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Background: Over the past decade, PD-1-based immune checkpoint inhibitors (ICI) and targeted therapies (TT) with BRAF and MEK inhibitors transformed melanoma treatment. Both are widely used in the adjuvant setting. However, for patients with a BRAF V600 mutation, the optimal adjuvant therapy remains unclear due to the lack of head-to-head comparison studies., Methods: We conducted a systematic review of real-world data on adjuvant therapy in stage III melanoma to determine the best option for patients with BRAF V600 mutations. Kaplan-Meier curves were generated for TT and ICI using Digitizelt software., Results: Nine publications with 3625 patients were included. TT showed better relapse-free survival (RFS) at 6, 12, 24, and 36 months than ICI. A similar trend was observed for distant metastasis-free survival (DMFS), with no apparent difference in overall survival., Conclusion: Real-world data suggest that adjuvant TT may be associated with better RFS and DMFS in stage III BRAF V600-mutated melanoma compared to ICI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TA reports personal fees for advisory board membership from Delcath and Philogen; personal fees as an invited speaker from Bristol Myers Squibb (BMS), Neracare, Novartis and Pierre Fabre; personal fees for a writing engagement from CeCaVa and Medtrix; institutional fees as local principal investigator (PI) from Agenus Inc., AstraZeneca, BioNTech, BMS, HUYA Bioscience, Immunocore, IO Biotech, MSD, Pfizer, Philogen, Regeneron, Roche and University Hospital Essen; institutional fees as coordinating PI from Unicancer; institutional research grants from iFIT and Novartis; institutional funding from MNI - Naturwissenschaftliches und Medizinisches Institut, Neracare, Novartis, Pascoe, Sanofi and Skyline-Dx; non-remunerated membership of the American Society of Clinical Oncology (ASCO) and the Portuguese Society for Medical Oncology; and a role as clinical expert in the area of medical oncology for Infarmed.LN nothing to report. LMSH nothing to report. PA reports personal fees for advisory board membership from Anaveon, Bayer and BioNTech; personal fees for a consultancy role from Bio-Al Health, BMS, Boehringer Ingelheim, Erasca, Immunocore, Italfarmaco, Lunaphore, Medicenna, Merck Serono, MSD, Nouscom, Novartis, Pfizer, Pfizer/Array, Philogen, Pierre Fabre, Regeneron, Replimmune, Roche Genentech, Sandoz, Sanofi, Sun Pharma and ValoTx; personal fees for an advisory role from BMS, Boehringer Ingelheim, Erasca, Immunocore, Merck Serono, MSD, Novartis, Pfizer/Array, Pierre Fabre, Regeneron, Replimune, Roche, Sandoz, Sanofi and Sun Pharma; institutional funding for clinical trials from BMS, Pfizer/Array, Roche, Genentech and Sanofi; travel grants from Bio-Al Health, MSD, Pfizer/Array and Replimmune; and non-remunerated roles as President of the Campania Society of ImmunoTherapy of Cancer (SCITO) Italy, President of the Fondazione Melanoma Onlus Italy, member of the steering committee for the Society for Melanoma Research (SMR), member of AIOM, ASCO, EORTC Melanoma Cooperative Group, SITC and SMR and member of the Board of Directors for the SITC (November 2017-December 2021). CB reports honoraria for consulting/advisory board and/or speaker´s fees from Almirall Hermal, BMS, Delcath, Immunocore, Leo Pharma, MSD, Novartis, Pierre Fabre, Regeneron, and Sanofi, outside the submitted work. EMC reports consultant or Advisory Role Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Regeneron; Research Funding MSD, Sanofi, BMS; Speaking Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, MSD, Novartis, Pierre Fabre, Regeneron; Clinical trial participation (principal investigator) Amgen, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Iovance, Regeneron. MD reports consultancy fees from Achilles Therapeutics and membership of expert network of Guidepoint LLC and Alphasights, outside of the submitted work. RD reports honoraria from Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, T3 Pharma, MaxiVAX SA, Pfizer and Simcere.outside the submitted work. RG Honoraria for lectures/advisory boards BristolMyers Squibb, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron; Meeting support SUN Pharma, Boehringer Ingelheim, PierreFabre; Research support (to institution) Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Almirall Hermal. AH reports grants and personal fees from Amgen, grants and personal fees from BMS, grants and personal fees from MerckPfizer, grants and personal fees from MSD/Merck, grants and personal fees from Philogen, grants and personal fees from Pierre Fabre, grants and personal fees from Regeneron, personal fees from Roche, grants and personal fees from Sanofi-Genzyme, grants and personal fees from Novartis Pharma, personal fees from Eisai, personal fees from Immunocore, grants and personal fees from Replimune, personal fees from Seagen, personal fees from IO Biotech, personal fees from Dermagnostix, personal fees from Incyte, grants and personal fees from NeraCare, grants from Huya Biosciences, personal fees from Kyowa Kirin, personal fees from Highlight Therapeutics, personal fees from Iovance, personal fees from CureVac, personal fees from Xenthera, peronal fees from Agenus, personal fees from Almirall, and personal fees from Sun Pharma outside the submitted work. MJ reports fees for advisory board Pierre Fabre and AstraZeneca, paid to institution. RL has received institutional funding from Bristol Myers Squibb, Pierre Fabre, AstraZeneca, Chromition. Furthermore, speaker fees for Pierre Fabre. PL reports personal fees for advisory board membership from MLA Dx, MSD and Ultimovacs; personal fees as an invited speaker from BMS and Pierre Fabre; institutional research funding from BMS and Pierre Fabre; travel expenses from MSD; and non-remunerated roles for Cancer Research UK (clinical research committee), EORTC Melanoma Group (Chairman), Melanoma Focus charity (invited speaker) and Society for Melanoma Research (SMR) Edinburgh (invited session chair). IMR declares Advisory role: Amgen, Astra Zeneca, BiolineRx, BMS, Celegene, GSK, Highlight Therapeutics, Immunocore, Merck Serono, MSD, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi, Sun Pharma and Travel accommodation and congress: Amgen, BMS, GSK, Highlight Therapeutics, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma. OM reports personal fees for an advisory role from Amgen, BMS, GSL, MSD, Novartis, Pierre Fabre and Roche; personal fees for membership of the Scientific Board of Cellula Therapeutics; personal fees from stocks and shares from Cellula Therapeutics; institutional fees for advisory board membership from Amgen, BMS, MSD, Novartis, Pierre Fabre and Roche; institutional fees as an invited speaker from Amgen, BMS, Pierre Fabre and Roche, institutional funding from Amgen, BMS, MSD and Pierre Fabre, institutional research grants form Amgen, BMS, Merck, MSD and Pierre Fabre, institutional funding for a writing engagement from BMS and a non-remunerated role as PI for Amgen, BMS, MSD, Novartis, Pierre Fabre and Roche. PN reports personal fees for advisory board membership from 4SC, BMS, IDEAYA, Immunocore, Merck, Novartis and Pfizer; personal fees as an invited speaker from Immuncore and Novartis; personal fees for steering committee membership from 4SC; institutional research funding from Immunocore; and institutional funding as coordinating PI from BMS, Immunocore, Ipsen, Merck, Novartis and Pfizer. CR reports personal consultancy fees for advisory board membership from BMS, Egle Therapeutics, MaaT Pharma, Merck, MSD, Novartis, Pfizer, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi, Sun Pharma and Ultimovacs; personal fees as an invited speaker from BMS, MSD, Novartis, Pierre Fabre and Sanofi; personal fees as for steering committee membership from IO Biotech, Novartis, Pfizer and Regeneron; and personal fees as member of the Independent Data Monitoring Committee for Ultimovacs. DS reports personal fees for advisory board membership from Anaveon, BioNTech, BMS, CureVac, Erasca, Immatics, Immunocore, MSD, Neracare, Novartis, NoviGenix, Pfizer, Philogen, Pierre Fabre, Replimune, Sanofi/Regeneron, Sun Pharma and Ultimovacs; personal fees for expert testimony from AstraZeneca, BioAlta, Daiichi Sankyo, Formycon, InFlarX, PamGene and Seagen; personal fees as an invited speaker from BMS, Merck Serono, MSD, Neracare, Sanofi and Sun Pharma; personal fees for steering committee membership from BMS and MSD; institutional research funding from BMS and MSD; institutional funding as coordinating PI from BMS, MSD, Novartis and Pierre Fabre; institutional funding as local PI from Philogen and Sanofi; non-remunerated steering committee membership for Novartis; non-remunerated membership of the Board of Directors for EORTC-MG; and non-renumerated leadership roles as a founding member and steering committee chair for the European Melanoma Registry (EuMelaReg). PS received honoraria for lectures and consultancies from Gilead, Bristol-Myers. Squibb and Sandoz, travel grants from Pierr Fabre, MSD and Novartis; is a stockholder of Celon Pharma. LF reports grants or contracts from Hookipa Pharma, SAKK/Immunophotonics, DFG Grant Deutsche Forschungsgemeinschaft, Philogen and Mundipharma; consulting fees from Philogen, Sanofi, Novartis, BMS; participation on Data Safety Board University of Basel and stocks or stock options from Hookipa Pharma, outside the submitted work. UL reports research support from MSD, consulting fees and honoraria from Sun Pharma, Sanofi (personal and institutional), MSD (personal and institutional), Novartis, Roche, Almirall Hermal, support for attending meeting from Sun Pharma and participation on a Data Safety Monitoring Board or Advisory Board from Sun Pharma, Sanofi, MSD, Novartis, Roche, Almirall Hermal, outside the submitted work. CG reports personal fees for advisory board membership from MSD and Philogen; personal fees for an advisory role from CeCaVa and NeraCare; and a non-remunerated role as President of the European Association of Dermato-Oncology (EADO)., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To investigate the predictive value of RECIST response within 3, 6, or 12 months on long-term survival, and explore differences between nivolumab+ipilimumab and nivolumab monotherapy, we analyzed pooled 5-year data of 935 responder and non-responder patients at various time points after treatment initiation in CheckMate 069, 066, and 067 studies., Patients and Methods: Treatment-naive advanced melanoma patients received nivolumab+ipilimumab or nivolumab monotherapy. To decrease immortal time bias, 3-, 6-, or 12-month overall survival (OS) and progression-free survival (PFS) landmark analyses were performed. Association between characteristics and response was evaluated by univariate and multivariate analyses., Results: Response rates at any time were 58 % (239/409) for nivolumab+ipilimumab and 44 % (230/526) for nivolumab monotherapy. In 12-month landmark analyses, 5-year OS rates for responders versus non-responders were 82 % versus 40 % with nivolumab+ipilimumab (HR=0.23 [95 % CI, 0.15-0.35]) and 76 % versus 32 % with nivolumab monotherapy (HR=0.22 [95 % CI, 0.16-0.31]). PFS rates were 83 % versus 32 % and 69 % versus 46 %, respectively. Similar strong associations between response at 3 and 6 months and 5-year OS and PFS were also observed with more than 70 % of the responses observed in the first 3 months. Response rates correlated with baseline LDH and PD-L1 status by multivariate analysis but the association between response and long-term survival was maintained in landmark analyses even among patients with high LDH and low PD-L1 expression., Conclusion: Clinical response evaluated in the first months of therapy is a strong predictor of long-term survival, even in patients with poor prognostic biomarkers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. C. Robert disclosed medical writing support from Bristol Myers Squibb and received personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Regeneron, Roche, and Sunpharma (consulting fees); Bristol Myers Squibb, Pierre Fabre, and Sanofi (honoraria); and Regeneron and Ultimovacs (safety monitoring or advisor board). G.V. Long received consulting fees from Agenus Inc, Amgen Inc, Array Biopharma, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA Inc, Merck Sharp & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, and Regeneron Pharmaceuticals and received honoraria from Bristol Myers Squibb and Pierre Fabre. J. Larkin received consulting fees from Apple Tree, Bristol Myers Squibb, Debipharm, Eisai, Incyte, iOnctura, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Philogen, and Telix; grants or contracts to his institution from Achilles, AVEO, Bristol Myers Squibb, Immunocore, Merck Sharp & Dohme, Nektar, Pfizer, Pharmacyclics, and Roche; honoraria from Agence Unik, Bristol Myers Squibb, Eisai, GCO, Immatics, Incyte, Insighter, Merck, Novartis, Pfizer, Royal College of Physicians, TouchEXPERTS, TouchIME, and VJOncology; and discloses participation in a data safety monitoring or advisory board for IKCC. J.D. Wolchok disclosed support for the current manuscript to self as well as grant support to his institution from Bristol Myers Squibb; disclosed leadership or fiduciary role with AACR, SITC, and Ludwig Institute for Cancer Research; disclosed stock or stock options with Apricity, Ascentage Pharma, ArsenalIO/CellCarta, Georgiamune, Imvaq, Maverick, Psioxus, Tizona, and Xenimmune; received royalties and/or licenses for Xenogenic DNA Vaccines, Newcastle Disease viruses for Cancer Therapy, Myeloid-derived suppressor cell assay, Prediction of Responsiveness to treatment with immunomodulatory, anti-PD1 antibody, Anti-CTLA4 antibody, and anti-GITR antibodies and methods thereof; received consulting fees from Apricity, Ascentage Pharma, AstraZeneca, CellCarta, Bicara Therapeutics, Bristol Myers Squibb, CellCarta, Chugai, Daiichi Sankyo, Dragonfly, Imvaq, Psioxus, Takeda, Tizona, Trishula Therapeutics, Xenimmune;. J.C. Hassel received honoraria from Amgen, Bristol Myers Squibb, Delcath, GlaxoSmithKline, Immunocore, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sunpharma; advisory board support from GSK, Onkowissen, Pierre Fabre, and Sunpharma; and travel support from Bristol Myers Squibb, Iovance, and Sunpharma. D. Schadendorf disclosed personal interest as an invited speaker for Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Roche, and Sanofi; personal interest for advisory board participant for Bristol Myers Squibb, Immunocore, Merck Sharp & Dohme, Neracare, Novartis, Pfizer, Philogen, Pierre Fabre, and Sanofi/Regeneron; received institutional grant support from Bristol Myers Squibb, and Merck Sharp & Dohme; disclosed no financial interest as an institutional primary investigator for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Philogen, Pierre Fabre, and Sanofi; disclosed interest as a. F.S. Hodi disclosed support for the current manuscript from Bristol Myers Squibb; royalties or licences from Bristol Myers Squibb and from Novartis (both to institution), leadership or fiduciary role as well as stock options for Apricity and Biocara; and receipt of gifts or services from Bristol Myers Squibb and Merck; received grants from 7 Hills, Amgen, Apricity, Bicara, Bioentre, Catalym, Checkpoint Therapeutics, Compass, Gossamer, Immunocore, Iovance, Merck, Novartis, Rheos, Solu Therapeutics, Surface, and Zumutor; received honoraria from George Washington University; and has patents planned, issued or pending for Methods for Treating MICA-Related Disorders (#20100111973), Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603), Therapeutic peptides (#20160046716), Tumor antigens and uses thereof (#7250291), Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407), METHODS OF USING PEMBROLIZUMAB AND TREBANANIB, Vaccine compositions and methods for restoring NKG2D pathway function against cancers (#10279021), Antibodies that bind to MHC class I polypeptide-related sequence A (#10106611), ANTI-GALECTIN ANTIBODY BIOMARKERS PREDICTIVE OF ANTI-IMMUNE CHECKPOINT AND ANTI-ANGIOGENESIS RESPONSES (# 20170343552), and Antibodies against EDIL3 and methods of use thereof. C. Lebbe received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre; grants from Bristol Myers Squibb, Melbase project, Melbase and PREDIMEL projects, and Pierre Fabre; travel expenses from Pierre Fabre; and has participated on a data safety or advisory board for Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. J.-J. Grob received consulting fees from Bristol Myers Squibb and Novartis; and participated on advisory boards for Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Philogen, Pierre Fabre, Roche, and Sanofi. J.R. Hyngstrom disclosed institutional trial support from Amgen, Bristol Myers Squibb, Iovance, Lyell, Merck, Natera, Philogen, Regeneron, Skyline, and Takara. J. Wagstaff has no conflicts to disclose. J. Chesney disclosed medical writing support and article processing and charges from Bristol Myers Squibb for the current manuscript. M.O. Butler received consulting fees from Adaptimmune, Bristol Myers Squibb, GlaxoSmithKline, Immunocore, Ideaya Bio, Instil Bio, IOVANCE, LaRoche Possey, Medison, Merck, Novartis, Pfizer, Regeneron, Sanofi, and Sun Pharma; grants from Merck, Novartis, and Takara Bio; honoraria from Bristol Myers Squibb, Merck, Novartis, Pfizer, and Sanofi; and participated on safety review committees for Adaptimmune and GlaxoSmithKline. O. Bechter disclosed medical writing support from Bristol Myers Squibb for the current manuscript. I. Márquez-Rodas received consulting fees from Amgen, Astra Zeneca, BiolineRx, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Highlight Therapeutics, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi, and Sun Pharma; received travel fees from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Highlight Therapeutics, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sun Pharma; and discloses a leadership or fiduciary role for Spanish Melanoma Group. A.C. Pavlick received consulting fees and honoraria from Bristol Myers Squibb, Merck, and Replimune. P. Durani disclosed employment and stock or stock options with Bristol Myers Squibb. M. Pe Benito disclosed employment and stock or stock options with Bristol Myers Squibb. P. Wang disclosed employment and stock or stock options with Bristol Myers Squibb. M.A. Postow received support for the current manuscript from Bristol Myers Squibb, grants from Bristol Myers Squibb, Infinity, Merck, Novartis, and RGenix, consulting fees from Bristol Myers Squibb, Chugai, Eisai, Merck, Nektar, Novartis, Pfizer, and Replimune; travel support from Bristol Myers Squibb and Pfizer; and also participated in a data safety monitoring or advisory board for Bristol Myers Squibb and Pfizer. P.A. Ascierto received consulting fees from Bayer, Bio-Al Health, Bristol Myers Squibb, Italfarmaco, Lunaphore, Merck Serono, Merck Sharp & Dohme, Nektar, Novartis, Pfizer Medicenna, Philogen, Pierre-Fabre, Replimmune, Roche-Genentech, Sandoz, Sanofi, Sun Pharma, and ValoTx; participated on a safety monitoring or advisory board for AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Erasca, Italfarmaco, iTeos, Lunaphore, Merck Serono, Merck Sharp & Dohme, Nektar, Nouscom, Novartis, Oncosec, Pfizer Medicenna, Philogen, Pierre-Fabre, Regeneron, Replimmune, Roche-Genentech, Sandoz, Sanofi, Seagen, Sun Pharma, and ValoTx; received grants from Bristol Myers Squibb, Pfizer, Roche-Genentech, and Sanofi; and received travel fees from Bio-Al Health, Merck Sharp & Dohme, Pfizer, and Replimmune., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Advances in cancer treatments have significantly improved their effectiveness, yet access to first-line therapies remains limited. A 2017 survey revealed that over 25 % of metastatic melanoma patients in Europe lacked access to recommended therapies. To address this, the European Association of Dermato-Oncology and the European Melanoma Registry conducted a follow-up study on the registration and reimbursement of first-line treatments.A web-based survey using LimeSurvey was distributed to melanoma experts across 27 European countries from February to April 2022 and updated from February to April 2024. The questionnaire covered the percentage of patients receiving recommended treatments, as well as treatment authorization and reimbursement dates for systemic and adjuvant therapies.There has been significant improvement in the registration and reimbursement of BRAFi/MEKi, anti-PD1, and anti-PD1/anti-CTLA4 therapies, increasing from 48 %, 63 %, and 37 % in 2017 to 96 %, 96 %, and 78 % in 2024, respectively. Despite these gains, restrictions persist. Anti-PD1/anti-CTLA4 combination immunotherapy is still not available without restrictions in 48 % of the surveyed countries. The nivolumab/relatlimab combination is licensed only for PDL-1-negative melanoma and reimbursed in seven countries of Europe. Tebentafusp is reimbursed in 15 countries and talimogene laherpervec in 5. In 2024, adjuvant treatments for stage III melanoma are reimbursed in 22 countries for dabrafenib/trametinib and 24 of 27 for anti-PD1 antibodies. Pembrolizumab and nivolumab are reimbursed in 15 and 8 countries, respectively, for stage IIB/IIC disease.While there have been improvements in the reimbursement of metastatic melanoma treatments in Europe, challenges and discrepancies remain. Further efforts at European and global levels are needed to harmonize and enhance access to cancer medicines., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:LK received consulting fees from MSD, Merck, AbbVie, and Janssen; honoraria for lectures and presentations from BMS, MSD, Novartis, Merck, Roche, AbbVie, and Janssen, support for attending meetings and travel from BMS, MSD, Novartis, and Janssen, outside of submitted work. NCS received consulting fees from MSD, Roche, and Novartis. JKS received non-financial support from MSD and Amgen, personal fees from Novartis, and payments to her institution from AstraZeneca, Roche, MSD, BMS, Servier, and Lilly for advisory boards, consultancy, lectures, and travel. PL received consulting fees from Amgen, BMS, MSD, Nektar, Novartis, and Pierre Fabre, honoraria for lectures and presentations from Amgen, BMS, Merck, MSD, Nektar, NeraCare GmbH, Novartis, Oncology Education, Pierre Fabre, and Roche, and support for attending meetings and travel from BMS and MSD. IS received honoraria for lectures and presentations from Roche, Novartis, Swixx, Pierre Fabre, BIOCAD, and R-Farm, with no other financial or non-financial interests reported. PA has nothing to disclose. CH reports personal fees from MSD, Roche, Novartis, BMS, Pierre Fabre, outside the submitted work. HG includes honoraria from BMS, MSD Oncology, Pierre Fabre, and Sanofi/Regeneron, consulting or advisory roles with BMS, MSD Oncology, Pierre Fabre, and Sanofi/Regeneron, research funding from BMS, Roche, MSD Oncology, Amgen, Novartis, and Iovance Biotherapeutics (all to the institution), and travel, accommodations, and expenses covered by MSD, Pfizer, and Sanofi. IG reported roles with speakers' bureaux for Roche, Novartis, MSD, BMS, Sanofi, Merck, Pierre Fabre, and Medison, received honoraria from Roche, Novartis, MSD, BMS, Sanofi, Merck, Pierre Fabre, and Medison, and held consulting/advisory roles with MSD, BMS, Pierre Fabre, and Medison, along with travel/accommodations expenses from MSD, BMS, and Pierre Fabre. JH received honoraria from BMS, MSD, Novartis, Pierre Fabre, and Sunpharma, with consulting/advisory roles at AstraZeneca, BioNTech, BMS, Novartis, research funding from BMS, MSD, Novartis, Amgen, Roche, and Pfizer (to institution), and travel/accommodations support from Pierre Fabre. PA held consultant/advisory roles with Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, and other companies, received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, and Sanofi (to institution), and received travel support from Pfizer, Bio-Al Health, Replimmune, MSD, and Pierre Fabre. LM declared no known competing financial interests or personal relationships. JM reported consulting/advisory roles with Merck/Pfizer, Merck Sharp & Dohme, Novartis, Roche, Pierre Fabre, and Bristol Myers Squibb, and received travel/congress support from Ultrasun, L′Oreal, Merck Sharp & Dohme, Bristol Myers Squibb, and Pierre Fabre. PR reported consulting fees from BMS, MSD, Novartis, Pierre Fabre, Philogen, Pfizer, Genesis, and Madison Pharma, received payment or honoraria from BMS, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, Merck, and AstraZeneca, was part of speakers’ bureau for Pfizer, Novartis, Pierre Fabre, MSD, and BMS, and received support for meetings/travel from Orphan Europe and Pierre Fabre, along with research funding from Novartis, Pfizer, Roche, and BMS (to institution). JO declared no known competing financial interests or personal relationships. MR held advisory roles at Amgen, AstraZeneca, BiolineRx, BMS, Celegene, GSK, Highlight Therapeutics, Immunocore, Merck Serono, MSD, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi, and Sun Pharma, and received travel/accommodation support from Amgen, BMS, GSK, Highlight Therapeutics, MSD, Novartis, Pierre Fabre, Roche, and Sun Pharma. MK gave lectures for MSD, Novartis, and Roche, and received travel grants from MSD, Novartis, and Roche. JuO received speaker fees from MSD, Sanofi, Novartis, and BMS. IS declared no known competing financial interests or personal relationships. JK was a speaker for BMS and Janssen. LB declared no known competing financial interests or personal relationships. PM received honoraria for advisory or consultancy roles with Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi, Immunocore, Sun Pharma, and Regeneron, research grant/funding from BMS, Novartis, and MSD, and travel/accommodations support from Pierre Fabre, MSD, Merck, Sun Pharma, and Regeneron. CG reported consulting fees and honoraria from MSD, Novartis, NeraCare, BMS, Philogen, and Sanofi. PS received honoraria from Novartis, BMS, Pierre Fabre, MSD, and Merck-Serrono, with travel support from ASCO, EADV, and ESMO. AH received grants from MSD/Merck, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis, and Eisai, honoraria from MSD/Merck, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis, and Eisai, and served on advisory boards for MSD/Merck, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis, Eisai, Immunocore, Replimune, and Seagen. AL declared no competing interests. AMF received honoraria from Novartis., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: There is currently no staging system for cutaneous squamous cell carcinoma (cSCC) that is adapted to decision-making and universally used. Experts have unconscious ability to simplify the heterogeneity of clinical situations into a few relevant groups to drive their therapeutic decisions. Therefore, we have used unsupervised clustering of real cases by experts to generate an operational classification of cSCCs, an approach that was successful for basal cell carcinomas., Objective: To generate a consensual and operational classification of cSCCs., Method: Unsupervised independent clustering of 248 cases of cSCCs considered difficult-to-treat. Eighteen international experts from different specialties classified these cases into what they considered homogeneous clusters useful for management, each with freedom regarding clustering criteria. Convergences and divergences between clustering were analysed using a similarity matrix, the K-mean approach and the average silhouette method. Mathematical modelling was used to look for the best consensual clustering. The operability of the derived classification was validated on 23 new practitioners., Results: Despite the high heterogeneity of the clinical cases, a mathematical consensus was observed. It was best represented by a partition into five clusters, which appeared a posteriori to describe different clinical scenarios. Applicability of this classification was shown by a good concordance (94%) in the allocation of cases between the new practitioners and the 18 experts. An additional group of easy-to-treat cSCC was included, resulting in a six-group final classification: easy-to-treat/complex to treat due to tumour and/or patient characteristics/multiple/locally advanced/regional disease/visceral metastases., Conclusion: Given the methodology based on the convergence of unguided intuitive clustering of cases by experts, this new classification is relevant for clinical practice. It does not compete with staging systems, but they may complement each other, whether the objective is to select the best therapeutic approach in tumour boards or to design homogeneous groups for trials., (© 2024 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Competing Interests: Disclosure IL reports personal fees for writing engagements for ESMO and Roche; personal and institutional fees as coordinating principal investigator (PI) for Agenus, Amgen, AstraZeneca, Bristol Myers Squibb (BMS), Celon, Incyte, Janssen, Menarini, MSD, Pfizer, Rhizen, Roche, RyVu and Siropa; institutional research grants from Agenus and Roche; non-financial interests as project lead for MSCI and board member for OECI; spouse has co-ownership of Clininote. JCB reports personal fees as a data safety monitoring board member for 4SC; personal fees as an advisory board member for Almirall, Amgen, Boehringer, InProTher, Merck, Recordati and Sanofi; institutional research grants from Alcedis, IQVIA and Merck; non-financial interests for receipt of product samples from 4SC. PAA reports personal fees for consultancy roles for 4SC, AstraZeneca, Bio-AI Health, BMS, Boehringer Ingelheim, Daiichi Sankyo, Idera, Immunocore, Italfarmaco, iTeos, Lunaphone, Medicenna, Merck Serono, MSD, Nektar, Nouscom, Novartis, Oncosec, Pfizer, Pfizer/Array, Pierre Fabre, Regeneron, Replimmune, Roche Genentech, Sandoz, Sanofi, Sun Pharma and ValoTx; personal fees for advisory roles for 4SC, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eisai, Idera, Immunocore, iTeos, Merck Serono, MSD, Nektar, Novartis, Pfizer/Array, Pierre Fabre, Regeneron, Replimmune, Roche Genentech, Sandoz, Sanofi, Seagen, Sun Pharma and ValoTx; personal fees as an advisory board member from Erasca, iTeos, Replimmune and ValoTx; personal fees as travel support from Bio-AI-Health, Pfizer/Array and Replimmune; institutional funding from BMS, Pfizer/Array, Roche Genentech and Sanofi; non-financial interests as President of SCITO (Campania Society of ImmunoTherapy of Cancer) and Fondazione Melanoma Onlus Italy; non-financial interests as a member of the board of directors of the Society for Immunotherapy of Cancer (SITC; November 2017-December 2021) and a member of the steering committee for the Society for Melanoma Research (SMR); non-financial interests as a member of the Associazione Italiana di Oncologia Medica (AIOM), American Society of Clinical Oncology (ASCO), the European Organisation for Research and Treatment of Cancer (EORTC), Melanoma Cooperative Group, SITC and SMR. MV reports no potential conflicts of interests. ABl reports personal fees for advisory board membership from Merck (consultant for revision of approval of avelumab by French authorities). CL reports personal fees as an advisory board member from Amgen, BMS, Merck Serono, MSD, Novartis, Pierre Fabre, Roche and Sanofi; funding from BMS and Roche; non-financial interests for advisory roles for Amgen, BMS, Merck Serono, MSD, Novartis, Pierre Fabre, Roche and Sanofi; honoraria from Amgen, BMS, Incyte, MSD, Novartis, Pfizer, Pierre Fabre and Roche; travel/accommodation expenses from Avantis Medical Systems, BMS, Jazz Pharmaceuticals, MSD, Novartis, Pierre Fabre and Sanofi; research funding from BMS and Roche; participation on a data safety monitoring board/advisory board for InfalRx. EM reports no potential conflicts of interests. OH-V reports no potential conflicts of interests. MG reports personal fees for expert testimony from Almirall; personal fees as an advisory board member for GSK, Leo Pharma and Pfizer; personal fees as an invited speaker from GSK, Janssen, Lilly and Novartis; personal stocks/shares in BioNTech, Novo Nordisk and Siemens Healthineers; institutional fees as coordinating PI for Argenx and as local PI for Boehringer Ingelheim, Galderma, Janssen, Novartis and UCB Pharma; non-financial interests as Treasurer of the Deutsche Dermatologische Gesellschaft (DDG) and member of the board of directors of University Hospital Würzburg. HK reports no potential conflicts of interests. PN reports personal fees as an advisory board member for 4SC, BMS, IDEAYA Biosciences, Immunocore, Merck, Novartis and Pfizer; personal fees as an invited speaker for Novartis; institutional research support from Immunocore; non-financial interests as a steering committee member (personal) for 4SC and coordinating PI (institutional) for BMS, Immunocore, Ipsen, Merck, Novartis and Pfizer. PR reports personal fees as an invited speaker for AstraZeneca, BMS, Merck, MSD, Novartis, Pierre Fabre and Sanofi; personal fees as an advisory board member for Blueprint Medicines, BMS, Merck, MSD, Philogen, Pierre Fabre and Sanofi; institutional research grants from BMS and Pfizer; non-financial interests as President of the Polish Oncological Society and a member of the board of directors of the Polish Society of Surgical Oncology. MS reports personal fees as an invited speaker for Aristo-Pharma, Medac, Novartis and Takeda; personal fees as an advisory board member for Novartis and Takeda; personal fees as a PI for Amgen, Dermira, Eli Lilly and Company, Galderma, Parexel International and Regeneron; personal fees as a sub-investigator (SI) for OBWF NIO-PIB, Eli Lilly and Takeda. DS reports personal fees as an invited speaker for BMS, Merck Serono, MSD, Novartis, Roche and Sanofi; personal fees as an advisory board member for BMS, Immunocore, MSD, Neracare, Novartis, Pfizer, Philogen, Pierre Fabre and Sanofi/Regeneron; personal fees as a steering committee member for BMS, MSD and Novartis; institutional research grants from BMS and MSD; institutional fees as coordinating PI for BMS, MSD, Novartis and Pierre Fabre; institutional fees as local PI for Philogen and Sanofi; a non-financial interest as a member of the board of directors of EORTC-MG. JMP reports personal fees as an advisory board member for Astellas, AstraZeneca, BeiGene, BMS, Janssen, MSD, Roche and VCN Biosciences; personal and institutional research grants from BeiGene, BMS, Janssen, Mirati and Pfizer. FP reports no potential conflicts of interests. ACJvA reports institutional fees as an advisory board member for 4SC, Amgen, BMS, Merck–Pfizer, MSD–Merck, Novartis, Pierre Fabre, Provectus, Sanofi and Sirius Medical; institutional research grants from Amgen and Merck–Pfizer. ABe reports personal fees as an invited speaker for Amgen and HRA; personal fees as an advisory board member for Amgen, Astellas, Ipsen and Janssen; institutional funding from Astellas and Janssen; non-financial interests for receipt of product samples from Novartis and Sanofi.

Most anti-cancer modalities are designed to directly kill cancer cells deploying mechanisms of action (MOAs) centered on the presence of a precise target on cancer cells. The efficacy of these approaches is limited because the rapidly evolving genetics of neoplasia swiftly circumvents the MOA generating therapy-resistant cancer cell clones. Other modalities engage endogenous anti-cancer mechanisms by activating the multi-cellular network (MCN) surrounding neoplastic cells in the tumor microenvironment (TME). These modalities hold a better chance of success because they activate numerous types of immune effector cells that deploy distinct cytotoxic MOAs. This in turn decreases the chance of developing treatment-resistance. Engagement of the MCN can be attained through activation of immune effector cells that in turn kill cancer cells or when direct cancer killing is complemented by the production of proinflammatory factors that secondarily recruit and activate immune effector cells. For instance, adoptive cell therapy (ACT) supplements cancer cell killing with the release of homeostatic and pro-inflammatory cytokines by the immune cells and damage associated molecular patterns (DAMPs) by dying cancer cells. The latter phenomenon, referred to as immunogenic cell death (ICD), results in an exponential escalation of anti-cancer MOAs at the tumor site. Other approaches can also induce exponential cancer killing by engaging the MCN of the TME through the release of DAMPs and additional pro-inflammatory factors by dying cancer cells. In this commentary, we will review the basic principles that support emerging paradigms likely to significantly improve the efficacy of anti-cancer therapy., (© 2024. The Author(s).)

Background: Immune checkpoint blockade in monotherapy or combinatorial regimens with chemotherapy or radiotherapy have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) antibody, Relatlimab, has been approved by FDA in combination with Nivolumab for metastatic melanoma therapy. Moreover, Atezolizumab is actually under study in association with Ipilimumab for therapy of metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies could expose patients to more adverse cardiovascular events., Methods: Human cardiomyocytes co-cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, troponin-T, BNP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Mitochondrial functions were studied in cardiomyocyte cell lysates through quantification of intracellular Ca ++ , ATP content and NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) levels. Histone deacetylases type 4 (HDAC-4) protein levels were also determined in cardiomyocyte cell lysates to study potential epigenetic changes induced by immunotherapy regimens., Results: Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. HDAC4 and intracellular Ca ++ levels were increased, instead ATP content and Ndufs1 were reduced in myocardial cell lysates ( p  < 0.001 vs. untreated cells). Troponin-T, BNP, NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy compared to monotherapy regimen. NLRP3 expression, IL-6 and IL-1β levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies., Conclusions: Data of the present study, although in vitro , indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists., Competing Interests: All 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., (© 2024 Quagliariello, Passariello, Bisceglia, Paccone, Inno, Maurea, Rapuano Lembo, Manna, Iovine, Canale, Scherillo, Ascierto, Gabrielli, De Lorenzo and Maurea.)

Background: Immune checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients; however, 65-80% of patients treated with ICI experience immune-related adverse events (irAEs). Given the plausible link of irAEs with underlying host immunity, we explored whether germline genetic variants controlling the expression of 42 immunomodulatory genes were associated with the risk of irAEs in melanoma patients treated with the single-agent anti-CTLA-4 antibody ipilimumab (IPI)., Methods: We identified 42 immunomodulatory expression quantitative trait loci (ieQTLs) most significantly associated with the expression of 382 immune-related genes. These germline variants were genotyped in IPI-treated melanoma patients, collected as part of a multi-institutional collaboration. We tested the association of ieQTLs with irAEs in a discovery cohort of 95 patients, followed by validation in an additional 97 patients., Results: We found that the alternate allele of rs7036417, a variant linked to increased expression of SYK, was strongly associated with an increased risk of grade 3-4 toxicity [odds ratio (OR) = 7.46; 95% confidence interval (CI) = 2.65-21.03; p = 1.43E-04]. This variant was not associated with response (OR = 0.90; 95% CI = 0.37-2.21; p = 0.82)., Conclusion: We report that rs7036417 is associated with increased risk of severe irAEs, independent of IPI efficacy. SYK plays an important role in B-cell/T-cell expansion, and increased pSYK has been reported in patients with autoimmune disease. The association between rs7036417 and IPI irAEs in our data suggests a role of SYK overexpression in irAE development. These findings support the hypothesis that inherited variation in immune-related pathways modulates ICI toxicity and suggests SYK as a possible future target for therapies to reduce irAEs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RF, VC, LM, DS, KM, EC, SZ, GM, MC, ES, IO and TK have no competing interests to report. AP: consultant for BMS, Merck and Regeneron. JL is on Data and Safety Monitoring Board (DSMB): Abbvie, Agenus, Amgen, Immutep and Evaxion; Scientific Advisory Board: (no stock) 7 Hills, Affivant, BioCytics, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe and Tempest; consultancy with compensation: Abbvie, Agenus, Alnylam, Atomwise, Bayer, Bristol-Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic and Synthekine; research support: (all to institution for clinical trials unless noted) AbbVie, Astellas, Astrazeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona and Xencor; patents: (both provisional) Serial #15/612657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). TFG is a consultant on advisory boards for Merck, Jounce, Fog Pharma, Adaptimmune, Pyxis, Allogene, Catalym, Bicara, Maia and Samyang; he has research support from BMS, Merck, Seattle Genetics, Evelo, Bayer and Pyxis; he has intellectual property/licensing with Aduro, Evelo and BMS and is a co-founder/shareholder for Jounce and Pyxis. PAA has/had consultant/advisory roles for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna and Bio-Al Health. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer and Sanofi; all of the above took place outside the submitted work. JW owns stock or other ownership at Altor BioScience, Biond, CytomX Therapeutics; received honoraria from Bristol-Myers Squibb, Merck, Genentech, AbbVie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Amgen, Roche, Ichor Medical Systems, Celldex, CytomX Therapeutics, Nektar, Novartis, Sellas, WindMIL and Takeda; has consulting/advisory role at Celldex, Ichor Medical Systems, Biond, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, AbbVie, Eisai, CytomX Therapeutics, Nektar, Novartis, Sellas, WindMIL and Takeda; obtained research funding (to the institution) from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Genentech, Astellas Pharma, Incyte, Roche and Novartis; and received funding for travel/accommodations/expenses from Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis, WindMIL and Takeda., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Skin metastases are an important co-morbidity in melanoma. Despite broad adoption, electrochemotherapy implementation is hindered by a lack of treatment indications, uncertainty regarding procedural aspects, and the absence of quality indicators. An expert consensus may harmonize the approach among centres and facilitate comparison with other therapies., Methods: An interdisciplinary panel was recruited for a three-round e-Delphi survey. A literature-based 113-item questionnaire was proposed to 160 professionals from 53 European centres. Participants rated each item for relevance and degree of agreement on a five-point Likert scale, and received anonymous controlled feedback to allow revision. The items that reached concordant agreement in two successive iterations were included in the final consensus list. In the third round, quality indicator benchmarks were defined using a real-time Delphi method., Results: The initial working group included 122 respondents, of whom 100 (82 per cent) completed the first round, thus qualifying for inclusion in the expert panel (49 surgeons, 29 dermatologists, 15 medical oncologists, three radiotherapists, two nurse specialists, two clinician scientists). The completion rate was 97 per cent (97 of 100) and 93 per cent (90 of 97) in the second and third rounds respectively. The final consensus list included 54 statements with benchmarks (treatment indications, (37); procedural aspects, (1); quality indicators, (16))., Conclusion: An expert panel achieved consensus on the use of electrochemotherapy in melanoma, with a core set of statements providing general direction to electrochemotherapy users to refine indications, align clinical practices, and promote quality assurance programmes and local audits. The residual controversial topics set future research priorities to improve patient care., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Immune Checkpoint inhibitors (ICI) are linked to a series of adverse systemic and/or oral side effects such as "stomatitis," "oral inflammation" and "mucositis." These oral lesions induced by target therapies and immune checkpoint inhibitors are different from traditional lesions associated with chemo/radiotherapy and they have not yet been correctly characterized. This paper aims to report retrospectively the oral immune-related adverse events caused by immune checkpoint inhibitors., Methods: A table in electronic format was prepared and sent by e-mail to several clinical structures in order to collect, for each patient, anamnestic data, discretionary habits, systemic risk factors, the presence and number of comorbidities, and the characteristics of the oral lesions in the course of oncological therapy with anti-PD1 (nivolumab, pembrolizumab). Following the collection of anamnestic and clinical data relating to patients treated with anti-PD1 (nivolumab, pembrolizumab) and the detection of oral lesions, data analysis was carried out., Results: A number of 364 patients treated with nivolumab (209) and pembrolizumab (155), administered intravenously at a therapeutic dose were selected. There have been cases of oral adverse effects in treated patients. The oral adverse effects found fell into the categories of stomatitis, xerostomia, candidiasis and taste disturbances. Analyzing the incidence of oral lesions in patients undergoing treatment with immune checkpoint inhibitors, there was no significant difference between the two drugs examined., Conclusions: Further studies are certainly needed to catalog, focus and identify in advance the adverse effects, including oral ones, in patients treated with ICI type PD1/PDL-1. It is necessary, for the benefit of patients, to pay particular attention to the adverse effects in order to recognize, treat and possibly modulate the therapy with an adequate assessment of the cost/benefit ratio and quality of life.

Background: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race., Patients and Methods: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted., Results: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01)., Conclusions: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival., Competing Interests: Disclosure FD: receives/received honoraria and travel support from Merck Sharp & Dohme Bristol-Myers Squibb and Sun Pharma. KN: honoraria from Ono Pharmaceutical, Novartis Pharma, Bristol-Myers Squibb and MSD. EIB: has received consulting fees from BMS and Novartis; has research funding paid to the institution from BMS, Merck, Novartis and Genentech. JAS: conference support from MSD. AZ: received travel support from Novartis, Sanofi Grenzyme and Bristol-Myers Squibb, outside the submitted work. MJM: served as a consultant for AstraZeneca, immunai, nektar therapeutics, catalyst pharmaceuticals and istari oncology. YN: consultant/advisory board—MSD, Novartis. Institutional research funding—Kaken, Ono pharma, Pola Pharma, Torii. Honoraria—BMS, Maruho, MSD, Novartis, Ono Pharma, Taisho Toyama, Taiho Pharma. XB: merit award supported by BMS.CA: Travel accommodations—meetings: Roche, BMS, AMGEN. AI: advisory board: Novartis. Honoraria for lectures: BMS, MSD, Novartis, Sanofi, Pierre-Fabre. MF: advisory board—Bayer. KCK: has served as consultant and/or 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. VA: personal fees: Bristol Myers Squibb, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Oncosec. OK: personal fees from Bristol Myers Squibb and Merck Sharp & Dohme, outside the submitted work. AH: has served on advisory boards for BMS, MSD, Novartis, Pierre Fabre and Q Biotic. RDC: consultant/advisory board—Alkermes, Aura Biosciences, Bristol Myers Squibb, Castle Biosciences, Chimeron, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Rgenix, Sanofi Genzyme, Sorrento Therapeutics, Trisalus. OH: speaker’s bureau honoraria from BMS, Novartis, Pfizer and Sanofi Regeneron, and is an advisory board member/consultant for Aduro, Akeso Bio, Amgen, Beigene, Bioatla, BMS, Roche Genentech, GSK, Immunocore, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi Regeneron, Seagen, Tempus and Zelluna. AH: received grants and personal fees from Amgen, BMS, Immunocore, Novartis, MerckSerono, MSD/Merck, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme and Sun Pharma, 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. MM: received honoraria for participation at advisory boards from Novartis, BMS, MSD, Pierre Fabre, Sanofi, reports lecture from Novartis, BMS, MSD, Pierre Fabre, Sanofi and reports grants from Roche, Novartis. CR: advisor for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Merck, Roche, AstraZeneca and is scientific founder of Aglaia therapeutics. CL: BMS: research grant, honoraria, consultancy, speaker’s bureau, travel accommodations—meetings, advisory role, serving on an advisory board; MSD: honoraria, consultancy, advisory role, serving on an advisory board, travel accommodations—meetings; Novartis: honoraria, consultancy, speaker’s bureau, advisory role, serving on an advisory board; Amgen: honoraria, consultancy, speaker’s bureau, serving on an advisory board; Roche: research grant, honoraria, consultancy, speaker’s bureau, advisory role, serving on an advisory board; Avantis Medical Systems: board; Pierre-Fabre/Pfizer/Incyte: honoraria. JG: consultant/advisory boards for MSD, Roche, Pfizer, Bayer, Novartis, Simcere Pharmaceutical Group, Shanghai Junshi Biosciences and Oriengene. DBJ: advisory boards for Array Biopharma, Bristol Myers Squibb, Catalyst Biopharma, Iovance Biotherapeutics, Janssen, Merck, Novartis and OncoSec. Research support from Bristol Myers Squibb and Incyte. PAA: has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. ANS: advisory board/personal fees: Bristol-Myers Squibb, Immunocore, Novartis, Castle Biosciences. Institutional trial support: Bristol-Myers Squibb, Immunocore, Novartis, Xcovery, Polaris, Pfizer, Checkmate Pharmaceuticals, Forghorn Therapeutics. RJS: advisory board—BMS, Merck, Novartis, Pfizer; research support from Merck. LZ: served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis. SS: grants from Novartis, AstraZeneca, Merck Sharp & Dohme and Genentech; and personal fees from AstraZeneca, Merck Sharp & Dohme and Bristol Myers Squibb, outside the submitted work. CUB: personal fees from BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, grants from BMS, Novartis, NanoString, other from Uniti Cars, Forty Seven, Neon Therapeutics, Verastem, other from Immagene B.V. RD: intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA and touchIME outside the submitted work. BCS: speaker’s bureau honoraria and personal fees from BMS, Novartis, MDS, Pierre Fabre. AMM: advisory board—BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. GVL: 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, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc. All other authors have declared no conflicts of interest. Data sharing Availability of data and material: patients’ medical records. All data were anonymized immediately after collection., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF V600 -mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy., Patients and Methods: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers., Results: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (

Background: Drug-induced interstitial lung disease (DIILD) is a form of interstitial lung disease resulting from exposure to drugs causing inflammation and possibly interstitial fibrosis. Antineoplastic drugs are the primary cause of DIILD, accounting for 23%-51% of cases, with bleomycin, everolimus, erlotinib, trastuzumab-deruxtecan and immune checkpoint inhibitors being the most common causative agents. DIILD can be difficult to identify and manage, and there are currently no specific guidelines on the diagnosis and treatment of DIILD caused by anticancer drugs., Objective: To develop recommendations for the diagnosis and management of DIILD in cancer patients., Methods: Based on the published literature and their clinical expertise, a multidisciplinary group of experts in Italy developed recommendations stratified by DIILD severity, based on the Common Terminology Criteria for Adverse Events., Results: The recommendations highlight the importance of multidisciplinary interaction in the diagnosis and management of DIILD. Important components of the diagnostic process are physical examination and careful patient history-taking, measurement of vital signs (particularly respiratory rate and arterial oxygen saturation), relevant laboratory tests, respiratory function testing with spirometry and diffusing capacity of the lung for carbon monoxide and computed tomography/imaging. Because the clinical and radiological signs of DIILD are often similar to those of pneumonias or interstitial lung diseases, differential diagnosis is important, including microbial and serological testing to exclude or confirm infectious causes. In most cases, management of DIILD requires the discontinuation of the antineoplastic agent and the administration of short-term steroids. Steroid tapering must be undertaken slowly to prevent reactivation of DIILD. Patients with severe and very severe (grade 3 and 4) DIILD will require hospitalisation and often need oxygen and non-invasive ventilation. Decisions about invasive ventilation should take into account the patient's cancer prognosis., Conclusions: These recommendations provide a structured step-by-step diagnostic and therapeutic approach for each grade of suspected cancer-related DIILD., Competing Interests: Disclosure PC has received honoraria for consultation from Daiichi Sankyo. PAA has received grants and honoraria for consultation from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Idera Pharmaceuticals, Immunocore, Italfarmaco, iTeos Therapeutics, Lunaphore Technologies, Merck Serono, MSD, Nektar Therapeutics, Nouscom, Novartis, OncoSec, Pfizer, Pierre Fabre Pharma, 4SC, Regeneron Pharmaceuticals, Roche-Genentech, Sandoz, Sanofi, Seagen and Sun Pharma. RD has received grants and honoraria for consultation from AstraZeneca, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Novartis and Pfizer. PT has received grants and honoraria for consultation from Daiichi Sankyo, Incyte, MedicAir and Vertex. AC has received honoraria for consultation from Angelini, Gilead Sciences and Janssen. MDL has received honoraria for consultation from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead Sciences, MSD, Novartis, Pfizer, Pierre Fabre Pharma, Roche-Genentech and Seagen. AF has received grants and honoraria for consultation from Amgen, Bayer HealthCare Pharmaceuticals, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Incyte, Merck Serono, MSD, Pierre Fabre Pharma, Roche-Genentech and Servier. LR has received grants and honoraria for consultation from Biogen, Boehringer Ingelheim, Celgene Corporation, Cipla, CSL Behring, FibroGen, Nitto BioPharma, Pliant Therapeutics, Promedior, Respivant Sciences, Roche-Genentech, Sanofi Aventis and Zambon. SS has received grants and honoraria for consultation from Agenus, AstraZeneca, Bayer HealthCare Pharmaceuticals, Bristol Myers Squibb, CheckMab, Daiichi Sankyo, Merck Serono and Seagen. The remaining authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Real-world data on extended follow-up of patients with BRAF V600-mutant metastatic melanoma are limited. We investigated dabrafenib plus trametinib (dab + tram) outside of a clinical trial setting (Individual Patient Program; DESCRIBE Italy)., Objective: To describe the baseline features, treatment patterns, efficacy, and safety outcomes in patients with BRAF V600-mutant unresectable or metastatic melanoma who had received dab + tram as part of the Managed Access Program (MAP) in Italy., Patients and Methods: An observational, retrospective chart review was conducted in Italian patients with BRAF V600-mutant unresectable stage III/IV melanoma receiving dab + tram as part of the MAP. Baseline features, treatment patterns, efficacy, and safety outcomes were evaluated., Results: Overall, 499 patients were included in this analysis. BRAF V600E mutation was seen in 81.4% of patients. Overall response rate achieved in 243 of the 390 evaluable patients was 62.3% (95% CI 57.5-67.1). Median progression-free survival (PFS) was 9.3 months (95% CI 8.6-10.6). Subgroup analyses revealed that patients with normal lactate dehydrogenase (LDH) and ≤ three metastatic sites without brain metastases at baseline had better outcomes. With normal LDH at baseline, median PFS for patients with one or two metastatic sites other than cerebral was 18 months. No new safety signals were observed. Treatment was permanently discontinued because of treatment-emergent adverse events (TEAEs) in 9.2% of patients, and pyrexia (27.3%) was the most common TEAE, with a lower incidence than that in the phase 3 studies of dab + tram., Conclusion: Treatment of BRAF V600E-mutant metastatic melanoma with dab + tram in the real-world setting was effective and safe, including the unselected population with several patients having a high tumor burden - concordant with the results of the pivotal phase 3 studies of dab + tram., (© 2021. The Author(s).)

Background: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy., Patients and Methods: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined., Results: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%)., Conclusions: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE., Competing Interests: Disclosure CNO has received non-financial support from Merck Sharp & Dohme. XB receives a merit award supported by BMS. CA has received travel support from Amgen, BMS and Roche. PB has received sponsorship from MSD. WX has served on advisory boards for Merck Serono and Novartis and has received research funding from Merck Serono. BN has received personal financial compensation from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and AstraZeneca, for public speaking, consultancy and participation in advisory board meetings. His institution (UZ Brussel) received research funding related to research projects conducted by his team from Pfizer, Novartis, Roche and Merck-Serono. CUB has an advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre and Third Rock Ventures. He has received research funding from BMS, Novartis and NanoString. He has stock ownership in Uniti Cars and is co-founder of Immagene B.V. SJW has received travel support from Ipsen. SS has served on advisory boards for BMS, MSD, Merck, Novartis, Roche, Janssen, AstraZeneca and Amgen and has received research funding from Amgen, Endocyte, MSD and AstraZeneca. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers Squibb, Sanofi and Pierre Fabre and has received travel support from Ultrasun, L'oreal, Merck Sharp & Dohme, Bristol Myers Squibb and Pierre Fabre outside of the submitted work. JLM is consultant advisor for BMS, Roche and Novartis. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai and Regeneron. He also received research funds from Bristol Myers Squibb, Roche-Genentech and Array, and travel support from MSD. LZ has received honoraria from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre, research funding from Novartis and has served on advisory boards for Bristol Myers Squibb, Novartis, Pierre Fabre, Sun Pharma, Sanofi and Merck Sharp & Dohme. He has received travel support from Bristol Myers Squibb, Pierre Fabre, Sanofi, Amgen, Novartis and Sun Pharma. DBJ has served on advisory boards for Array Biopharma, BMS, Iovance, Jansen, Merck and Novartis, and received research funding from BMS and Incyte. CL has served on advisory boards for BMS, MSD, Novartis, Amgen, Roche, Merck, Serono and Sanofi. She has received honoraria from Roche, BMS, Novartis, Amgen, MSD, Pierre Fabre, Pfizer and Incyte, and speaker's bureau from Roche, BMS, Novartis, Amgen and MSD. She has received research funding from Roche and BMS. She has received travel support from BMS and MSD. She serves on the board of Avantis Medical Systems. MSC has served on advisory boards for Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar and Eisai and honoraria from Bristol Myers Squibb, MSD and Novartis. RJS has received research support from Amgen and Merck, as well as served as a paid consultant and/or on a scientific advisory board for Array, AstraZeneca, Asana Biosciences, Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, Oncosec, Pfizer and Replimune. GVL 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, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc. AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre Fabre and QBiotics. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Cutaneous melanoma is the most lethal form of skin cancer and its incidence has been increasing in the past 30 years. Although this is completely resectable in most cases, thicker melanoma and those with regional lymph-node involvement are at a high risk of relapse. In recent years, the management of locoregional disease has drastically changed. In particular, in the 8th Edition of the American Joint Committee on Cancer (AJCC), subgroup classification of TNM (tumor-node-metastasis) has been modified, with the addition of the IIID stage. Furthermore, in recent randomized trials, completion lymph node dissection in case of sentinel lymph node biopsy positivity has not been shown to offer any improvement in overall survival versus observation. Consequently, radical dissection has been recommended as the standard treatment, but only in patients with palpable nodal metastases. However, the major novelty in the treatment of locally advanced melanoma has been the introduction of drugs, already used for metastatic disease, that have also shown clinical efficacy in the adjuvant setting. In fact, immunotherapies and, in the case of BRAF V600E/K-mutated melanoma, combination treatment of BRAF and MEK inhibitors have improved recurrence-free survival in these patients. In this paper, we will describe the current management of a patient with radically resectable melanoma and discuss the key points in light of the latest scientific evidence., Competing Interests: Disclosure TT serves on the advisory board for Amgen, Bayer, Merck, Novartis, Roche, and Sanofi. PAA reports consultant/advisory role for Bristol Myers-Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, and Boehringer-Ingelheim; has received research funds from Bristol Myers-Squibb, Roche-Genentech, Array; and travel support from MSD. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Malignant melanoma metastases occur in about 15% of patients. The most common localizations are lymph nodes, lungs, pancreas, bones. The central nervous system and the perineural region are rarely affected. In case of distant metastases, the survival rate is lower (about 25%). Involvement of peripheral nerve metastases from melanoma is reported in the literature just in one case. We report the ultrasound (US) integrated with Color-Doppler Ultrasound (CDU), elastosonography, and magnetic resonance imaging (MRI) findings of a rare case of metastatic endo- and perineural involvement of the ulnar nerve from cutaneous melanoma. Our purpose is to increase the clinicians' and radiologists' awareness on the possibility of metastatic spread to the peripheral nervous system and improve the differential diagnosis with other peripheral nerve sheath tumors.

Background: The easy access to a quick diagnosis of coronavirus disease 2019 (COVID-19) is a key point to improve the management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to contain its spread. Up to now, laboratory real-time PCR is the standard of care, but requires a fully equipped laboratory and significant infrastructure. Consequently, new diagnostic tools are required., Methods: In the present work, the diagnostic accuracy of the point-of-care rapid test "bKIT Virus Finder COVID-19" (Hyris Ltd ) is evaluated by a retrospective and a prospective analysis on SARS CoV-2 samples previously assessed with an FDA "authorized for the emergency use-EUA" reference method. Descriptive statistics were used for the present study., Results: Results obtained with the Hyris Kit are the same as that of standard laboratory-based real time PCR methods for all the analyzed samples. In addition, the Hyris Kit provides the test results in less than 2 h, a significantly shorter time compared to the reference methods, without the need of a fully equipped laboratory., Conclusions: To conclude, the Hyris kit represents a promising tool to improve the health surveillance and to increase the capacity of SARS-CoV-2 testing.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript., Competing Interests: Disclosure AA consultancy to and travel support from Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Roche; PAA consultancy to Amgen, Array, Bristol-Myers Squibb, Genmab, Idera, Immunocore, Incyte, MedImmune, Merck Sharp & Dohme, NewLink Genetics, Novartis, Pierre Fabre, Roche Genentech, Sandoz, Sanofi, Sindax, Sun Pharma, Ultimovacs; contracted research for Array, Bristol-Myers Squibb, Roche; travel support from Merck Sharp & Dohme; CUB advisor to Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, Genmab, Pierre Fabre, Third Rock Ventures; research funding from Bristol-Myers Squibb, Novartis, NanoString; Stock ownership in Uniti Cars; cofounder of Immagene BV; VCS travel support from Bristol-Myers Squibb, Pierre Fabre; advisory boards for Pierre Fabre; invited speaker for Novartis, Merck-Serono, Sanofi; MD honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; travel support from Merck Sharp & Dohme, Novartis; access to virtual conference services from Merck Sharp & Dohme; RD consultancy to and/or advisory relationships with Amgen, Bristol-Myers Squibb, CatalYm, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Second Genome, Sun Pharma, Takeda; MBF advisory boards for Amgen, Array Bioscience, Bristol-Myers Squibb, Novartis, Pulse Bioscience, Sanofi; consultancy to Delcath Systems; CG-M travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; speaker honorarium from Bristol-Myers Squibb; HG consultancy to and/or advisory relationships with Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Roche; institutional research grants from Bristol-Myers Squibb, Merck Sharp & Dohme; JJG advisory relationships with Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi; JH consultancy, advisory boards and/or lectures for Amgen, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Ipsen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics; scientific advisory boards for Achilles Therapeutics, AIMM Therapeutics, Celsius Therapeutics, Immunocore, Neogene Therapeutics, Neon Therapeutics, Vaximm; institutional research grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Neon Therapeutics; CH consultancy, advisory boards and/or lectures for Amgen, AstraZeneca, Bristol-Myers Squibb, Inzyte, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; UK consultancy, advisory boards and/or lectures for Amgen, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, Glycotope, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Sanofi; institutional research grants from AstraZeneca/Medimmune, Bayer; CL consultancy, advisory boards, speakers bureau and/or advisory relationships with Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; advisory board for Avantis Medical Systems; travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; other honoraria from Incyte, Pierre Fabre, Pfizer; PL sponsored research for Bristol-Myers Squibb; speaker bureau for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre; paid advisor to Amgen, Bristol-Myers Squibb, MelaGenix, Merck Sharp & Dohme, Novartis, Pierre Fabre; travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; IL sponsored research for Amgen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, Microgenics; travel support from Bristol-Myers Squibb, Roche; MM advisory boards for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; research grants from Novartis, Roche; IM-R advisory boards for Amgen, Bioncotech, Bristol-Myers Squibb, Incyte, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi; travel and congress accommodation support from Bioncotech, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; OM honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; PN advisory boards and/or speakers bureau for AstraZeneca, Bristol-Myers Squibb, Immunocore, Ipsen, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; BN advisory boards, public speaking and consultancy for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; research funding for institution from Merck-Serono, Novartis, Pfizer, Roche; ROB research grants from AstraZeneca; speaker honoraria from Pfizer, Roche; advisory boards for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme; SP grants, personal fees and nonfinancial support from Almirall, Sanofi, ISDIN, La Roche Posay; grants and personal fees from Amgen, Leo Pharma, OJER Pharma; nonfinancial support from Lilly, AbbVie; personal fees from Bristol-Myers Squibb; grants from Novartis, Sun Pharma, MELAGENICS, Castle; personal fees and nonfinancial support from Pfizer, Roche; CR consultancy to and/or advisory boards for Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi; PR speakers bureau for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; advisory boards for Amgen, Blueprint Medicines, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre; BS honoraria from Amgen, Bristol-Myers Squibb, Incyte, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre; VKS consultancy to and/or advisory boards for Bristol-Myers Squibb, Merck, Novartis, Regeneron; data safety monitoring boards for Array, Bristol-Myers Squibb, Novartis, Pfizer, Polynoma; HT advisory relationships with Bristol-Myers Squibb, Merck, Novartis, Roche/Genentech; research grants from Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Roche/Genentech; AT travel and congress registration support from Agenus; AvA honoraria paid to institute for consultancy to and/or advisory boards for 4SC, Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck-Pfizer, Novartis; institutional research grants from Amgen, Bristol-Myers Squibb, Novartis. All remaining authors have declared no conflict of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Pneumonia is the most frequent complication of COVID-19, due to an aberrant host immune response that is associated with an acute respiratory distress syndrome, and, in most critical patients, with a "cytokine storm". IL-6 might play a key role in the cytokine storm and might be a potential target to treat severe and critical COVID-19. Tocilizumab is a recombinant humanized monoclonal antibody, directed against IL-6 receptor., Methods: This multicentre study project includes a single-arm phase 2 study and a further parallel cohort, enrolling hospitalized patients with COVID-19 pneumonia and oxygen saturation at rest in ambient air ≤93% or requiring respiratory support. Patients receive tocilizumab 8 mg/kg (up to 800 mg) as one intravenous administration. A second administration (same dose) after 12 h is optional. Two-week and one-month lethality rates are the co-primary endpoints. Sample size planned for the phase 2 study is 330 patients. The parallel cohort will include patients who cannot enter the phase 2 study because being intubated from more than 24 h, or having already received tocilizumab, or the phase 2 study has reached sample size. Primary analysis will include patients enrolled in the phase 2 study. Results of the primary analysis will be validated in the prospective cohort of patients consecutively registered after phase 2 closure from March 20 to March 24, who were potentially eligible for the phase 2 study., Conclusion: This trial aims to verify the safety and efficacy of tocilizumab in the Italian population with COVID-19 pneumonia and respiratory impairment. EudraCT Number: 2020-001110-38; Clinicaltrials.gov ID NCT04317092., (Copyright © 2020. Published by Elsevier Inc.)

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript., Competing Interests: Disclosure AA consultancy to and travel support from Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Roche; PAA consultancy to Amgen, Array, Bristol-Myers Squibb, Genmab, Idera, Immunocore, Incyte, MedImmune, Merck Sharp & Dohme, Newlinks Genetics, Novartis, Pierre Fabre, Roche Genentech, Sandoz, Sanofi, Sindax, Sun Pharma, Ultimovacs; contracted research for Array, Bristol-Myers Squibb, Roche; travel support from Merck Sharp & Dohme; CB adviser to Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, Genmab, Pierre Fabre, Third Rock Ventures; research funding from Bristol-Myers Squibb, Novartis, Nanostring; stock ownership in Uniti Cars; co-founder of Immagene BV; VCS travel support from Bristol-Myers Squibb, Pierre Fabre; advisory boards for Pierre Fabre; invited speaker for Novartis, Merck Serono, Sanofi; MD honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; travel support from Merck Sharp & Dohme, Novartis; access to virtual conference services from Merck Sharp & Dohme; RD consultancy to and/or advisory relationships with Amgen, Bristol-Myers Squibb, CatalYm, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Second Genome, Sun Pharma, Takeda; MF advisory boards for Amgen, Array Bioscience, Bristol-Myers Squibb, Novartis, Pulse Bioscience, Sanofi; consultancy to Delcath Systems; CG-M travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; speaker honorarium from Bristol-Myers Squibb; HG consultancy to and/or advisory relationships with Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; institutional research grants from Bristol-Myers Squibb, Merck Sharp & Dohme; J-JG advisory relationships with Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi; JH consultancy, advisory boards and/or lectures for Amgen, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Ipsen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics; scientific advisory boards for Achilles Therapeutics, AIMM Therapeutics, Celsius Therapeutics, Immunocore, Neogene Therapeutics, Neon Therapeutics, Vaximm; institutional research grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Neon Therapeutics; CH consultancy, advisory boards and/or lectures for Amgen, AstraZeneca, Bristol-Myers Squibb, Inzyte, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; UK consultancy, advisory boards and/or lectures for Amgen, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, Glycotope, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Sanofi; institutional research grants from AstraZeneca/Medimmune, Bayer; CL consultancy, advisory boards, speakers bureau and/or advisory relationships with Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; advisory board for Avantis Medical Systems; travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; other honoraria from Incyte, Pierre Fabre, Pfizer; PL sponsored research for Bristol-Myers Squibb; speaker bureau for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre; paid advisor to Amgen, Bristol-Myers Squibb, MelaGenix, Merck Sharp & Dohme, Novartis, Pierre Fabre; travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; IL sponsored research for Amgen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, Microgenics; travel support from Bristol-Myers Squibb, Roche; MM advisory boards for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; research grants from Novartis, Roche; IM-R advisory boards for Amgen, Bioncotech, Bristol-Myers Squibb, Incyte, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi; travel and congress accommodation support from Bioncotech, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; OM honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; PN advisory boards and/or speakers bureau for AstraZeneca, Bristol-Myers Squibb, Immunocore, Ipsen, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; BN advisory boards, public speaking and consultancy for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; research funding for institution from Merck Serono, Novartis, Pfizer, Roche; ROB research grants from AstraZeneca; speaker honoraria from Pfizer, Roche; advisory boards for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme; SP grants, personal fees and non-financial support from Almirall, Sanofi, ISDIN, La Roche Posay; grants and personal fees from Amgen, Leo Pharma, OJER Pharma; non-financial support from Lilly, AbbVie; personal fees from Bristol-Myers Squibb; grants from Novartis, Sun Pharma, Melagenics, Castle; personal fees and non-financial support from Pfizer, Roche; CR consultancy to and/or advisory boards for Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi; PR speakers bureau for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; advisory boards for Amgen, Blueprint Medicines, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre; BS honoraria from Amgen, Bristol-Myers Squibb, Incyte, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre; VS consultancy to and/or advisory boards for Bristol-Myers Squibb, Merck, Novartis, Regeneron; data safety monitoring boards for Array, Bristol-Myers Squibb, Novartis, Pfizer, Polynoma; HT advisory relationships with Bristol-Myers Squibb, Merck, Novartis, Roche/Genentech; research grants from Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Roche/Genentech; AT travel and congress registration support from Agenus; AvA honoraria paid to institute for consultancy to and/or advisory boards for 4SC, Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck-Pfizer, Novartis; institutional research grants from Amgen, Bristol-Myers Squibb, Novartis; all remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Patients with BRAF-mutant melanoma commonly develop resistance to BRAF inhibitor and MEK inhibitor (BRAF/MEKi) treatment, resulting in disease recurrence or progression. Repeated treatment after a break or an intervening therapy may provide clinical benefit. To ensure a common understanding when discussing the treatment of BRAF-mutant melanoma, we propose consensus definitions for retreatment and rechallenge. 'Retreatment' should be defined as 'repeated treatment with the same therapeutic class following relapse after adjuvant treatment has ended.' Retreatment may be an option for patients with unresectable or metastatic disease who have completed prior adjuvant therapy or discontinued adjuvant therapy early due to toxicity or patients with locoregional recurrence after adjuvant treatment who subsequently underwent resection. 'Rechallenge' should be defined as 'repeated treatment with the same therapeutic class following disease progression in patients who had clinical benefit with prior treatment for unresectable or metastatic disease.' Rechallenge may be an option for patients who had disease progression after an initial response and received an alternative intervening treatment or patients with unresectable or metastatic melanoma who had a treatment break after responding to BRAF/MEKi therapy. Clinical benefits may be possible with repeated BRAF/MEKi treatment because of the role of the MAPK pathway in melanoma oncogenesis and resistance mechanisms specific to BRAF/MEKi, which are discussed in this article. The concepts of retreatment and rechallenge may also be relevant for treatment with immune checkpoint inhibitors in patients with melanoma. Use of consistent terminology will help to stimulate and align further research in this area., Competing Interests: Conflict of interest statement P.A. reports a consultant/advisory role for Bristol Myers-Squibb (BMS), Roche-Genentech, Merck Sharp & Dohme (MSD), Array, Novartis, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar and Boehringer-Ingelheim; receiving research funds from Bristol Myers-Squibb, Roche-Genentech and Array; and receiving travel support from MSD. V.A. reports receiving speaker/advisory board fees from BMS, MSD, Merck, Novartis, Roche, Pierre Fabre and NEKTAR therapeutics. P.C. reports receiving personal speaker/advisory board fees from BMS, Merck & Co, Novartis and Pierre Fabre. R.D. reports intermittent, project-focused consulting and/or advisory relationships with Novartis, MSD, BMS, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron and Alligator outside the submitted work. C.G. reports receiving personal speaker/advisory board fees from Amgen, Beiersdorf, BMS, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma and Sanofi Genzyme. D.S. reports 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, Philiogen, Regeneron, Sun Pharma, Sandoz, Sanofi, Ultimovacs and 4SC. D.S. also reports receiving research funds from Bristol Myers-Squibb, Roche, Amgen and Novartis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Sonidegib and vismodegib are hedgehog pathway inhibitors (HhIs) approved for the treatment of advanced basal cell carcinoma (BCC). Until recently, vismodegib was the only targeted treatment available for patients with locally advanced BCC (laBCC) in cases where surgery and radiotherapy are inappropriate. Sonidegib has recently been approved and now presents an alternative treatment option. The clinical differences between the two HhIs in patients with laBCC are unclear, as no head-to-head randomized controlled trials are or will be initiated. Moreover, there were important differences in the designs of their pivotal studies, BOLT (sonidegib) and ERIVANCE (vismodegib), and these differences complicate evidence-based analysis of their relative efficacy and safety profiles. In this paper, a group of clinical experts in the management of laBCC summarizes the clinical and pharmacological profiles of sonidegib and vismodegib based on published data and their own clinical experience. One key difference between the two pivotal studies was the criteria used to assess BCC severity. ERIVANCE (a single-arm phase II trial) used the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while the more recent double-blind randomized BOLT trial used the stringent modified RECIST. A preplanned analysis adjusted the outcomes from BOLT with RECIST-like criteria, and this enabled the experts to discuss relative efficacy outcomes for the two treatments. Centrally reviewed objective response rate (ORR) for vismodegib was 47.6% (95% CI: 35.5-60.6) at 21-month follow-up using RECIST. After adjusting with RECIST-like criteria, the ORR for sonidegib according to central review at 18-month follow-up was 60.6% (95% CI: 47.8-72.4). Both treatments were associated with similar patterns of adverse events. Sonidegib and vismodegib share the same efficacy and tolerability profiles, but their pharmacokinetic profiles show several differences, such as volume of distribution and half-life. Further studies are needed to understand how these differences may impact clinical practice., (© 2020 European Academy of Dermatology and Venereology.)

Background: We conducted a retrospective exploratory analysis to evaluate the effects of baseline tumour immune infiltrate on disease-free survival (DFS) outcomes in patients with fully resected stage IIC-IIIC melanoma receiving adjuvant vemurafenib monotherapy or placebo in the BRIM8 study., Patients and Methods: BRIM8 was a phase III, international, double-blind, randomised, placebo-controlled study. Eligible patients with BRAF V600 mutation-positive, completely resected melanoma were randomly assigned to oral vemurafenib (960 mg twice daily) or matching placebo for 52 weeks. The primary end point was DFS. The association of CD8+ T-cell infiltration and programmed death ligand 1 (PD-L1) expression with DFS, as measured by immunohistochemistry, was explored retrospectively., Results: Four hundred ninety-eight patients were randomly assigned to receive adjuvant vemurafenib (n = 250) or placebo (n = 248); tumour samples were available for biomarker analysis for approximately 60% of patients. In the pooled biomarker population, placebo-treated patients with <1% CD8+ T cells in the tumour centre had shorter median DFS than those with ≥1% CD8+ T cells (7.7 versus 47.8 months). DFS benefit from vemurafenib versus placebo was greater in patients with <1% CD8+ T cells [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.34-0.92) than in patients with ≥1% CD8+ T cells (HR 0.77; 95% CI 0.48-1.22). Likewise, median DFS was shorter among placebo-treated patients with <5% versus ≥5% PD-L1+ immune cells (IC) in the tumour (7.2 versus 47.8 months). A greater DFS benefit with vemurafenib versus placebo was observed in patients with <5% PD-L1+IC (HR 0.36; 95% CI 0.24-0.56) than in patients with ≥5% PD-L1+IC (HR 0.99; 95% CI 0.58-1.69)., Conclusions: The presence of CD8+ T cells and PD-L1+IC are favourable prognostic factors for DFS. Treatment with adjuvant vemurafenib may overcome the poor DFS prognosis associated with low CD8+ T-cell count or PD-L1 expression. CLINICALTRIALS., Gov Identifier: NCT01667419., (Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: The immunotherapy has revolutionized the world of oncology in the last decades with considerable advantages in terms of overall survival in cancer patients. The association of Pembrolizumab and Trastuzumab was recently proposed in clinical trials for the treatment of Trastuzumab-resistant advanced HER2-positive breast cancer. Although immunotherapies are frequently associated with a wide spectrum of immune-related adverse events, the cardiac toxicity has not been properly studied., Purpose: We studied, for the first time, the putative cardiotoxic and pro-inflammatory effects of Pembrolizumab associated to Trastuzumab., Methods: Cell viability, intracellular calcium quantification and pro-inflammatory studies (analyses of the production of Interleukin 1β, 6 and 8, the expression of NF-kB and Leukotriene B4) were performed in human fetal cardiomyocytes. Preclinical studies were also performed in C57BL6 mice by analyzing fibrosis and inflammation in heart tissues., Results: The combination of Pembrolizumab and Trastuzumab leads to an increase of the intracellular calcium overload (of 3 times compared to untreated cells) and to a reduction of the cardiomyocytes viability (of 65 and 20-25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively) indicating cardiotoxic effects. Notably, combination therapy increases the inflammation of cardiomyocytes by enhancing the expression of NF-kB and Interleukins. Moreover, in preclinical models, the association of Pembrolizumab and Trastuzumab increases the Interleukins expression of 40-50% compared to the single treatments; the expression of NF-kB and Leukotriene B4 was also increased., Conclusion: Pembrolizumab associated to Trastuzumab leads to strong cardiac pro-inflammatory effects mediated by overexpression of NF-kB and Leukotriene B4 related pathways., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: The aim of the present study was to assess the estimated "per patient" total cost for a single Oncologic Italian Cancer Center participating in a multicenter clinical trial with new anticancer biological agents using the activity-based costing (ABC) methodology., Methodology: Nine randomized phase 3 clinical trials employing biological agents at the National Cancer Institute of Napoli, Italy, were analyzed to indentify "per patient" costs of each trial, according to the ABC methodology. The average consumption of resources for a patient completing the entire planned treatment was estimated for each trial. Through interviews of the personnel (doctors, nurses and technicians) and by analyses of the clinical trials protocols, the main activities of the 9 clinical trials were identified and, for each trial, the complete health care pathway of the patients and the treatment programmes were minutely reconstructed. Drug costs were not included because provided by Sponsors., Principal Findings: The average costs of the pre-study, treatment, monitoring, follow-up, audit, and administrative activities accounted for 2.357, 4.783, 700, 372, 1.263, and 9 Euro, respectively. The average total cost estimated for all "per patient" activities, including overhead costs, was 11.379 Euro. Staff costs accounted for € 5.988, while costs of diagnostic test accounted for 3.494 Euro. Clinical trials with immunotherapeutic drugs accounted for higher costs (+601 Euro as oncological staff costs, +1.318 Euro as intermediate services cost and +384 Euro as overheads)., Conclusions: The average total cost estimated for all "per patient" activities of a clinical trial with new anticancer biological agents was 11.379 Euro using the ABC methodology., Competing Interests: The authors have declared that no competing interests exist.

It is important to differentiate between two concepts of adjuvant therapy in melanoma-what we have come to call late adjuvant and early adjuvant therapy. Early adjuvant therapy is defined as a medical intervention that is done after resection of a primary melanoma to eradicate possible undetectable minimal residual disease, whereas late adjuvant therapy is done when an overt metastatic disease (nodal or visceral) has been completely resected, to control disease better than if the same treatment were given at a later time, in the presence of multiple metastases. Early adjuvant therapy is thus a preventive treatment strategy, whereas late adjuvant therapy aims at anticipating treatment of metastatic disease. For patients with melanoma, 1-year treatment with targeted therapies and immunotherapy have only been assessed in late adjuvant settings, the outcomes of which more or less reproduce the same dramatic effect as they have in metastatic disease. However, early adjuvant therapy could provide greater benefits in terms of public health, since thin melanomas without nodal metastases are so common that they account for most deaths by melanoma. In the early adjuvant setting, a treatment course of less than 1 year might be sufficient to control the disease, with less toxicity and at reduced costs. In this Personal View, we discuss the potential benefit of short-term early adjuvant treatment in patients with stage II melanoma, with the hope that sentinel-node biopsy and the American Joint Committee on Cancer staging will soon be replaced by more relevant biomarkers to identify the most suitable candidates for early adjuvant therapy for this disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.

Background: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial., Methods: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC., Results: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup., Conclusions: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: There is a scarcity of real-world data on treatment patterns and outcomes among advanced melanoma patients treated with immunotherapies including ipilimumab, an anti-CTLA-4 antibody approved since 2011., Objective: To evaluate ipilimumab and postipilimumab treatment patterns and outcomes among patients with advanced melanoma in Australia, Germany, Italy and Spain, following regulatory approval., Methods: Retrospective multicentre, multinational, observational chart review study. Data were extracted from the start of ipilimumab therapy until the end of at least 40 weeks of follow-up, or death., Results: Data from 371 patients (Australia, 103; Germany, 152; Italy, 76; Spain, 40) were analysed. Mean age was 65 years; 62% were male. Eastern Cooperative Oncology Group performance status (ECOG PS) was 0 or 1 for 94%. In 67%, ipilimumab was initially received as second-line or later therapy. Patients received on average 3.4 ipilimumab doses. The ipilimumab-refractory cohort comprised of 226 patients. Of these, 17% in Australia, 47% in Germany, 29% in Italy and 14% in Spain received another antimelanoma treatment after ipilimumab including chemotherapy in 26% and BRAF/other kinase inhibitors in 11%. Ipilimumab-refractory patients who received postipilimumab treatment showed a 40% reduced hazard of dying than those not receiving treatment after ipilimumab (HR 0.60; 95% CI 0.43-0.83), after adjustment for potential confounders., Conclusion: During the time observed, ipilimumab was mainly used as second-line or later therapy. A significant proportion of patients received postipilimumab therapy, most of which was chemotherapy. Nevertheless, overall survival following progression on ipilimumab treatment remained poor, highlighting the need for research to develop more effective end-of-life treatment options., (© 2017 European Academy of Dermatology and Venereology.)

Background: The SafeTy Events in VIsmodEgib study (STEVIE, ClinicalTrials.gov, NCT01367665), assessed safety and efficacy of vismodegib-a first-in-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC)-in a patient population representative of clinical practice. Primary analysis data are presented., Patients and Methods: Patients with locally advanced or metastatic BCC received oral vismodegib 150 mg/d until progressive disease, unacceptable toxicity, or withdrawal. Primary objective was safety. Efficacy variables were assessed as secondary end-points., Results: Evaluable adult patients (N = 1215, 1119 locally advanced; 96 metastatic BCC) from 36 countries were treated; 147 patients (12%) remained on study at time of reporting. Median (range) treatment duration was 8.6 (0-44) months. Most patients (98%) had ≥1 treatment-emergent adverse event (TEAE). The incidence of the most common TEAEs was consistent with reports in previous analyses. No association between creatine phosphokinase (CPK) abnormalities and muscle spasm was observed. Serious TEAEs occurred in 289 patients (23.8%). Exposure ≥12 months did not lead to increased incidence or severity of new TEAEs. The majority of the most common TEAEs ongoing at time of treatment discontinuation resolved by 12 months afterwards, regardless of Gorlin syndrome status. Response rates (investigator-assessed) in patients with histologically confirmed measurable baseline disease were 68.5% (95% confidence interval (CI) 65.7-71.3) in patients with locally advanced BCC and 36.9% (95% CI 26.6-48.1) in patients with metastatic BCC., Conclusions: The primary analysis of STEVIE demonstrates that vismodegib is tolerable in typical patients in clinical practice; safety profile is consistent with that in previous reports. Long-term exposure was not associated with worsening severity/frequency of TEAEs. Investigator-assessed response rates showed high rate of tumour control. CLINICALTRIALS.GOV: NCT01367665., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3., Patients and Methods: Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib., Results: Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0-15.4] versus 9.7 months [95% CI 7.9-12.8; hazard ratio (HR) 0.81 [95% CI 0.67-0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0-15.4) versus 10.3 months (95% CI 9.1-12.8); HR 0.81 (95% CI 0.68-0.96); P = 0.01]. Kaplan-Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis., Conclusions: Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies., Clinicaltrials.gov: NCT01006980., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study., Patients and Methods: Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations., Results: Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation., Conclusions: These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care., Clinicaltrials.gov: NCT01689519., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Cutaneous metastases represent a therapeutic challenge. An increasing body of experience suggests that electrochemotherapy (ECT) provides effective tumor control, although its evidence basis should be strengthened., Methods: This prospective, multicenter, observational study enrolled patients with superficial metastases, who underwent ECT at 10 centers between 2008 and 2013. Outcomes included adherence to European Standard Operating Procedures of ECT (ESOPE), tumor response, local progression-free survival (LPFS), toxicity and patient-reported outcomes (PROs, EORTC QLQ-C30 plus an 8-item questionnaire)., Results: We enrolled 376 eligible patients. Tumor histotype distribution was as follows: melanoma, 56%; squamous cell carcinoma, 11%; Kaposi sarcoma, 11%; breast carcinoma, 8%; basal cell carcinoma, 6%; soft tissue sarcomas, 3%; others, 5%. We registered 1304 target tumors (median size 1 cm). Treatment adhered to ESOPE in 88% of patients as to the route of drug administration, and in 70% as to electrode application. The procedure was mainly performed under sedation (64.6%) and by using intravenous chemotherapy (93.4%). Tumor response rate at 60 days was 88% (complete, 50%). Small tumor size predicted complete response achievement (OR 2.24, p = 0.003), higher LPFS (HR 0.68, p = 0.004) and improved PROs (Global Health Status, p < 0.001; wound bleeding, p < 0.001; healing, p = 0.002; and aesthetics, p < 0.001). Skin toxicity (grade ≥3, 7.8%) was lower in patients with tumors <2 cm (p≤0.001). One-year LPFS was 73.7% (95%CI 68.4-78.3)., Conclusions: ECT represents a valuable skin-directed therapy across a range of malignancies. The most frequently applied treatment modality is intravenous chemotherapy under sedation. Small tumor size predicts durable tumor control, fewer side-effects and better PROs., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This report covers the Immunotherapy sessions of the 2016 Organisation of European Cancer Institutes (OECI) Oncology Days meeting, which was held on 15th-17th June 2016 in Brussels, Belgium. Immunotherapy is a potential cancer treatment that uses an individual's immune system to fight the tumour. In recent years significant advances have been made in this field in the treatment of several advanced cancers. Cancer immunotherapies include monoclonal antibodies that are designed to attack a very specific part of the cancer cell and immune checkpoint inhibitors which are molecules that stimulate or block the inhibition of the immune system. Other cancer immunotherapies include vaccines and T cell infusions. This report will summarise some of the research that is going on in this field and will give us an update on where we are at present.

Background: Nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-naïve patients with metastatic melanoma in the CheckMate 066 phase III study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented., Patients and Methods: HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus ≥1 post-baseline assessment., Results: Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to week 43, although the high attrition rate after week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index., Conclusions: In addition to prolonged survival, these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit, compared with dacarbazine in patients with advanced melanoma., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Genomic profiling of tumor tissue may aid in identifying predictive or prognostic gene signatures (GS) in some cancers. Retrospective gene expression profiling of melanoma and non-small-cell lung cancer led to the characterization of a GS associated with clinical benefit, including improved overall survival (OS), following immunization with the MAGE-A3 immunotherapeutic. The goal of the present study was to prospectively evaluate the predictive value of the previously characterized GS., Patients and Methods: An open-label prospective phase II trial ('PREDICT') in patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma., Results: Of 123 subjects who received the MAGE-A3 immunotherapeutic, 71 (58.7%) displayed the predictive GS (GS+). The 1-year OS rate was 83.1%/83.3% in the GS+/GS- populations. The rate of progression-free survival at 12 months was 5.8%/4.1% in GS+/GS- patients. The median time-to-treatment failure was 2.7/2.4 months (GS+/GS-). There was one complete response (GS-) and two partial responses (GS+). The MAGE-A3 immunotherapeutic was similarly immunogenic in both populations and had a clinically acceptable safety profile., Conclusion: Treatment of patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma with the MAGE-A3 immunotherapeutic demonstrated an overall 1-year OS rate of 83.5%. GS- and GS+ patients had similar 1-year OS rates, indicating that in this study, GS was not predictive of outcome. Unexpectedly, the objective response rate was lower in this study than in other studies carried out in the same setting with the MAGE-A3 immunotherapeutic. Investigation of a GS to predict clinical benefit to adjuvant MAGE-A3 immunotherapeutic treatment is ongoing in another melanoma study.This study is registered at www.clinicatrials.gov NCT00942162., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)