodations, expenses, and research funding from BMS; and personal fees from Immunocore, Incyte, 4SC, Pierre Fabre, Sanofi, Array BioPharma, Pfizer, Philogen, Regeneron, Nektar, and Sandoz, outside the submitted work. GVL reports personal fees from Aduro Biotech, Amgen, Array Biopharma, Boehringer Ingelheim, BMS, Highlight Therapeutics, MSD, Novartis Pharma, QBiotics, Rhegeneron Pharmaceuticals, and SkylineDX, outside the submitted work. NI and CK report personal fees from Merck & Co during the conduct of the study. J-JG reports personal fees from BMS, MSD, Novartis, Roche, Amgen, Pierre Fabre, and Sanofi; and personal fees from Merck and Pfizer, outside the submitted work. JL reports grants and personal fees from BMS, MSD, Pfizer, Novartis, Roche, Immunocore, Achilles therapeutics, and Nektar; personal fees from Eisai, GSK, Kymab, Secarna, AstraZeneca, Boston Biomedical, EUSA Pharma, Ipsen, Imugene, Incyte, iOnctura, Merck Serono, Pierre Fabre, Vitaccess, and Covance; and grants from Aveo and Pharmacyclics, outside the submitted work. LH-A reports personal fees from Merck during the conduct of the study; and personal fees from BMS, Merck, Amgen, Roche, Regeneron, Novartis, Immunocore, Merck-EMD, Corvus, Polynoma, and Genentech, outside the submitted work. MM reports grants from BMS, MSD, and Roche; and advisory board from Pierre Fabre, BMS, and MSD, outside the submitted work. MSC reports personal fees from MSD, BMS, Novartis, Roche, Pierre Fabre, and Sanofi; and personal fees from Merck Serono, Nektar, Eisia, and Ideaya, outside the submitted work. PAA reports grants and personal fees from BMS, Roche-Genentech, and Array; personal fees, advisory or consultant role, and travel support from MSD; personal fees from Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, NewLink Genetics, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, and Boehringer Ingelheim, outside the submitted work. PCL reports personal fees and advisory, speaker, and trials roles for BMS, Novartis, Amgen, GSK, and Chugai; and personal fees from Merck, outside the submitted work. PR reports personal fees from MSD, BMS, Novartis, Pierre Fabre, Blueprint Medicines, and Pfizer outside the submitted work. RG reports documentation fees to institution from MSD during the conduct of the study; personal fees and non-financial support from BMS, Roche Pharma, Merck Serono, Pierre Fabre, and Sanofi Regeneron; fees from MSD, Almirall Hermal, SUN Pharma, and 4SC; grants, personal fees, and non-financial support from Amgen and Novartis; grants and personal fees from Pfizer; and grants from Johnson & Johnson, outside the submitted work. RJ reports grants, fees paid to institution for the conduct of studies in melanoma, and grant for Investigator Initiated Trial in metastatic melanoma from BMS during the conduct of the study; grants, per patients fees paid to the institution for the conduct of the study, and grant for Investigator Initiated Trial in metastatic melanoma from Merck; fees paid to the institution for the conduct of studies in melanoma from Roche/Genentech, GSK, AstraZeneca, and Novartis; and grants from Iovance, outside the submitted work; and has acted as a presenter or as a consultant in advisory boards for both BMS and Merck but has not received any monetary compensation for those roles. SD acts as principal investigator in clinical trials promoted by BMS and MSD and has received institutional research grants from BMS and MSD. SP reports grants from Leo Pharma, Almirall, Castle Bioscience, AMLO Bioscience, and Melagenics; personal fees from Amirall, Leo Pharma, Isdin, Sanofi, La Roche Posay, Regeneron, and Pfizer; speaker bureau from La Roche Posay, Roche, Pierre Fabre, BMS, Bioderma, and Sanofi, outside the submitted work. SSa reports personal fees from BMS and MSD outside the submitted work. SSu, MK, CC, and AK report grants from MSD during the conduct of the study. VGA reports personal fees and non-financial support from BMS; personal fees from Merck, MSD, Novartis, Pierre Fabre, Roche, and Nektar; and travel support from Onco-sec, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear., Patients and Methods: Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres., Results: We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1-181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels., Conclusion: Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency., Competing Interests: Conflict of interest statement Honoraria: R.G. (Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre Fabre), C.P. (Roche, BMS, MSD, Novartis, Merck Serono, Celgene, AbbVie, LEO), L.Z. (Roche, BMS, MSD, Novartis, Sanofi, Pierre Fabre), K.-M.T. (Roche, BMS, MSD, Novartis, Pierre Fabre, LEO, Galderma, Candela, CSL Behring), K.C.K. (Merck sharp and Dohme, Novartis and Bristol Myers Squibb and travel support from Novartis), J.C.H. (BMS, MSD, Roche, Novartis, Sanofi), S.U. (BMS, MSD, Merck Serono, Novartis and Roche), C.B. (Roche, BMS, MSD, Novartis, Sanofi-Aventis), D.D. (MSD, Novartis, Roche, Sanofi), J.U. (Amgen, Bristol Myers Squibb, GSK, LEO Pharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi), R.H. (Roche, BMS, MSD, Novartis, Pierre Fabre), L.H. (BMS, Roche, Novartis, MSD, Amgen, CureVac, Sanofi, Pierre Fabre), C.L. (Roche, Pierre Fabre, Novartis, BMS, MSD, Merck, Almirall Hermall, Sun Pharma, Sanofi, BioNTech, Kyowa Kirin), F.M. (Novartis, Roche, BMS, MSD, Pierre Fabre), I.G. (Novartis, Roche, BMS, MSD, Sanofi), T.K.E. (Roche, Pierre Fabre, Novartis, BMS, MSD, Sanofi). Consultant or Advisory Role: R.G. (BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre Fabre, Merck Serono, Bayer, Pfizer), C.P. (Roche, Novartis, Merck Serono), L.Z. (MSD, BMS, Novartis, Pierre Fabre, Sanofi), K.-M.T. (Roche, BMS, MSD, Novartis, Pierre Fabre, LEO, CSL Behring) K.C.K. (BMS, MSD, Novartis, Pierre Fabre), J.C.H. (MSD, Sun Pharma, Pierre Fabre), S.U. (BMS, MSD, Merck Serono, Novartis and Roche), C.B. (Roche, BMS, MSD, Novartis, Merck Serono, Sanofi-Aventis, Pierre Fabre), D.D. (Novartis, Roche, Sanofi), J.U. (Amgen, Bristol Myers Squibb, GSK, Leo Pharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi), R.H. (Roche, BMS, Novartis, Pierre Fabre), L.H. (BMS, Roche, Novartis, MSD, Amgen, Curevac, Sanofi, Pierre Fabre), C.L. (Roche, Pierre Fabre, Novartis, BMS, MSD, Merck, Almirall Hermal, Sun Pharma, Sanofi, BioNTech, Kyowa Kirin), F.M. (Novartis, Roche, BMS, MSD, Pierre Fabre), I.G. (Novartis, Roche, BMS, MSD, Sanofi), T.K.E. (Roche, Pierre Fabre, Novartis, BMS, MSD, Sanofi). Research Funding: R.G. (Novartis, Pfizer, Johnson & Johnson, Amgen, Merck Serono, SUN Pharma, Sanofi), L.Z. (Novartis), K.C.K. (Novartis, Merck Sharp and Dohme), J.C.H. (BMS), S.U. (BMS, Merck Serono), J.U. (Apogenix, NOXXON Pharma, Elsalys Biotech, TILT Biotherapeutics, BioNTech RNA Pharmaceuticals, RHEACELL, Merck), L.H. (Novartis), F.M. (Novartis, Roche), I.G. (Roche, Pfizer, Novartis). Travel, Accommodations, Expenses: R.G. (Roche, BMS, SUN, Merck Serono, Pierre Fabre), C.P. (Roche, BMS, MSD, Novartis, Merck Serono, Celgene, AbbVie, LEO), L.Z. (BMS, Pierre Fabre, Amgen, Sanofi, Sun Pharma, Novartis), K.-M.T. (Roche, BMS, MSD, Novartis, Pierre-Fabre, LEO, Candela) K.C.K. (MSD, Novartis and Bristol Myers Squibb, Novartis), J.C.H. (Pierre Fabre, BMS), S.U. (BMS, MSD), D.D. (Amgen, BMS, MSD, Mylan, Novartis, Pierre Fabre, Roche, Sanofi), J.U. (Amgen, Bristol Myers Squibb, GSK, Leo Pharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi), C.L. (Roche, Pierre Fabre, Novartis, BMS, MSD, Merck, Almirall Hermall, Sun Pharma, Sanofi, BioNTech, Kyowa Kirin), F.M. (Novartis, Roche, BMS, MSD, Pierre Fabre), I. G. (Novartis, Roche, BMS, MSD). Stock ownership: none. Patent application/registration: none. Employment: none. No conflict of interest: C.R. and C.K. had no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking., Methods: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting., Results: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4-1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2-2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3-1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8-2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6-1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5-1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding., Conclusions: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone., Competing Interests: Conflicts of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sarah Knispel: Travel support from Bristol-Myers Squibb and Amgen. Maximilian Gassenmaier: Consultant or Advisory Role: Novartis; Research funding: Novartis. Carmen Loquai: Advisory role/Speakers fee/Travel support: BMS, MSD, Merck, Novartis, Pierre Fabre, Sunpharma, Sanofi, Roche, Almirall Hermal, Biontech, Kyowa Kirin. Cindy Franklin: Advisory board or received honoraria of BMS and Novartis and received travel grants from BMS, Novartis and Pierre Fabre. Ralf Gutzmer: Personal Honoraria from Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Consultant or advisory role: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, MerckSerono, Bayer, Pfizer. Research funding: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi, all paid to the institution. Travel, accommodations, expenses: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. Bastian Schilling: Personal honoraria from Bristol-Myers Squibb, Merck Sharpe and Dome, Novartis, Pfizer/EMD Serono, Pierre Fabre and Roche; has an advisory role for Bristol-Myers Squibb, Merck Sharpe and Dome, Novartis, Pierre Fabre and Roche; and has received research funding from Bristol-Myers Squibb, Merck Sharpe and Dome, and Pierre Fabre, all paid to the institute. Andreas Stang: Speaker honoraria from Merck Serono. Selma Ugurel: Research support from Bristol-Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and Travel support from Bristol-Myers Squibb, and Merck Sharp & Dohme. Lisa Zimmer: Honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre; Consultant or advisory role: BMS, Novartis, Pierre Fabre, Sunpharma, Sanofi, MSD; Research funding to institution: Novartis; Travel support: BMS, Pierre Fabre, Sanofi, Amgen, Novartis, Sunpharma. Carina N Owen: Travel support from Merck Sharp Dohme. Jessica C Hassel: Honoraria from BMS, MSD, Novartis, Roche, Pierre Fabre, Sanofi; Consultant or advisory role: MSD, Pierre Fabre, Sunpharma; Research funding: BMS; Travel support: Pierre Fabre. Friedegund Meier has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. Carola Berking: Honoraria from BMS, Immunocore, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi-Aventis for consultancy and/or presentations on scientific symposia. Douglas B Johnson: Advisory boards for Array Biopharma, BMS, Iovance, Jansen, Merck and Novartis and research funding from BMS and Incyte. Elisabeth Livingstone: Intermittent advisory board relationships with Roche, BMS, Novartis, Sanofi and Actelion and has received travel grants and honoraria from Roche, BMS, MSD, Amgen, Pierre Fabre, SunPharma, Novartis, Boehringer-Ingelheim, medac. Alexander M Menzies: Advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. Simone M Goldinger: past advisory boards for BMS, MSD, Roche and Novartis. Kai-Martin Thoms: Honoraria from BMS, MSD, Roche, Novartis, Pierre Fabre, Sun Pharma, LEO, Candela; Consultant or advisory role: BMS, MSD, Roche, Novartis, Pierre Fabre, Sun Pharma, LEO; Travel support: BMS, MSD, Roche, Novartis, Pierre Fabre, LEO. Dirk Schadendorf: Has/had a consultant/advisory role in the last 2 years for Bristol-Myers Squibb (BMS), Roche-Genentech, Merck Sharp & Dohme (MSD), Array, Immunocore, InFlaRX, Nektar, Novartis, Merck Serono, Pierre Fabre, Pfizer, Philogen, Regeneron, SunPharma, Sandoz, Sanofi, Ultimovacs and 4SC. He also received research funds from Bristol-MyersSquibb, Roche, Amgen and Novartis. Travel support: BMS, Pierre Fabre, Sanofi, Nektar, Novartis, Roche, Merck Serono and Sunpharma. Dennis Niebel: Has received speakers’ honoraria or travel expense reimbursements from BMS, Novartis, GSK, Celgene and MSD. Judith Sirokay: Honoraria from Roche, BMS, MSD, Novartis, Consultant or advisory role: Novartis, MSD; Travel support: BMS, Pierre Fabre. Peter Mohr: Has/had a consultant/advisory role in the last 2 years for Amgen, Bristol-Myers Squibb (BMS), Roche-Genentech, Merck Sharp & Dohme (MSD), Novartis, Merck Serono, Pierre Fabre, Pfizer, Philogen, Sanofi. He also received research funds from Bristol-Myers Squibb, Merck Sharp & Dohme (MSD) and Novartis. Travel support: Amgen, BMS, Merck Sharp & Dohme (MSD), Pierre Fabre, Sanofi, Novartis, Roche and Sunpharma. Laura Susok: Collaboration with BMS, Novartis, Sunpharma, MSD, Roche, Pierre Fabre. Paolo Ascierto: Has/had a consultant/advisory role for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pierre-Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Array and travel support from MSD. Claudia Pföhler: Consultancy, speaker fees, travel grants: BMS, MSD, Merck Serono, Roche, Amgen, GSK, Novartis, Sanofi Genzyme, Pierre Fabre, LEO, UCB, Sunpharma. Clinical studies: Novartis, BMS. Lucie Heinzerling: Consultant or advisory role: Amgen, BMS, Curevac, Novartis, Pierre Fabre, Roche, Sanofi, MSD; research funding (to institution): Novartis. Patrick Schummer: honoraria: Bristol-Myers Squibb (BMS); institutional research grant: Novartis; Travel support: Novartis, Lilly and BMS. Thomas Eigentler: Has/had a consultant/advisory role in the last 2 years for Bristol-Myers Squibb (BMS), Roche-Genentech, Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Philogen, Sanofi. He also received research funds from Bristol-Myers Squibb, Merck Sharp & Dohme (MSD) and Novartis. Katharina C. Kähler: Serves as consultant to Roche, BMS, MSD, Pierre Fabre and received travel grants and speaker fees from Roche, BMS, MSD, Amgen, Pierre Fabre and Philogen. Julia Tietze: Honoraria from Roche, BMS, MSD, Amgen, Sanofi, Travel support: Pierre Fabre, Novartis, BMS. Georgina V. Long: Is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V. All other authors (Felix Kiecker, Raphael Reinhard, Konstantin Drexler, Christopher Cann, Lydia Reinhardt, Carsten Weishaupt, Maria I Fleischer, Leonie Bluhm) declared to have no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response., Methods: In this phase II study in patients with unresectable stage IIIB-IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8 + T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response., Results: Of 112 enrolled patients, 111 received ≥1 dose of T-VEC. After a median follow-up of 108.0 weeks, objective/complete response rates were 28%/14% in the overall population and 32%/18% in patients with stage IIIB-IVM1a disease. No unexpected toxicity occurred. Baseline and week 6 change from baseline CD8 + T-cell density results were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8 + T-cell density correlated with objective response rate, changes in tumor burden, duration of response or durable response rate. However, a 2.4-fold median increase in CD8 + T-cell density in non-injected lesions from baseline to week 6 was observed. In exploratory analyses, multiparameter immunofluorescence showed that after treatment there was an increase in the proportion of infiltrating CD8 + T-cells expressing granzyme B and checkpoint markers (programmed death-1, programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4) in non-injected lesions, together with an increase in helper T-cells. Consistent with T-cell infiltrate, we observed an increase in the adaptive resistance marker PD-L1 in non-injected lesions., Conclusions: This study indicates that T-VEC induces systemic immune activity and alters the tumor microenvironment in a way that will likely enhance the effects of other immunotherapy agents in combination therapy., Trial Registration Number: NCT02366195., Competing Interests: Competing interests: JM has acted as a consultant/advisor for and has received honoraria from Almirall, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Leo Pharma, Novartis, Pierre Fabre and Roche. IS has acted as a consultant and served on a speaker’s bureau for Biocad, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Roche. DS has received research support from Bristol-Myers Squibb and Novartis; has acted as a consultant for and received royalties from Amgen, Array, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Roche; and has acted as a consultant for Immunocore, Incyte, LeoPharma, Merck Serono, Pfizer, Philogen, and Regeneron. RG has received research support from Johnson & Johnson, Novartis, Merck Serono, Amgen and Pfizer; has received honoraria for advice and/or lectures from Almirall Hermal, Amgen, Bayer, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi/Regeneron, SUN Pharma and 4SC. J-JG has acted as a consultant/in an advisory role for and has received honoraria from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Merck-Pfizer, Pierre Fabre, and Roche. JJS has received research support from AstraZeneca, Bristol-Myers Squibb and Immunocore; has acted as a consultant/in an advisory role for Immunocore, Delcath, Merck Sharp & Dohme, Amgen and Pierre Fabre; and served on a speaker’s bureau for Bristol-Myers Squibb. KSG and AA are employees and stock holders of Amgen. KL is an employee of Amgen. CAP was previously an employee of Amgen. HG has acted as a consultant/in an advisory role for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Roche and Pierre Fabre., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)