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Background: In the European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 study, adjuvant pembrolizumab improved recurrence-free survival and distant-metastasis-free survival in patients with resected stage III melanoma. Earlier results showed no effect of pembrolizumab on health-related quality of life (HRQOL). Little is known about HRQOL after completion of treatment with pembrolizumab, an important research area concerning patients who are likely to become long-term survivors. This study reports long-term HRQOL results., Methods: This double-blind, randomised, controlled, phase 3 trial compared adjuvant pembrolizumab with placebo in patients aged 18 years or older with previously untreated stage IIIA, IIIB, or IIIC resected cutaneous melanoma and an Eastern Cooperative Oncology Group performance status score of 1 or 0, recruited from 123 academic centres and community hospitals in 23 countries. Patients were randomly assigned (1:1) with a minimisation technique stratified for stage and geographical region to receive 200 mg of intravenous pembrolizumab or placebo every 3 weeks for up to 18 doses. Investigators, patients, and those collecting or analysing data were masked to group assignment. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, measured with the EORTC Quality of Life Questionnaire-Core 30. All patients with a baseline HRQOL evaluation available who were alive 108 weeks from randomisation were included in this analysis of long-term HRQOL. Long-term HRQOL included assessments measured every 6 months between 108 weeks and 48 months after randomisation. The threshold of clinical relevance for all HRQOL scales used was an average change of 5 points. The trial is ongoing, recruitment is completed, and HRQOL data collection is finalised. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37., Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were randomly assigned to pembrolizumab (n=514) or placebo (n=505). Completion of the HRQOL evaluation at baseline exceeded 90% (481 [94%] patients in the pembrolizumab group and 467 [92%] in the placebo group), and ranged between 60% and 90% for post-baseline timepoints. Among patients with a baseline HRQOL evaluation, 365 (39%) were female and 583 (61%) were male. The mean change from baseline to long-term HRQOL was -0·56 (95% CI -2·33 to 1·22) in the pembrolizumab group and 1·63 (-0·12 to 3·38) in the placebo group. The difference between the two groups was -2·19 (-4·65 to 0·27, p=0·081). Differences for all other scales were smaller than 5 and not statistically significant., Interpretation: Adjuvant pembrolizumab did not have a significant impact on long-term HRQOL compared with placebo in patients with resected stage III melanoma. These findings, together with earlier results on efficacy and HRQOL, support the use of pembrolizumab in this setting., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests EB's spouse and daughter hold shares in Sandoz, Galenica, Alcon, Roche, and Novartis. MK reports study funding paid to the institution by Merck Sharp & Dohme (MSD) since the initial planning of the work, and study funding paid to the institution from Bristol Myers Squibb (BMS), Immunocore, Johnson & Johnson, and Pierre Fabre in the past 36 months. MM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sun Pharma. GVL reports consulting fees from Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics, IOBiotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR, Pierre Fabre, Regeneron, Scancell, and SkylineDX BV. VA reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD, Novartis; support from BMS for attending meetings or travel; participation on a data safety monitoring board or advisory board for BMS, MSD, Novartis, and Immunocore; CUB reports personal fees from MSD, grants and personal fees from Novartis and BMS, personal fees from Roche, GSK, AstraZeneca, Pfizer, Lilly, GenMAB, Pierre Fabre, and Third Rock ventures, grants from NanoString and 4SC, during the conduct of the study. CUB has patents pending (WO 2021/177822 A1 and WO 2023/022596 A1), and reports stock ownership: co-founder of Immagene BV and Signature Oncology. AH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, and Novartis; payments for participation on a data safety monitoring board or advisory board with BMS, MSD, and Novartis. SD reports research funding from BMS, MSD, and Pierre Fabre to the institution; payment or honoraria to the institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS and MSD; support for attending meetings or travel from BMS and MSD; trim 24 patent pending; participation on a data safety monitoring board or advisory board at BMS and MSD, with payments made to the institution; spouse being a Sanofi employee. AK reports consulting fees for an advisory role at Moderna and speaker honorarium from MSD. MSC reports honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD and Novartis; having served on advisory boards for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi. AM reports support of scientific and educational conference from Janssen. SS reports grants or contracts from Novartis/Advanced Accelerator Applications (AAA), AstraZeneca, MSD, Genentech, Senhwa, and Pfizer; funding goes to the institution to undertake investigator initiated clinical trial and translational research. SS reports participation on advisory boards for MSD, BMS, AstraZeneca—fees for attending go to research funds at the institution. SS is the chair of DSMB for two Novartis/AAA sponsored phase 3 trials—no fee accepted for chair role. SP reports payment or honoraria to her and her institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, and Novartis, and to her partner and her institution from Amgen and Phylogen; payments to her institution for participation on a data safety monitoring board or advisory board with MSD; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid from GEM, EORTC melanoma group, and ASEICA. DS reports research grants to his institution from Amgen, Array/Pfizer, BMS, MSD, Novartis, and Roche; consulting fees paid personally from 4SC, Amgen, Array Biopharma, AstraZeneca, BMS, Daiichi Sankyo, Haystack, Immunocore, InFlarX, Innovent, Labcorp, Merck Serono, MSD, Nektar, Neracare, Novartis OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Merck Serono, Novartis, Roche, Sanofi, and SunPharma; personal support for attending meetings or travel from BMS, Merck Serono, MSD, Novartis, Sanofi, and Pierre Fabre; personal payments for participation on a data safety monitoring board or advisory board at 4SC, Amgen, Array Biopharma, AstraZeneca, BMS, Daiichi Sankyo, Haystack, Immunocore, InFlarX, Merck Serono, MSD, Nektar, Neracare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; leadership or fiduciary role, paid or unpaid, at Dermatologic Cooperative Oncology Group, German Cancer Society, Hiege Stiftung, Deutsche Hautkrebsstiftung, Nationale Versorgungskonferenz Hautkrebs eV, and European Melanoma Registry; drug supply (nivolumab, ipilimumab) from BMS. RJ reports research funding from Iovance Biotherapeutics; honoraria for advisory role or speaker presentation from Merck, BMS, Medison, Pfizer, and Novartis. PR reports consulting fees paid to himself from MBS, MSD, Novartis, Pierre Fabre, Philogen, and Pfizer; honoraria for lectures, presentations, speakers bureau, manuscript writing, or educational events paid to himself from BMS, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, MSD, and AstraZeneca; speakers bureau Pfizer, Novartis, Pierre Fabre, MSD, and BMS paid to himself; support for attending meetings or travel from Orphan Europe and Pierre Fabre paid to himself; research funding to his institution from Novarits, Pfizer, Roche, and BMS. AJMvdE reports study grants from BMS and Idera; travel expenses from Ipsen; advisory board from BMS, MSD Oncology, Ipsen, Pierre Fabre, and Janssen Cilag BV. CC reports support for attending meetings or travel from Orphan Europe and Pierre Fabre. DG reports stock or stock options from Merck & Co. CK reports stock or stock options from Merck & Co and being an employee of Merck & Co. CR reports consulting fees (payments made to her) from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sunpharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma, and IO Biontech; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (payments made to her) from Pierre Fabre, Sanofi, BMS, MSD, and Novartis; support for attending meetings or travel from Pierre Fabre; participation on a data safety monitoring board or advisory board (payments made to her) with BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sunpharma, Ultimovacs, Regeneron, Egle, Philogen, and Maat Pharma. AMME reports honoraria for scientific advisory board or independent data monitoring committee functions from Agenus, BioInvent, BioNTech, Boehringer Ingelheim, Brenus, CatalYm, Ellipses, EikonTX, Eurobio, Galecto, IO Biotech, IQVIQ, ISA Pharmaceuticals, Merck & Co, MSD, Pfizer, Pierre Fabre, Scorpion TX, Sairopa, Sellas, SkylineDX, TigaTx, and Trained Therapeutics Discovery; honoraria from Acetra, GenOway, GSK, Moderna, and Trained Immunity Tx; equity from IO Biotech, Sairopa, and SkylineDx; being the Editor in Chief of the European Journal of Cancer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Pembrolizumab adjuvant therapy was shown to significantly improve recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB or IIC melanoma in earlier analyses of the randomized, double-blind, phase III KEYNOTE-716 study (ClinicalTrials.gov identifier: NCT03553836). We report results of the protocol-specified final analysis of DMFS for KEYNOTE-716. Overall, 976 patients were randomly allocated to pembrolizumab (n = 487) or placebo (n = 489). As of January 4, 2023, median follow-up was 39.4 months (range, 26.0-51.4 months). The median DMFS was not reached in either treatment group, and the estimated 36-month DMFS was 84.4% for pembrolizumab and 74.7% for placebo (hazard ratio [HR], 0.59 [95% CI, 0.44 to 0.79]). The median RFS was not reached in either treatment group, and the estimated 36-month RFS was 76.2% for pembrolizumab and 63.4% for placebo (HR, 0.62 [95% CI, 0.49 to 0.79]). DMFS and RFS results were consistent across most prespecified subgroups, including stage IIB and stage IIC melanoma. The safety profile of pembrolizumab was manageable and consistent with previous reports. These results continue to support the use of pembrolizumab adjuvant therapy in patients with resected stage IIB or IIC melanoma.

Background: Pain is common in patients with cancer. The World Health Organisation recommends paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and combined with other agents for moderate/severe pain. This study estimated associations of NSAIDs with recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and the incidence of immune-related adverse events (irAEs) in high-risk patients with resected melanoma in the EORTC 1325/KEYNOTE-054 phase III clinical trial., Patients and Methods: Patients with AJCC7 stage IIIA, IIIB or IIIC resected melanoma were randomized to receive 200 mg of adjuvant pembrolizumab (N = 514) or placebo (N = 505) 3-weekly for one year or until recurrence. As previously reported, pembrolizumab prolonged RFS and DMFS. NSAID use was defined as administration between 7 days pre-randomization and starting treatment. Multivariable Cox and Fine and Gray models were used to estimate hazard ratios (HRs) for associations of NSAIDs with RFS, DMFS and irAEs., Results: Of 1019 patients randomized, 59 and 44 patients in the pembrolizumab and placebo arms, respectively, used NSAIDs. NSAIDs were not associated with RFS (HR 0.91, 95% CI 0.58-1.43) or DMFS in the pembrolizumab (HR 1.03, 95% CI 0.65-1.66) or placebo arms (for RFS, HR 0.76, 95% CI 0.48-1.20; for DMFS, HR 0.80, 95% CI 0.49-1.31). NSAIDs were associated with the incidence of irAEs in the placebo arm (HR 3.06, 95% CI 1.45-6.45) but not in the pembrolizumab arm (HR 0.94, 95% CI 0.58-1.53)., Conclusion: NSAIDs were not associated with efficacy outcomes nor the risk of irAEs in patients with resected high-risk stage III melanoma receiving adjuvant pembrolizumab., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Oliver John Kennedy. None declared. Nina Glassee. Grants or contracts from any entity: MSD. Michal Kicinski. Grants or contracts from any entity: Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Pierre Fabre. Christian Blank. Grants or contracts from any entity: BMS, Novartis, NanoString, 4SC. Consulting fees - consultant advisor for: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre- Payments were made to my institution, Third Rock Venture - Payments were made to me. Stock or stock options: Immagene BV and Signature Oncology - Co-founder. Georgina V Long. Consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, MSD Australia, MSD, Novartis, OncoSec Australia, PHMR Ltd, Pierre Fabre, Provectus Australia, Qbiotics, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS - Personal 1 h lecture of my own slides, Pierre Fabre, Personal 1 h lecture of my own slides. Victoria Atkinson. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Novartis, Pierre Fabre- Speakers bureaus fees. Support for attending meetings and/or travel: BMS, Travel support. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards. Stéphane Dalle. Grants or contracts from any entity: BMS, MSD - My Institution. Support for attending meetings and/or travel: BMS, Pierre Fabre, MSD. Other financial or non-financial interests: Sanofi Pasteur - My wife is an employee of Sanofi Pasteur. Andrew M. Haydon. Payment or honoraria for lectures, presentations, speakers bureaus: BMS, MSD, Novartis. Participation to Advisory Board: BMS, Novartis, Pierre Fabre, MSD. Andrey Meshcheryakov. Grants or contracts from any entity: Sanofi, AstraZeneca, MSD - My institution, me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Bayer AG, BIOCAD, BMS, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Honoraria for lectures, presentations, speakers bureaus. Support for attending meetings and/or travel: BIOCAD, SERVIER, MSD, Sanofi-Aventis, Merck - Attending meetings and/or travel. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bayer AG, BIOCAD, BMS, Eli Lilly, Merck, Servier, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Advisory Board. Adnan Khattak. None declared. Matteo S. Carlino. Participation on Advisory Board for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche. Consulting fees: BMS, MSD, Novartis. Shahneen Sandhu. Grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, MSD, Senwha, Genentech, AstraZeneca - Funding to the institution. Participation on an Advisory Board: AstraZeneca, BMS, MSD, Advanced Accelerators Applications (a Novartis company). - Funding to the institution. James Larkin. Grants or contracts from any entity: Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics. Institutional research support: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo. Consulting fees from iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte. Honorariums from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS. Speaker fee from Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, Inselgruppe, Pfizer, Goldman Sachs, MSD. Susana Puig. Grants or contracts from any entity: Almirall, ISDIN, La Roche Posay - To My Institution. Consulting fees: ISDIN, Almirall, La Roche Posay, MSD, Sanofi, Sun Pharma, Pfizer, Roche, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche Posay, Leo Pharma, Pfizer, Roche, Regeneron, BMS, Sun Pharma. Support for attending meetings and/or travel: Almirall. Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Sanofi, Sun Pharma, Almirall, ISDIN, Pfizer, Novartis. Paolo A. Ascierto. Grants or contracts from any entity: BMS, Roche-Genentech, Pfizer/Array, Sanofi. Consulting fees: BMS, Roche-Genentech, MSD, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, Medicenna, Bio-Al Health, ValoTx, Replimmune, Bayer. Support for attending meetings and/or travel: Pfizer, Bio-Al Health, Replimmune. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, Roche-Genentech, MSD, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos. Piotr Rutkowski. Consulting fees: Amgen, Blueprint Medicine, BMS, Merck, MSD, Novartis, Philogen, Pierre Fabre, Sanofi - Advisory Role - Personal fees. Payment or honoraria for lectures: BMS, Merck, MSD, Novartis, Pierre Fabre, Sanofi Pasteur. Dirk Schadendorf. Grants or contracts from any entity: Amgen, Array BioPharma, Novartis. Consulting fees: 4SC, Angenus, Astra Zeneca, BMS, Daiichi Sankyo, EMD Serano, Roche, Genentech, InFlarX, Merck, Nektar, Novartis, Pfizer, Philogen, Pierre Fabre, Regeneron, Sandoz, Sanofi, UltimoVacs. Participation on a Data Safety Monitoring Board: Immunocore. Honoraria for lectures: Amgen, Novartis. Support for attending meetings and/or travel: Amgen, Novartis. Marye Boers-Sonderen. None declared. Anna Maria di Giacomo. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Pierre Fabre, Sanofi. Support for attending meetings and/or travel: BMS, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Pierre Fabre, Sanofi, GSK, Novartis. Alfonsus J.M. van den Eertwegh. Grants or contracts from any entity: Roche, Sanofi, Bristol Myers Squibb, Idera. Consulting fees: BMS. Support for attending meetings and/or travel: MSD Oncology, Roche, Pfizer, Sanofi, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre. Jean-Jacques Grob. Payment for participation to an advisory board: Amgen, BMS, Hoffmann-La Roche. Consulting fees: MSD, Novartis, Philogen, Pierre Fabre, Sanofi Pasteur. Ralf Gutzmer. Grants or contracts from any entity: Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma Industries, Sanofi. Consulting fees: BMS, MSD, Roche, Genentech, Novartis, Merck Serono, Almirall, Amgen, Sun Pharma Industries, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, Bayer AG, Immunocore. Support for attending meetings and/or travel: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Industries. Rahima Jamal. Grants or contracts from any entity: MSD, BMS, Iovance Biotherapeutics. Consulting fees: BMS. Alexander C.J. van Akkooi. Grants or contracts from any entity: Amgen, Merck, Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, BMS, Novartis, MSD, Merck, Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC. Sara Gandini. None declared. Emanuel Buhrer. None declared. Stefan Suciu. Grants or contracts from any entity: MSD. Caroline Robert. Consulting fees: AstraZeneca, BMS, MSD, Merck, Roche, Novartis, Pfizer, Pierre Fabre, Sanofi. Co-founder: Ribonexus. Alexander Eggermont. Consulting fees: Agenus, BioInvent, BMS, Brenus, CatalYm, Ellipses, Galecto, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck, MSD, Pierre Fabre, Sairopa, Sellas, SkylineDX, TigeTx, Trained Immunity TX. Participation on a Data Safety Monitoring Board: BioNTech, GSK, and Pfizer. Lectures: BMS, MSD. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences, German Cancer Aid. Stock or stock options: IO Biotech, SkylineDx and SaiRoPA. Mario Mandala. Participation to Advisory Board: BMS, MSD, Novartis, Pierre Fabre Pharmaceuticals. Paul Lorigan. Grants or contracts from any entity: BMS, Pierre Fabre. Consulting fees: Amgen, BMS, MSD, Nektar, Novartis, Pierre Fabre. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, BMS, Merck, MSD, Nektar, NeraCare GmbH, Novartis, Oncology Education, Pierre Fabre, Roche. Support for attending meetings and/or travel: BMS, MSD. Sara Valpione. Receipient of an Institutional Amgen Research Grant., (Copyright © 2024. Published by Elsevier Ltd.)

Immunotherapy with checkpoint inhibitors has revolutionised the outcomes for melanoma patients. In the metastatic setting, patients treated with nivolumab and ipilimumab have an expected 5-year survival of> 50%. For patients with resected high-risk stage III disease, adjuvant pembrolizumab, nivolumab or dabrafenib and trametinib are associated with a significant improvement in both relapse-free survival (RFS) and distant metastasis-free survival (DMFS). More recently neoadjuvant immunotherapy has shown very promising outcomes in patients with clinically detectable nodal disease and is likely to become a new standard of care. For stage IIB/C disease, two pivotal adjuvant trials of pembrolizumab and nivolumab have also reported a significant improvement in both RFS and DMFS. However, the absolute benefit is low and there are concerns about the risk of severe toxicities as well as long-term morbidity from endocrine toxicity. Ongoing registration phase III trials are currently evaluating newer immunotherapy combinations and the role of BRAF/MEK-directed targeted therapy for stage II melanoma. However, our ability to personalise therapy based on molecular risk stratification has lagged behind the development of novel immune therapies. There is a critical need to evaluate the use of tissue and blood-based biomarkers, to better select patients that will recur and avoid unnecessary treatment for the majority of patients cured by surgery alone., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RL: Advisory board Pierre Fabre. Research funding BMS, Astra Zeneca and Pierre Fabre. MM: Advisory board and lectures fees: MSD, BMS, Novartis, Pierre Fabre, Sanofi, Sun Pharma. Research grant: Novartis. GVL: consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. AMME: Consulting Fees: Agenus, BioInvent, BioNTech, Brenus, CatalYm, Clover Pharmaceuticals, Ellipses, Galecto, GenOway, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck&Co, MSD, Pierre Fabre, Pfizer, Scorpion Pharmaceuticals, Sairopa, Sellas, SkylineDX, TigaTx, Trained Therapeutics. Lectures: BMS, MSD; Equity: IO Biotech, SkylineDX, Sairopa. CG: reports personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, personal fees from BMS, personal fees from Philogen, grants and personal fees from Sanofi, during the conduct of the study. AvA: advisory board/consultancy: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC. Research grants Amgen, Merck-Pfizer. Chief Investigator for Combi AD Study which is funded by Pierre Fabre. SS: is consultant advisor for AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, and Advanced Accelerators Applications (a Novartis company). SS reports receiving grant funding to the institution from Advanced Accelerators Applications (a Novartis company), Amgen, Merck Sharp & Dohme, Senwha, Genentech, AstraZeneca to undertake investigator-initiated research. PCL: consultancy fees BMS, MSD, Pierre Fabre, Novartis, Melagenix/Nera Care, Ultimovacs, MLA Diagnostics. Research funding: BMS and Pierre Fabre. Chief Investigator for the DETECTION Trial, funded by Cancer Research UK., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Metformin is a commonly prescribed and well-tolerated medication. In laboratory studies, metformin suppresses BRAF wild-type melanoma cells but accelerates the growth of BRAF-mutated cells. This study investigated the prognostic and predictive value of metformin, including with respect to BRAF mutation status, in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 randomised controlled trial., Methods: Patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma received 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for twelve months. Pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at approximately 42 months median follow-up (Eggermont et al., TLO, 2021). Multivariable Cox regression was used to estimate associations of metformin with RFS and DMFS. Interaction terms were used to model effect modification by treatment and BRAF mutation., Results: Fifty-four patients (0.5%) used metformin at baseline. Metformin was not significantly associated with RFS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.52-1.45) and DMFS (HR 0.82, 95% CI 0.47-1.44). The interaction between metformin and the treatment arm was not significant for either RFS (p = 0.92) or DMFS (p = 0.93). Among patients with mutated BRAF, the association of metformin with RFS (HR 0.70, 95% CI 0.37-1.33) was greater in magnitude though not significantly different to those without mutated BRAF (HR 0.98, 95% CI 0.56-1.69)., Conclusions: There was no significant impact of metformin use on pembrolizumab efficacy in resected high-risk stage III melanoma. However, larger studies or pooled analyses are needed, particularly to explore a possible effect of metformin in BRAF-mutated melanoma., Competing Interests: Declaration of Competing Interest Oliver John Kennedy. None declared. Michal Kicinski. Grants or contracts from any entity: BMS, MSD, Pierre Fabre. Sara Valpione None declared. Sara Gandini None declared. Stefan Suciu. Grants or contracts from any entity: MSD. Christian Blank. Grants or contracts from any entity: BMS, Novartis, NanoString, 4SC. Consulting fees - consultant advisor for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre- Payments were made to my institution, Third Rock Venture - Payments were made to me. Stock or stock options: Immagene BV and Signature Oncology - Co-founder. Georgina V Long. Consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme (Australia), Merck Sharpe & Dohme, Novartis, OncoSec Australia, PHMR Ltd, Pierre Fabre, Provectus Australia, Qbiotics, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb - Personal 1 h lecture of my own slides, Pierre Fabre, Personal 1 h lecture of my own slides. Victoria Atkinson. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre- Speakers bureaus fees. Support for attending meetings and/or travel: BMS, Travel support. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards. Stephane Dalle. Grants or contracts from any entity: Bristol Myers Squibb, Merck Sharp & Dohme - My Institution. Support for attending meetings and/or travel: Bristol Myers Squibb, Pierre Fabre, Merck Sharp &. Dohme. Other financial or non-financial interests: Sanofi Pasteur - My wife is an employee of Sanofi Pasteur. Andrew M. Haydon. Payment or honoraria for lectures, presentations, speakers bureaus: BMS, Merck Sharp & Dohme Novartis. Participation to Advisory Board: BMS, Novartis, Pierre Fabre, Merck Sharp & Dohme. Andrey Meshcheryakov. Grants or contracts from any entity: Sanofi, AstraZeneca, Merck Sharp & Dohme - My institution, me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or. educational events: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Honoraria for lectures, presentations, speakers bureaus. Support for attending meetings and/or travel: BIOCAD, SERVIER, Merck Sharp & Dohme, Sanofi- Aventis, Merck - Attending meetings and/or travel. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, Servier, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis. - Advisory Board. Adnan Khattak None declared. Matteo S. Carlino. Participation on Advisory Board for Amgen, Bristol-Myers Squibb, Eisai, Ideaya, Merck Sharp and Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche. Consulting fees: Bristol Myer Squibb, Merck Sharp & Dohme, Novartis. Shahneen Sandhu. Grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, Merck Sharp & Dohme, Senwha, Genentech, AstraZeneca - Funding to the institution. Participation on an Advisory Board: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Advanced Accelerators Applications (a Novartis company). - Funding to the institution. James Larkin. Grants or contracts from any entity: Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics. Institutional research support: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo. Consulting fees from iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte. Honorariums from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS. Speaker fee from Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, Inselgruppe, Pfizer, Goldman Sachs, MSD. Susana Puig. Grants or contracts from any entity: Almirall, ISDIN, La Roche Posay - To My Institution. Consulting fees: ISDIN, Almirall, La Roche Posay, MSD, Sanofi, Sun Pharma, Pfizer, Roche, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche Posay, Leo Pharma, Pfizer, Roche, Regeneron, BMS, Sun Pharma. Support for attending meetings and/or travel: Almirall. Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Sanofi, Sun Pharma, Almirall, ISDIN, Pfizer, Novartis. Paolo A. Ascierto. Grants or contracts from any entity: Bristol Myers Squibb, Roche-Genentech, Pfizer/Array, Sanofi. Consulting fees: Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, Medicenna, Bio-Al Health, ValoTx, Replimmune, Bayer. Support for attending meetings and/or travel: Pfizer, Bio-Al Health, Replimmune. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, Roche- Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos. Piotr Rutkowski. Consulting fees: Amgen, Blueprint Medicine, Bristol Myers Squibb, Merck, MSD, Novartis, Philogen, Pierre Fabre, Sanofi - Advisory Role - Personal fees. Payment or honoraria for lectures: Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Sanofi Pasteur. Dirk Schadendorf. Grants or contracts from any entity: Amgen, Array BioPharma, Novartis. Consulting fees: 4SC, Angenus, Astra Zeneca, Bristol Myers Squibb, Daiichi Sankyo, EMD Serano, Roche, Genentech, InFlarX, Merck, Nektar, Novartis, Pfizer, Philogen, Pierre Fabre, Regeneron, Sandoz, Sanofi, UltimoVacs. Participation on a Data Safety Monitoring Board: Immunocore. Honoraria for lectures: Amgen, Novartis. Support for attending meetings and/or travel: Amgen, Novartis. Marye Boers-Sonderen. None declared. Anna Maria di Giacomo. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Pierre Fabre, Sanofi. Support for attending meetings and/or travel: BMS, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Pierre Fabre, Sanofi, GSK, Novartis. Alfonsus J.M. van den Eertwegh. Grants or contracts from any entity: Roche, Sanofi, Bristol Myers Squibb, Idera Consulting fees: Bristol Myers Squibb. Support for attending meetings and/or travel: MSD Oncology, Roche, Pfizer, Sanofi, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre. Jean-Jacques Grob. Payment for participation to an advisory board: Amgen, Bristol Myers Squibb, Hoffmann-La Roche. Consulting fees: MSD, Novartis, Philogen, Pierre Fabre, Sanofi Pasteur. Ralf Gutzmer. Grants or contracts from any entity: Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma Industries, Sanofi. Consulting fees: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Genentech, Novartis, Merck Serono, Almirall, Amgen, Sun Pharma Industries, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, Bayer AG, Immunocore. Support for attending meetings and/or travel: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Industries. Rahima Jamal. Grants or contracts from any entity: Merck Sharp & Dohme, Bristol Myers Squibb, Iovance Biotherapeutics. Consulting fees: Bristol Myers Squibb. Alexander C.J. van Akkooi. Grants or contracts from any entity: Amgen, Merck, Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck, Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC. Caroline Robert. Consulting fees: AstraZeneca, BMS, MSD, Merck, Roche, Novartis, Pfizer, Pierre Fabre, Sanofi. Co-founder: Ribonexus. Alexander Eggermont. Consulting fees: Agenus, BioInvent, BMS, Brenus, CatalYm, Ellipses, Galecto, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck&Co, MSD, Pierre Fabre, Sairopa, Sellas, SkylineDX, TigeTx, Trained Immunity TX. Participation on a Data Safety Monitoring Board: BioNTech, GSK, and Pfizer. Lectures: BMS, MSD. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences, German Cancer Aid. Stock or stock options: IO Biotech, SkylineDx and SaiRoPA. Paul Lorigan. Grants or contracts from any entity: BMS, Pierre Fabre. Consulting fees: Amgen, BMS, MSD, Nektar, Novartis, Pierre Fabre. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, BMS, Merck, MSD, Nektar, NeraCare GmbH, Novartis, Oncology Education, Pierre Fabre, Roche. Support for attending meetings and/or travel: BMS, MSD. Mario Mandala. Participation to Advisory Board: BMS, Merck Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals., (Copyright © 2023. Published by Elsevier Ltd.)

Sentinel lymph node biopsy (SLNB) has been introduced in the 1990s to identify patients who might benefit from completion lymph node dissection. Neither SLNB nor CLND improved survival, but SLNB staging did provide the best staging, above Breslow thickness and ulceration. The SLN status and SLN tumour burden were used in all trials until date looking at modern adjuvant systemic therapy with immune checkpoint inhibition (ICI) or targeted therapies (TT). Adjuvant ICI and TT are shifting towards stage II melanoma. The question is whether there is still role for SLNB in melanoma, in this day and age, and if so, how does the future look for SLNB staging? The SLN status and SLN tumour burden might be useful for a consultation to discuss the number needed to treat in a risk/benefit discussion. For stage IIB/C patients, it seems likely, however, that patients will forego a nuclear scan followed by the risk of surgical intervention and morbidity associated with SLNB if they opt to receive adjuvant therapy regardless of the SLNB result. For stage I/IIA, it is still required to detect high-risk patients who might benefit from adjuvant therapy. However, biomarkers are emerging, such as gene expression profilers (GEP), immunohistological signatures and liquid biopsies with ctDNA. There still is a role for SLNB staging in melanoma today, but we expect that the availability of therapeutic option independent of SLNB status as well as emergence of validated biomarkers to predict risk will reduce the need for SLNB staging in the upcoming decade to the point it will no longer be used., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Clinical Question: Is there nowadays any benefit of continuing the practice of routine wide local excision (WLE) for primary stage I/II cutaneous melanoma?, Background: WLE aims to eradicate potential microsatellites around melanomas and thereby reduce local recurrence rates and improve overall survival. Six large prospective randomised trials investigated WLE versus wider WLE, they all failed to show any effect on overall survival (OS)., Methods: A literature search was performed to identify data on outcome after omitting WLE. Additionally circumstantial evidence was gathered from pathology studies and outcomes of modified surgical techniques, as well as publications on morbidity., Results: No prospective and one retrospective study was found. The retrospective study showed no difference in OS after correction for confounding factors. Pathology studies showed a low incidence of residual melanoma in WLE specimen (0-4.2%). Mohs surgery does not show a difference in recurrence rates or OS. WLE is associated with considerable postoperative morbidity, which increases with wider excision margins., Conclusion: There is no solid prospective evidence to support the classic dogma of a 2-step approach with the use of WLE for primary cutaneous melanoma that has been completely excised on diagnostic excision biopsy. We recommend to setup and conduct a prospective randomised trial to compare the classical 2-step approach with WLE to a complete diagnostic excision only to abolish the routine practice of WLE in the future., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ms Zijlker declares: No conflict of interest. Professor Eggermont has received honoraria for participation in Scientific Advisory Board or IDMC over the last 3 years from: Agenus, Biocad, BioNTech, BioInvent, CatalYm, Ellipses, Galecto, GenoWay, GSK, Immunicum, IO Biotech, IQVIA, Merck/MSD, Pfizer, Sairopa, Sellas, SkylineDx, TigaTx, Trained Therapeutics For Speaker Engagements from: BMS, Merck/MSD. Professor van Akkooi declares: Advisory Board & Consultancy Honoraria: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC. Research Grants: Amgen, Merck-Pfizer. All unrelated to the current work under consideration., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: The first randomized trial of adjuvant treatment with checkpoint inhibitor in stage II melanoma reported a significant reduction in risk of tumor recurrence. This study evaluates two independent data sets to further document survival probabilities for patients with primary stage I and II melanoma., Patients and Methods: The Central Malignant Melanoma Registry (CMMR) in Germany evaluated 17,544 patients with a primary diagnosis of stage I and II melanoma from 2000 to 2015. The exploratory cohort consisted of 6,725 patients from the Center for Dermato-Oncology at the University of Tübingen, and the confirmatory cohort consisted of 10,819 patients from 11 other German centers. Survival outcomes were compared with published American Joint Committee on Cancer version 8 (AJCCv8) stage I and II survival data., Results: For the two CMMR cohorts in stage IA compared with the AJCCv8 cohort, melanoma-specific survival rates at 10 years were 95.1%-95.6% versus 98%; 89.7%-90.9% versus 94% in stage IB; 80.7%-83.1% versus 88% in stage IIA; 72.0%-79.9% versus 82% in stage IIB; and 57.6%-64.7% versus 75% in stage IIC, respectively. Recurrence rates were approximately twice as high as melanoma-specific mortality rates in stages IA-IIA., Conclusion: The melanoma-specific survival rates in the two CMMR cohorts across stages I and II are less favorable than published in AJCCv8. This has important implications for the consideration of adjuvant treatment in this population.

Background: Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up., Methods: KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment., Findings: Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [<1%]), rash (seven [1%] vs two [<1%]), autoimmune hepatitis (seven [1%] vs two [<1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported., Interpretation: Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co., Competing Interests: Declaration of interests GVL reports research funding to their institution from Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co; fees for consulting or advisory roles for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim International, Bristol Myers Squibb, Evaxion Biotech, Hexal (Sandoz Company), Highlight Therapeutics, MSD (Australia), Novartis, Oncosec Medical Australia, Pierre Fabre, Provectus, Qbiotics, and Regeneron Pharmaceuticals; and honoraria for speaker's bureau from Bristol-Myers Squibb (BMS) and Pierre Fabre. JJL reports research funding to the institution for clinical studies from MSD, AbbVie, Agios, Array, Astellas, AstraZeneca, BMS, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; membership on data safety monitoring board for AbbVie and Immutep; membership on scientific advisory boards for 7 Hills, Bright Peak, Fstar, Inzen, RefleXion, and Xilioo; stocks for Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, Pyxis, and Tempest; compensation for consultancy with AbbVie, Alnylam, Bayer, BMS, CheckMate, Codiak, Crown, Cstone, Day One, Eisai, EMD Serono, Flame, Genentech, Gilead, HotSpot, Kadmon, KSQ, Janssen, Ikena, Immunocore, Incyte, Macrogenics, Merck, Mersana, Nektar, Novartis, Pfizer, Regeneron, Ribon, Rublus, Silicon, Synlogic, Synthekine, TRex, Werewold, and Xencor; and patents (provisional) for cancer immunotherapy (PCT/US18/36052; microbiome biomarkers for Anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic and therapeutic uses thereof). MAK, J-JG, FdG, and CHY report research funding to their institution for clinical studies from MSD. LdlCM reports research funding to their institution for clinical studies from Celgene, MSD, and Roche; reimbursement for travel expenses from Roche; and consultant or advisory roles for BMS, MSD, Novartis, and Roche. MDV reports research funding to their institution for clinical studies from MSD and honoraria as a consultant or advisor for Novartis, BMS, MSD, and Pierre Fabre. PR reports research funding to their institution from MSD and Pfizer; honoraria for lectures and advisory board participation for MSD, BMS, Novartis, Pierre Fabre, Sanofi, Merck, Philogen, and Blueprint Medicines. FS reports research funding to their institution for clinical studies from MSD; and fees for consulting and honoraria for speakers bureaus from MSD, Novartis, Pierre Fabre, Philogen, Sun Pharma, Merck, and BMS. JM reports research funding to their institution for clinical studies from MSD; honoraria from BMS, MSD, Roche, Novartis, and Pierre Fabre; and consultant or advisory roles for BMS and MSD. VC-S reports research funding to their institution for clinical studies from MSD; reimbursement for travel and accommodation for medical congress from Novartis and Pierre Fabre; and honoraria for advisory board participation for Novartis, Pierre Fabre, BMS, and Merck-Serono. JMK reports research funding to their institution from MSD, Amgen, BMS, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapies, Novartis Pharmaceuticals, Castle Biosciences, and Merck; fees from Amgen, Ankyra Therapeutics, Axios Research Instil Bio, BMS, Checkmate Pharmaceuticals, DermTech, Elsevier, Harbour BioMed, Immunocore, Iovance Biotherapies, Istari Oncology, Millenium Pharmaceuticals or Takeda Pharmaceuticals, Natera, Novartis Pharmaceutical, OncoCyte Corporation, OncoSec Medical, Pfizer, Scopus BioPharma, and Merck. CR reports research funding to their institution for clinical studies from MSD and fees as a consultant or advisor for Amgen, AstraZeneca, BMS, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi. DS reports research finding to their institution for clinical studies from BMS, MSD, Novartis, Amgen, and Array; patient fees to their institution from BMS, MSD, Novartis, Merck–EMD, Philogen, Pfizer, Array, InflarX, OncoSec, Replimune, Neracare, Nektar, Sun Pharma, Sandoz, and UltimoVacs; reimbursement for travel from BMS, Merck, Novartis, Merck-EMD, Pfizer, Pierre Fabre, InflarX, NeraCare, and Nektar; and non-financial support from BMS, MSD, Novartis, Merck-EMD, Pierre-Fabre, InFlarX, Neracare, Nektar, Sun Pharma, and Sandoz. MSC reports research funding to their institution for clinical studies for MSD and honoraria for consulting from BMS, Eisia, IDEAYA Biosciences, Merck Serono, MSD, Novartis, Oncosec, Pierre Fabre, Qbiotics, Roche, and Sanofi. PM reports research funding to their institution for clinical studies from MSD, Amgen, Johnson & Johnson, Merck Serono, Novartis, Pfizer, Sanofi, and Sun Pharma; honoraria from Amgen, BMS, Merck, MSD, Novartis, Pierre Fabre, Genentech (Roche Group), and Sanofi; consulting or advisory roles for Amgen, BMS, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi; fees for speakers bureau from Amgen, BMS, MSD, Novartis, Roche, and Sanofi; and reimbursement for travel, accommodations, and expenses from Amgen, BMS, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma. RD reports research funding to their institution for clinical studies from MSD and consulting or advisory roles with MSD, Novartis, Roche, BMS, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX, Pfizer, and touchIME. JEG reports research funding to their institution for clinical studies from Merck; royalties for content contribution to UpToDate; consulting or advisory roles for Merck, Regeneron, Syndax, and Bristol-Myers Squibb; fees for speakers bureau for Banner MD Anderson Phoenix; reimbursement for travel to meetings from American Joint Committee on Cancer (AJCC), American College of Surgeons, Melanoma Research Alliance, and Bridges Melanoma meeting; and leadership roles for AJCC and Melanoma Research Alliance. XLW, MF-K, and CK are employees of and own stock in MSD. AMME reports research funding to their institution for clinical studies from MSD; fees for advisory board membership for Merck, Agenus, Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, Galecto, GSK, IO Biotech, ISA Pharmaceuticals, Merck, MSD, Nektar, Novartis, Pfizer, Sellas, SkylineDX, TigaTx, and TxDiscovery; fees for independent data monitoring committee for Biocad, GSK, Pfizer, and Novartis;fees for speakers bureau from Biocad, BMS, and Merck; and equity in IO Biotech and SkylineDX. PAA reports research funding to their institution for clinical studies by MSD, BMS, Genentech (Roche Group), Sanofi, and Pfizer or Array BioPharma; fees as a consultant or advisor from BMS, Genentech (Roche Group), MSD, Novartis, Merck Serono, Pierre Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Nektar, Italfarmaco, Pfizer or Array BioPharma, Lunaphore, Medicenna, Bio-Al Health, and ValoTx; and participation on data safety monitoring boards or advisory boards for BMS, Genentech (Roche Group), MSD, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, and ITeos., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

BACKGROUND: In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence- and distant metastasis-free survival than placebo in patients with resected high-risk stage III melanoma. To confirm the stability of these benefits, longer-term data were needed. METHODS: We randomly assigned 1019 patients to receive 200 mg of pembrolizumab or placebo intravenously every 3 weeks for a total of 18 doses (approximately 1 year) and had previously reported data with a 15-, 36-, and 42-month median follow-up. We now report data at a median follow-up of 4.9 years. We report a number of outcomes, including recurrence-free survival in the overall population and in the subgroup of patients with cancer who were positive for the programmed death-ligand 1 (PD-L1). Distant metastasis-free survival was a secondary end point. RESULTS: In the overall intention-to-treat population, pembrolizumab was still associated with longer recurrence-free survival than placebo (5-year rate of recurrence-free survival, 55.4% [95% confidence interval (CI), 50.8 to 59.8] vs. 38.3% [95% CI, 33.9 to 42.7]; hazard ratio for recurrence or death, 0.61 [95% CI, 0.51 to 0.72]) and a longer distant metastasis-free survival (5-year rate of distant metastasis-free survival, 60.6% [95% CI, 56.0 to 64.9] vs. 44.5% [95% CI, 39.9 to 48.9]; hazard ratio for distant metastasis or death, 0.62 [95% CI, 0.52 to 0.75]). Similar findings were obtained in the subgroup of 853 patients with PD-L1–positive tumors. CONCLUSIONS: The 5-year analysis of adjuvant therapy with pembrolizumab resulted in a sustained improvement in the long-term recurrence- and distant metastasis-free survival compared with placebo in patients with resected stage III melanoma. (Funded by Merck & Co., Inc.; ClinicalTrials.gov number, NCT02362594, and EudraCT number, 2014-004944-37.)

Immunotherapy with immune-checkpoint inhibitors and molecularly targeted therapy with BRAF inhibitors were pioneered in the setting of advanced-stage, unresectable melanoma, where they revolutionized treatment and considerably improved patient survival. These therapeutic approaches have also been successfully transitioned into the resectable disease setting, with the regulatory approvals of ipilimumab, pembrolizumab, nivolumab, and dabrafenib plus trametinib as postoperative (adjuvant) treatments for various, overlapping groups of patients with high-risk melanoma. Moreover, these agents have shown variable promise when used in the preoperative (neoadjuvant) period. The expanding range of treatment options available for resectable high-risk melanoma, all of which come with risks as well as benefits, raises questions over selection of the optimal therapeutic strategy and agents for each individual, also considering that many patients might be cured with surgery alone. Furthermore, the use of perioperative therapy has potentially important implications for the management of patients who have disease recurrence. In this Viewpoint, we asked four expert investigators and medical or surgical oncologists who have been involved in the key studies of perioperative systemic therapies for their perspectives on the optimal management of patients with high-risk melanoma., (© 2022. Springer Nature Limited.)

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

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

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

Purpose: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up., Patients and Methods: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors., Results: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600 E/K v wild type)., Conclusion: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.

Purpose: Patients with stage I/IIA cutaneous melanoma (CM) are currently not eligible for adjuvant therapies despite uncertainty in relapse risk. Here, we studied the ability of a recently developed model which combines clinicopathologic and gene expression variables (CP-GEP) to identify stage I/IIA melanoma patients who have a high risk for disease relapse., Patients and Methods: Archival specimens from a cohort of 837 consecutive primary CMs were used for assessing the prognostic performance of CP-GEP. The CP-GEP model combines Breslow thickness and patient age, with the expression of eight genes in the primary tumour. Our specific patient group, represented by 580 stage I/IIA patients, was stratified based on their risk of relapse: CP-GEP High Risk and CP-GEP Low Risk. The main clinical end-point of this study was five-year relapse-free survival (RFS)., Results: Within the stage I/IIA melanoma group, CP-GEP identified a high-risk patient group (47% of total stage I/IIA patients) which had a considerably worse five-year RFS than the low-risk patient group; 74% (95% confidence interval [CI]: 67%-80%) versus 89% (95% CI: 84%-93%); hazard ratio [HR] = 2.98 (95% CI: 1.78-4.98); P < 0.0001. Of patients in the high-risk group, those who relapsed were most likely to do so within the first 3 years., Conclusion: The CP-GEP model can be used to identify stage I/IIA patients who have a high risk for disease relapse. These patients may benefit from adjuvant therapy., Competing Interests: Conflict of interest statement Dr. Eggermont reports receiving honoraria from Actelion, Agenus, Bayer, BIOCAD, Biovent, BMS, CatalYm, Celldex, Ellipses, Forbion, Gilead, GSK, HalioDx, Incyte, IO Biotech, ISA Pharmaceuticals, MedImmune, Merck GmbH, MSD, Novartis, Pfizer, Polynoma, Regeneron, Sanofi, SkylineDx and Stellas over the past five years; having equity stakes in SkylineDx and THERANOVIR and speaker engagements with BIOCAD, MSD and Novartis. Dr. Bellomo reports equity stakes in SkylineDx and Synlogic. Dr. Hieken reports receiving research funding from Genentech and Roche through Mayo Clinic. Dr. Sluzevich reports receiving research funding from Merck through Mayo Clinic. Dr. Pernaciaro reports receiving honoraria from Myriad Genetics and travel, accommodations and expenses paid for by Myriad Genetics. Ms. Tjien-Fooh, Ms. Rentroia-Pacheco, Ms. Wever, Dr. van Vliet, and Dr. Dwarkasing reports equity stakes in SkylineDx. Dr. Bellomo, Ms. Tjien-Fooh, Ms. Rentroia-Pacheco, Ms. Wever, Dr. van Vliet, and Dr. Dwarkasing reports being employees of SkylineDx. Dr. Bellomo and Dr. Meves report patents pending for gene signatures for predicting melanoma metastasis. All remaining authors have no conflict of interest to declare., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Subgroup analyses of two large EORTC adjuvant interferon-alpha2b (IFNα-2b) vs observation randomised trials demonstrated that a treatment benefit was observed only in patients with an ulcerated melanoma without palpable nodes (hazard ratio [HR] for recurrence-free survival [RFS] was 0.69). This was confirmed by a meta-analysis of 15 adjuvant IFN trials (HR: 0.79)., Patients and Methods: In the EORTC 18081 trial, sentinel node-negative stage II patients with an ulcerated primary melanoma were 1:1 randomised between pegylated (PEG)-IFNα-2b at 3 μg/kg/week subcutaneously and observation, for 2 years, or until disease recurrence or unacceptable toxicity in spite of dose adjustments to maintain an Eastern Cooperative Oncology Group performance status of 0 or 1. Main end-point was RFS. Secondary end-points included distant metastasis-free survival (DMFS), overall survival, and safety (EudraCT Number: 2009-010273-20)., Results: Between February 2013 and January 2017, only 112 patients were randomised, 56 in each arm. The trial was stopped early for lack of recruitment. At a 3.4-year median follow-up, the estimated HR for the PEG-IFNα-2b group compared with the observation group regarding RFS was 0.66 (95% confidence interval [CI]: 0.32-1.37), and the 3-year RFS rate was 80.0% (95% CI: 65.7-88.8%) and 72.9% (95% CI: 58.3-83.0%), respectively. DMFS was prolonged: HR: 0.39 (95% CI: 0.15-0.97), and the 3-year DMFS rate was 90.6% (95% CI: 78.9-96.0%) vs 76.4% (95% CI: 62.1-85.9%). One patient in the PEG-IFNα-2b group died compared with 4 in the observation group. Fifty-four patients started PEG-IFNα-2b treatment, 16 (29%) completed 2 years of treatment, 2 (4%) stopped due to recurrence, 23 (43%) due to toxicity and 14 (25%) due to other reasons., Conclusions: The EORTC 18081 PEG-IFNα-2b randomised trial, observed a similar HR (0.69) for RFS as the previous EORTC trials (0.69). In countries without access to new drugs, adjuvant (PEG)-IFNα-2b treatment is an option for patients with ulcerated melanomas without palpable nodes., Competing Interests: Conflict of interest statement A.M.M.E. reports receiving personal fees as consultant advisor for Biocad, BioInvent, Bristol Myers Squibb (BMS), CatalYm, Ellipses, Glaxo Smith Kline (GSK), HalioDX, Incyte, IO Biotech, ISA Pharmaceuticals, Nektar, Merck Sharpe & Dohme (MSD), Novartis, Pfizer, Polynoma, Regeneron, Sanofi, Sellas, SkylineDx. P.R. reports receiving personal fees as consultant advisor for Novartis, MSD, BMS, Roche, Pfizer, Blueprint Medicines and Pierre Fabre, outside the submitted work. R.H.-W. reports receiving grants and non-financial support from EORTC, during the conduct of the study. C.R. reports personal fees as consultant advisor for Roche, Pierre Fabre, Merck, Novartis, Amgen, BMS, Novartis, MSD, Sanofi, Biothera, Ultimovacs, outside the submitted work. A.v.A. reports receiving grants from Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Sanofi and 4SC, outside the submitted work. L.B. reports receiving personal fees as consultant advisor for BMS, Novartis, MSD, Swedish Orphan, Bayer and Incyte outside the submitted work. A.M. reports receiving personal fees from Novartis, Pierre Fabre, MSD and SunPharma, outside the submitted work. J.J.G. reports receiving personal fees for advisory role from BMS, Novartis, MSD, Roche, Amgen,Pierre Fabre, Merck, Pfizer and Sanofi, and has also received travel support from BMS, Novartis, MSD, outside the submitted work. D.S. reports receiving grants, personal fees for consulting or advisory role; received honoraria; received travel expenses, accommodations, expenses from MSD, during the conduct of the study; and also received personal fees for consulting or advisory role; honoraria; travel expenses, accommodations, expenses from Roche / Genentech, personal fees, non-financial support and other from Novartis, grants and personal fees from BMS, personal fees and non-financial support from Merck Serono, and Amgen, personal fees from Immunocore, Incyte, 4SC, Pierre Fabre, Mologen, Sanofi / Regeneron, Roche, Sysmex, Agenus, Array BioPharma, AstraZeneca, InFlarX, Philogen, Nektar, Sandoz, non-financial support from Merck, outside the submitted work. M.M., F.G., E.P., E.M., O.B., S.M., M.K. and S.S. report no competing interests. A.A.E.T. reports receiving travel support from Agenus, outside the submitted work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Adjuvant therapy with PD-1 inhibitors for resected Stage III/IV melanoma reduces the risk of recurrence by 40-50% and is now a standard of care. Immune-related adverse events occurred in approximately 37% of patients in the pivotal trials, 10-15% were severe (grade III-IV). Endocrine toxicities were common and mostly irreversible. Thyroid toxicity occurred in 15-20% of patients, hypophysitis (2.2%), insulin-dependent diabetes mellitus (1%) and adrenalitis (1%). Revision of the American Joint Committee on Cancer staging system (version 8) has resulted in a significant improvement in prognosis for patients with Stage III disease. As a result, clinicians may now offer adjuvant immunotherapy to patients with a lower risk of recurrence than those in the pivotal trials. There is a need to balance the relatively small reduction of absolute risk of recurrence against the risk and impact of toxicity. Five-ten percent of biochemically euthyroid patients on levothyroxine report symptoms of depression. Hypogonadism can result from toxicity to the hypothalamic-pituitary axis, and can lead to sexual dysfunction and subfertility. Secondary hypogonadism can be treated by the administration of Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH) which induce spermatogenesis/ovulation in a functioning gonad but is not always successful. Insulin-dependent diabetes mellitus often presents with rapid onset of hyperglycemia and potentially life-threatening diabetic ketoacidosis. Long-term adverse outcomes are likely to mimic Type 1 DM with a 6-fold increase in cardiovascular disease related mortality and 3-fold in all-cause mortality. These survivorship issues are relevant to all melanoma patients but are particularly pertinent where the absolute benefit is modest., Competing Interests: Conflict of interest statement Claire Higham, Viktoria Chatzimavridou-Grigoriadou, Cheryl Fitzgerald, Peter Trainer: no conflict of interest; Alexander Eggermont: Adjuvant Trial Coordinator studies: EORTC 18071 / CA-029 and EORTC 1325 / Keynote-054. Paid advisor: Biocad, BioInvent, BMS, CatalYm, GSK, IO Biotech, MSD, Novartis, Pfizer, Regeneron, Sellas, SkylineDx; Paul Lorigan: Research Funding: BMS and JP Moulton Foundation. Paid advisor/speaker bureau: BMS, MSD, Novartis, Pierre Fabre, Amgen, Melagenix, Incyte, Nektar. Support for travel: BMS, MSD. All out with this work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In order to update recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed. Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. For common primary cSCC (the most frequent cSCC type), first-line treatment is surgical excision with postoperative margin assessment or microscopically controlled sugery. Safety margins containing clinical normal-appearing tissue around the tumour during surgical excision and negative margins as reported in the pathology report are necessary to minimise the risk of local recurrence and metastasis. In case of positive margins, a re-excision shall be done, for operable cases. Lymph node dissection is recommended for cSCC with cytologically or histologically confirmed regional nodal involvement. Radiotherapy should be considered as curative treatment for inoperable cSCC, or for non-surgical candidates. Anti-PD-1 antibodies are the first-line systemic treatment for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation therapy. Multidisciplinary board decisions are mandatory for all patients with advanced disease who require more than surgery. Patients should be engaged with informed decisions on management and be provided with best supportive care to optimise symptom management and improve quality of life. Frequency of follow-up visits and investigations for subsequent new cSCC depend on underlying risk characteristics., Competing Interests: Conflict of interest statement Dr. Stratigos reports personal fees and/or research support from Novartis, Roche, BMS, AbbVie, Sanofi, Regeneron, Genesis Pharma, outside the submitted work. Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Pierre Fabre, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted work. Dr. Dessinioti has nothing to disclose. Dr. Lebbe reports grants and personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Amgen, grants and personal fees from Roche, personal fees from Avantis Medical Systems, personal fees from Pierre Fabre, personal fees from Pfizer, personal fees from Incyte, outside the submitted work. Dr. Bataille reports personal fees from Novartis, personal fees from Merck MSD, outside the submitted work. Dr. Bastholt reports personal fees for advisory board activity: BMS, Roche, Novartis, Pierre Fabre, AstraZeneca, Incyte, MSD/Merck, Bayer. Dr. Dréno reports grants and personal fees from BMS, personal fees from MSD, grants and personal fees from Roche, grants and personal fees from Fabre, grants and personal fees from Sanofi, outside the submitted work. Dr. Fargnoli reports grants and personal fees from Almirall, grants and personal fees from Leo Pharma, personal fees from Janssen, grants and personal fees from Novartis, personal fees from Lilly, grants and personal fees from Sanofi, personal fees from UCB, grants and personal fees from AbbVie, personal fees from Celgene, personal fees from Pierre Fabre, grants and personal fees from Galderma, personal fees from Mylan, personal fees from Medac Pharma, personal fees from Roche, personal fees from Sun Pharma, outside the submitted work. Dr. Forsea reports scientific consultant/speaker fee from Novartis, Leo Pharma, Solartium, Pierre Fabre, outside the submitted work. Dr. Frenard has nothing to disclose. Dr. Harwood reports institutional research grants and honoraria from Sanofi, Novartis, Merck, Pfizer, Galderma, Meda, Almirall, PellePharm, Leo Pharma, Ceries. Dr. Hauschild reports honoraria and/or research grants from Almirall, BMS, Roche, Novartis, Pierre Fabre, Sun Pharma, Merck Serono, Sanofi-Aventis, Regeneron, MSD/Merck, Philogen, OncoSec outside the submitted work. Dr. Hoeller reports grants and personal fees from Amgen, personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Pierre Fabre, personal fees from Roche, personal fees from Sanofi, personal fees from Incyte, outside the submitted work. Dr. Kandolf-Sekulovic reports speakers’ honoraria for Roche, Novartis, MSD, BMS, Janssen outside the submitted work. Dr. Kaufmann reports institutional research grants (clinical trials) from AbbVie, Amgen, Biontech, BMS, Celgene, Galderma, Janssen, Leo, Lilly, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Regeneron, Roche, Wyeth. Advisory board and honoraria from Merz, Roche, Novartis. Dr. Kelleners-Smeets reports grants from Netherlands Organization for Health Research and Development, other from Janssen-Cilag, other from AbbVie, other from Galderma, outside the submitted work. Dr. Malvehy reports research grants from Almirall, ISDIN, Leo Pharma, Galderma, GSK, Cantabria; participation in advisory board meetings for Almirall, Sun Pharma, BMS, Roche, Novartis, Pierre Fabre. Dr. del Marmol reports personal fees from MSD, from BMS, personal fees from Sanofi, grants and personal fees from AbbVie, grants from Janssen, outside the submitted work. Dr. Middleton reports personal fees and/or grants from Amgen, Roche, AstraZeneca, GSK, Novartis, Immunocore, BMS, Eisai and Merck. Institutional funding from Millennium, Vertex, Pfizer, Regeneron, TC Biopharm, BioLineRx, Replimune, outside the submitted work. Dr. Moreno-Ramírez has nothing to disclose. Dr. Pellecani reports grants from university of Modena and Reggio Emilia, during the conduct of the study; grants from Novartis, grants and personal fees from Almirall, grants from Leo Pharma, from null, outside the submitted work. Dr. Peris reports honoraria for advisory board and grants from AbbVie, Almirall, Biogen Celgene, Lilly, Galderma, Leo Pharma, Novartis, Roche, Sanofi, Sun Pharma, Sandoz outside the submitted work. Dr. Saiag reports honoraria for advisory board and grants from Amgen, Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pfizer, Roche-Genentech, Pierre Fabre, and Sanofi, outside the submitted work. Dr. van den Beuken-van Everdingen has nothing to disclose. Dr. Vieira has nothing to disclose. Dr. Zalaudek reports honoraria and advisory board and grants from Sanofi, Sun Pharma, Novartis, Galderma, Roche, Celgene, Almirall, Leo Pharma, Mylan, Difa Cooper, Cieffe Labs, La Roche Posay, Pierre Fabre. Dr. Eggermont reports over the last 5 years personal fees as a consultant advisor for BIOCAD, BioInvent, Bristol-Myers Squibb (BMS), CatalYm, Ellipses, GlaxoSmithKline (GSK), HalioDx, Incyte, IO Biotech, ISA Pharmaceuticals, Merck Sharpe & Dohme (MSD), Novartis, Pfizer, Polynoma, Regeneron, Sanofi, SELLAS, SkylineDx. Dr. Grob reports personal fees for advisory board and as speaker from Amgen, Roche, GSK, Novartis, BMS, Pierre Fabre, Merck, Sanofi, Merck, Pfizer outside the submitted work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Invasive cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in the white populations, accounting for 20% of all cutaneous malignancies. Factors implicated in cSCC etiopathogenesis include ultraviolet radiation exposure and chronic photoaging, age, male sex, immunosuppression, smoking and genetic factors. A collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organisation of Research and Treatment of Cancer (EORTC) was formed to update recommendations on cSCC classification, diagnosis, risk stratification, staging and prevention, based on current literature, staging systems and expert consensus. Common cSCCs are typically indolent tumors, and most have a good prognosis with 5-year cure rates of greater than 90%, and a low rate of metastases (<4%). Further risk stratification into low-risk or high-risk common primary cSCC is recommended based on proposed high-risk factors. Advanced cSCC is classified as locally advanced (lacSCC), and metastatic (mcSCC) including locoregional metastatic or distant metastatic cSCC. Current systems used for staging include the American Joint Committee on Cancer (AJCC) 8th edition, the Union for International Cancer Control (UICC) 8th edition, and Brigham and Women's Hospital (BWH) system. Physical examination for all cSCCs should include total body skin examination and clinical palpation of lymph nodes, especially of the draining basins. Radiologic imaging such as ultrasound of the regional lymph nodes, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography-computed tomography (PET-CT) scans are recommended for staging of high-risk cSCC. Sentinel lymph node biopsy is currently not recommended. Nicotinamide, oral retinoids, and topical 5-FU have been used for the chemoprevention of subsequent cSCCs in high-risk patients but are not routinely recommended. Education about sun protection measures including reducing sun exposure, use of protective clothing, regular use of sunscreens and avoidance of artificial tanning, is recommended., Competing Interests: Declaration of competing interest Dr. Stratigos reports personal fees and/or research support from Novartis, Roche, BMS, Abbvie, Sanofi, Regeneron, Genesis Pharma, outside the submitted work. Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Pierre Fabre, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted work. Dr. Dessinioti has nothing to disclose. Dr. Lebbe reports grants and personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Amgen, grants and personal fees from Roche, personal fees from Avantis Medical Systems, personal fees from Pierre Fabre, personal fees from Pfizer, personal fees from Incyte, outside the submitted work. Dr. Bataille reports personal fees from Novartis, personal fees from MerckMSD, outside the submitted work. Dr. Bastholt reports personal fees for advisory board activity: BMS, Roche, Novartis, Pierre-Fabre, Astra Zeneca, InCyte, MSD/Merck, Bayer. Dr. Dréno reports grants and personal fees from BMS, personal fees from MSD, grants and personal fees from Roche, grants and personal fees from Fabre, grants and personal fees from Sanofi, outside the submitted work. Dr. Fargnoli reports grants and personal fees from Almirall, grants and personal fees from Leo Pharma, personal fees from Janssen, grants and personal fees from Novartis, personal fees from Lilly, grants and personal fees from Sanofi, personal fees from UCB, grants and personal fees from Abbvie, personal fees from Celgene, personal fees from Pierre Fabre, grants and personal fees from Galderma, personal fees from Mylan, personal fees from Medac Pharma, personal fees from Roche, personal fees from Sun Pharma, outside the submitted work. Dr. Forsea reports scientific consultant/speaker fee from Novartis, Leo Pharma, Solartium, Pierre-Fabre, outside the submitted work. Dr. Frenard has nothing to disclose. Dr. Harwood reports institutional research grants and honoraria from Sanofi, Novartis, Merck, Pfizer, Galderma, MEDA, Almirall, Pellepharm, Leo Pharma, CERIES. Dr. Hauschild reports honoraria and/or research grants from: Almirall, BMS, Roche, Novartis, Pierre-Fabre, Sunpharma, MerckSerono, SanofiAventis, Regeneron, MSD/Merck, Philogen, OncoSec outside the submitted work. Dr. Hoeller reports grants and personal fees from Amgen, personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Pierre Fabre, personal fees from Roche, personal fees from Sanofi, personal fees from Incyte, outside the submitted work. Dr. Kandolf-Sekulovic reports speakers’ honoraria for Roche, Novartis, MSD, BMS, Janssen outside the submitted work. Dr. Kaufmann reports institutional research grants (clinical trials) from: AbbVie, Amgen, Biontech, BMS, Celgene, Galderma, Janssen, Leo, Lilly, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Regeneron, Roche, Wyeth. Advisory Board and Honoraria from Merz, Roche, Novartis. Dr. Kelleners-Smeets reports grants from Netherlands Organization for Health Research and Development, other from Janssen-Cilag, other from AbbVie, other from Galderma, outside the submitted work. Dr. Malvehy reports research grants from Almirall, ISDIN, Leo Pharma, Galderma, GSK, Cantabria; participation in advisory board meetings for Almirall, Sunpharma, BMS, Roche, Novartis, Pierre-Fabre. Dr. del Marmol reports personal fees from MSD, from BMS, personal fees from Sanofi, grants and personal fees from ABVIE, grants from Jansen, outside the submitted work. Dr. Middleton reports personal fees and/or grants from Amgen, Roche, Astrazeneca, GSK, Novartis, Immunocore, BMS, Eisai and Merck. Institutional funding from Millennium, Vertex, Pfizer, Regeneron, TCBiopharma, BiolineRx, Replimune, outside the submitted work. Dr. Moreno-Ramírez has nothing to disclose. Dr. Pellecani reports grants from university of modena and reggio emilia, during the conduct of the study; grants from novartis, grants and personal fees from almirall, grants from leo pharma, from null, outside the submitted work. Dr. Peris reports honoraria for advisory board and grants from AbbVie, Almirall, BiogenCelgene, Lilly, Galderma, Leo Pharma, Novartis, Roche, Sanofi, Sun Pharma, Sandoz outside the submitted work. Dr. Saiag reports honoraria for advisory board and grants from Amgen, Bristol-Myers Squibb, MSD, Merck-Serono, Novartis, Pfizer, Roche-Genentech, Pierre Fabre, and Sanofi, outside the submitted work. Dr. van den Beuken-van Everdingen has nothing to disclose. Dr. Vieira has nothing to disclose. Dr. Zalaudek reports honoraria and advisory board and grants from Sanofi, Sun Pharma, Novartis, Galderma, Roche, Celgene, Almirall, Leofarma, Mylan, Difa Cooper, Cieffe Labs, La Roche Posay, Pierre Fabre. Dr. Eggermont reports over the last 5 years personal fees as a consultant advisor for Biocad, BioInvent, Bristol Myers Squibb (BMS), CatalYm, Ellipses, Glaxo Smith Kline (GSK), HalioDX, Incyte, IO Biotech, ISA Pharmaceuticals, Merck Sharpe & Dohme (MSD), Novartis, Pfizer, Polynoma, Regeneron, Sanofi, Sellas, SkylineDx. Dr. Grob reports personal fees for advisory board and as speaker from Amgen, Roche, GSK, Novartis, BMS, Pierre fabre, Merck, Sanofi, Merck, Pfizer outside the submitted work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Since 2015, adjuvant therapy with ipilimumab is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS). At a median follow-up of 5.3 years, RFS, distant metastasis-free survival (DMFS) and overall survival (OS) were each significantly prolonged in the ipilimumab group compared with the placebo group, despite a 53.3% (ipilimumab) versus 4.6% (placebo) treatment discontinuation rate due to adverse events. We present now long-term follow-up results of this European Organisation for Research and Treatment of Cancer 18071 trial., Patients, Methods and Results: A total of 99 sites randomised 951 patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes to receive intravenous infusions of ipilimumab 10 mg/kg or placebo, every 3 weeks for 4 doses, then every 3 months for up to 3 years. The RFS, DMFS and OS, as reported by the local investigators, were assessed by the intention-to-treat analysis. Among 431 patients randomised at 63 sites and who were still alive at the analysis reported in 2016, recent follow-up information could be obtained for 264 patients. The median OS follow-up was 6.9 years. The RFS (hazard ratio [HR] 0.75, 95% confidence interval 0.63-0.88; P < 0.001), DMFS (HR 0.76, 0.64-0.90; P = 0.002) and OS (HR 0.73, 0.60-0.89; P = 0.002) benefit observed in the ipilimumab group was durable with an 8.7% absolute difference at 7 years for OS. The benefit was consistent across subgroups., Conclusions: Adjuvant therapy with ipilimumab prolongs RFS, DMFS and OS significantly. The benefit is sustained long term and consistent across subgroups., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The American Joint Committee on Cancer-8 (AJCC) classification of melanoma was implemented in January 2018. It was based on data gathered when checkpoint inhibitors were not used as adjuvant therapy in stage III melanoma. The European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 double-blind phase III trial evaluated pembrolizumab vs placebo in AJCC-7 stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (without in-transit metastasis) patients after complete lymphadenectomy., Patients, Methods and Results: Patients (n = 1019) were randomised 1:1 to pembrolizumab 200 mg or placebo every 3 weeks (total of 18 doses, ∼1 year). At 1.25-year median follow-up, pembrolizumab prolonged relapse-free survival (RFS) in the total population (1-year RFS rate: 75.4% vs 61.0%; hazard ratio [HR] 0.57; logrank P < 0.0001) and consistently in the AJCC-7 subgroups. Prognostic and predictive values of AJCC-8 for RFS were evaluated in this study. Patient distribution according to the AJCC-8 stage subgroups was 8% (IIIA), 34.7% (IIIB), 49.7% (IIIC), 3.7% (IIID) and 3.8% (unknown). AJCC-8 classification was strongly associated with RFS (HRs for stage IIIB, IIIC and IIID vs IIIA were 4.0, 5.7 and 12.2, respectively) but showed no predictive importance for the treatment comparison regarding RFS (test for interaction: P = 0.68). The 1-year RFS rate for pembrolizumab vs placebo and the HRs (99% confidence interval) within each AJCC-8 subgroup were as follows: stage IIIA (92.7% vs 92.5%; 0.76 [0.11-5.43]), IIIB (79.0% vs 65.5%; 0.59 [0.35-0.99]), IIIC (73.6% vs 53.9%; 0.48 [0.33-0.70]) and IIID (50.0% vs 33.3%; 0.69 [0.24-2.00])., Conclusions: AJCC-8 staging had a strong prognostic importance for RFS but no predictive importance: the RFS benefit of pembrolizumab was observed across AJCC-8 subgroups in resected high-risk stage III melanoma patients., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Background: Patients with melanoma and negative sentinel nodes (SNs) have varying outcomes, dependent on several prognostic factors. Considering all these factors in a prediction model might aid in identifying patients who could benefit from a personalized treatment strategy. The objective was to construct and validate a nomogram for recurrence and melanoma-specific mortality (MSM) in patients with melanoma and negative SNs., Methods: A total of 3220 patients with negative SNs were identified from a cohort of 4124 patients from four EORTC Melanoma Group centres who underwent sentinel lymph node biopsy. Prognostic factors for recurrence and MSM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across the four centres. A nomogram was developed for graphical presentation., Results: There were 3180 eligible patients. The final prediction model for recurrence and the calibrated model for MSM included three independent prognostic factors: ulceration, anatomical location and Breslow thickness. The c-index was 0·74 for recurrence and 0·76 for the calibrated MSM model. Cross-validation across the four centres showed reasonable model performance. A nomogram was developed based on these models. One-third of the patients had a 5-year recurrence probability of 8·2 per cent or less, and one-third had a recurrence probability of 23·0 per cent or more., Conclusion: A nomogram for predicting recurrence and MSM in patients with melanoma and negative SNs was constructed and validated. It could provide personalized estimates useful for tailoring surveillance strategies (reduce or increase intensity), and selection of patients for adjuvant therapy or clinical trials., (© 2018 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background: In light of the evolving landscape of adjuvant therapy in melanoma and the recently confirmed absent survival benefit of completion lymph node dissection (CLND), it becomes important to explore possible consequences of omitting CLND, and whether it is possible to adequately stratify positive sentinel node (SN) patients solely based on information retrieved from the melanoma up to the sentinel lymph node biopsy (SLNB)., Methods: A retrospective cohort from nine European Organization for Research and Treatment of Cancer Melanoma Group centres was used. Patients were staged based on SLNB and CLND result according to the American Joint Committee on Cancer (AJCC) criteria and stratified by ulceration and SN tumour burden. These were incorporated in Cox regression models. Predictive ability was assessed using Harrell's concordance index (c-index) and the Akaike information criterion (AIC)., Results: In total, 1015 patients were eligible. CLND led to upstaging in N-category in 19% and in AJCC stage in 5-6%. The model incorporating only ulceration and SN tumour burden performed equally well as the model incorporating substages after CLND. The model incorporating substages based on SLNB had the lowest predictive ability. Stratifying by ulceration and SN tumour burden resulted in four positive SN groups from which low-, intermediate- and high-risk prognostic classes could be derived., Conclusions: Adequate stratification of positive SN patients was possible based on ulceration and SN tumour burden category. The identification of low-, intermediate- and high-risk patients could guide adjuvant therapy in clinical practice. Omitting CLND seems to have little consequences., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The aim of this study was to assess the prognostic importance of lymph node ratio (LNR) in stage III melanoma after complete lymph nodal dissections. From European Organization for Research and Treatment of Cancer randomized trials 18871, 18952, and 18991, 2358 patients had full information on positive and examined lymph nodes (LNs) and were included. Cox proportional hazards models stratified by trial were used to assess the prognostic impact of LNR adjusted for confounders on melanoma-specific survival. Optimal cutoff values for LNR were calculated for each LN dissection site (axillary, inguinal, and neck). LNR (≥ vs. <35%: hazard ratio=1.44, 95% confidence interval: 1.23-1.69) and number of positive LNs appeared to be of independent strong prognostic importance. Dissection sites impacted the optimal LNR cutoff: 35% for axillary, 40% for inguinal, and 50% for neck dissections. Combining these into one 'high versus low LNR' resulted in a highly significant multivariately adjusted hazard ratio of 1.48 (95% confidence interval: 1.26-1.74). In subgroup analyses, LNR was only significant in advanced disease (American Joint Committee on Cancer stage N2b, N3; IIIC). LNR was most significant for inguinal dissections, followed by axillary dissections, but seemed less useful in neck dissections. LNR is an independent significant prognostic factor in stage III melanoma patients. Our study showed higher than previously reported cutoffs that differed per dissection site. However, because of conflicting results compared with other studies and apparent limited prognostic impact confined to subgroups, the practical use of LNR seems limited.

Background: The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma., Methods: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated., Results: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group., Conclusions: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

Background: We assessed whether relapse-free survival (RFS; time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials., Methods: Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included. A two-level modeling approach was used for assessing Spearman's patient-level correlation (rho) of RFS and OS and the trial-level coefficient of determination (R²) of the treatment effects on RFS and on OS. The results were validated externally in 13 adjuvant studies without available IPD. We then tested the results on the European Organisation for Research and Treatment of Cancer (EORTC) 18071 double-blind trial comparing ipilimumab 10 mg/kg with placebo, which showed a statistically significant impact of the checkpoint inhibitor on RFS and OS. All statistical tests were two-sided., Results: With a median follow-up of seven years, 12 of 13 trials showed a consistency between the IFN vs No IFN differences regarding RFS (hazard ratio [HR]RFS = 0.88) and OS (HROS = 0.91), but the small trial, Eastern Cooperative Oncology Group 2696, was an outlier (HRRFS = 0.72 vs HROS = 1.11). Therefore, even if rho was high, R² was low and could not reliably be estimated. Based on the 12 trials, rho remained high (0.89), and the hazard ratios for RFS and OS were strongly correlated (R² = 0.91). The surrogate threshold effect for RFS was estimated to be 0.77. For the EORTC 18071 trial, the hazard ratio for RFS was 0.75, predicting an effect of ipilimumab on OS. This was subsequently confirmed (HROS = 0.72, 95.1% confidence interval = 0.58 to 0.88, P = .001)., Conclusions: In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate end point for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a hazard ratio for RFS of 0.77 or less would predict a treatment impact on OS., (© The Author 2017. Published by Oxford University Press.)

Answer questions and earn CME/CNE To update the melanoma staging system of the American Joint Committee on Cancer (AJCC) a large database was assembled comprising >46,000 patients from 10 centers worldwide with stages I, II, and III melanoma diagnosed since 1998. Based on analyses of this new database, the existing seventh edition AJCC stage IV database, and contemporary clinical trial data, the AJCC Melanoma Expert Panel introduced several important changes to the Tumor, Nodes, Metastasis (TNM) classification and stage grouping criteria. Key changes in the eighth edition AJCC Cancer Staging Manual include: 1) tumor thickness measurements to be recorded to the nearest 0.1 mm, not 0.01 mm; 2) definitions of T1a and T1b are revised (T1a, <0.8 mm without ulceration; T1b, 0.8-1.0 mm with or without ulceration or <0.8 mm with ulceration), with mitotic rate no longer a T category criterion; 3) pathological (but not clinical) stage IA is revised to include T1b N0 M0 (formerly pathologic stage IB); 4) the N category descriptors "microscopic" and "macroscopic" for regional node metastasis are redefined as "clinically occult" and "clinically apparent"; 5) prognostic stage III groupings are based on N category criteria and T category criteria (ie, primary tumor thickness and ulceration) and increased from 3 to 4 subgroups (stages IIIA-IIID); 6) definitions of N subcategories are revised, with the presence of microsatellites, satellites, or in-transit metastases now categorized as N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes, if any; 7) descriptors are added to each M1 subcategory designation for lactate dehydrogenase (LDH) level (LDH elevation no longer upstages to M1c); and 8) a new M1d designation is added for central nervous system metastases. This evidence-based revision of the AJCC melanoma staging system will guide patient treatment, provide better prognostic estimates, and refine stratification of patients entering clinical trials. CA Cancer J Clin 2017;67:472-492. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C-IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node-positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Many randomised trials assessing interferon-α (IFN-α) as adjuvant therapy for high-risk malignant melanoma have been undertaken. To better assess the role of IFN-α, an individual patient data (IPD) meta-analysis of these trials was undertaken., Methods: IPD was sought from all randomised trials of adjuvant IFN-α versus no IFN-α for high-risk melanoma. Primary outcomes were event-free survival (EFS) and overall survival (OS). Standard methods for quantitative IPD meta-analysis were used. Subgroup analyses by dose, duration of treatment and various patient and disease-specific parameters were performed., Findings: Fifteen trials were included in the analysis (eleven with IPD). EFS was significantly improved with IFN-α (hazard ratio [HR] = 0.86, CI 0.81-0.91; P < 0.00001), as was OS (HR = 0.90, CI 0.85-0.97; P = 0.003). The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. There was no evidence that the benefit of IFN-α differed depending on dose or duration of treatment, or by age, gender, site of primary tumour, disease stage, Breslow thickness, or presence of clinical nodes. Only for ulceration was there evidence of an interaction (test for heterogeneity: P = 0.04 for EFS; P = 0.002 for OS); only patients with ulcerated tumours appeared to obtain benefit from IFN-α., Conclusion: This meta-analysis provides clear evidence that adjuvant IFN-α significantly reduces the risk of relapse and improves survival and shows no benefit for higher doses compared to lower doses. The increased benefit in patients with ulcerated tumours, and lack of benefit in patients without ulceration, needs further investigation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: US-FNAC is a common diagnostic tool in the work-up of many cancers. Results in melanoma were initially poor (sensitivity 20-40%). Introduction of the Berlin Morphology criteria has shown potential improvement up to 65-80% in selected patients., Aim: This cohort study evaluates the long-term survival outcome of melanoma patients undergoing Ultrasound (US) guided Fine Needle Aspiration Cytology (FNAC) prior to sentinel node biopsy (SNB) or direct lymphadenectomy., Methods: Between 2001 and 2010 over 1000 consecutive melanoma patients prospectively underwent targeted US-FNAC prior to SNB. The Berlin US morphology criteria: peripheral perfusion (PP), loss of central echoes (LCE) and balloon shape (BS) were registered. FNAC was performed if any factor was present. All patients underwent SNB or lymphadenectomy in case of positive FNAC., Results: Median follow-up was 61 months (IQR 40-95). SN positivity rate was 21%. Survival analyses demonstrated that patients with positive US-FNAC had poor survival. After adjustment for SN status and other known prognostic features, patients with positive US-FNAC (hazard ratio (HR) 1.80, 95% CI 1.10-2.96) had worse survival than patients with normal US (reference). Patients with suspicious US and negative FNAC (HR 1.13, 95% CI 0.71-1.78) had survival comparable to patients with normal US., Conclusions: The long-term US-FNAC results support this step-wise approach to melanoma patients. Patients with positive US-FNAC have a poor survival and can be spared a SNB. Patients with suspicious US and negative FNAC should undergo SNB to detect microscopic occult disease. Completely US-FNAC negative patients might only require follow-up and no SN staging at all., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)