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Alexander M Menzies,1 Georgina V Long,1,2 Rajmohan Murali3,41Melanoma Institute Australia, Sydney, New South Wales, Australia; 2Westmead Institute for Cancer Research and Crown Princess Mary Cancer Centre Westmead, Sydney, New South Wales, Australia; 3Department of Pathology; 4Human Oncology and Pathogensis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: The purpose of this study is to review the development of BRAF inhibitors, with emphasis on the trials conducted with dabrafenib (GSK2118436) and the evolving role of dabrafenib in treatment for melanoma patients. Fifty percent of cutaneous melanomas have mutations in BRAF, resulting in elevated activity of the mitogen-activated protein kinase signaling pathway. Dabrafenib inhibits the mutant BRAF (BRAFmut) protein in melanomas with BRAFV600E and BRAFV600K genotypes. BRAFV600E metastatic melanoma patients who receive dabrafenib treatment exhibit high clinical response rates and compared with dacarbazine chemotherapy, progression-free survival. Efficacy has also been demonstrated in BRAFV600K patients and in those with brain metastases. Dabrafenib has a generally mild and manageable toxicity profile. Cutaneous squamous cell carcinomas and pyrexia are the most significant adverse effects. Dabrafenib appears similar to vemurafenib with regard to efficacy but it is associated with less toxicity. It is expected that new combinations of targeted drugs, such as the combination of dabrafenib and trametinib (GSK1120212, a MEK inhibitor), will provide higher response rates and more durable clinical benefit than dabrafenib monotherapy.Keywords: BRAF mutation, BRAF inhibitor, clinical trial, GSK1120212, GSK2118436, vemurafenib

BackgroundPrevious analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients.Patients and methodsThis double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.ResultsBetween 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and

Background/Objectives: In melanoma management, sentinel lymph node biopsy (SLNB) is used to stage patients and to indicate prognosis. More recently, it has been used to select patients for adjuvant therapy. This study aimed to report knowledge of and attitudes towards SLNB for patients with melanoma among Australian dermatologists. Methods: Mixed methods study using cross‐sectional questionnaires (n = 88) and semi‐structured interviews (n = 13), May–September 2019. Results: Of the dermatologists surveyed, 56% thought SLNB had an important role in melanoma management, 26% were unsure and 18% thought SLNB unimportant. Of the 92% who would discuss SLNB with their patients, the main stated value of SLNB was for assessing eligibility for adjuvant therapies (79%); only 60% indicated SLNB was of value for providing prognostic information, and just over half (53%) thought it could improve staging. Interview data indicated that attitudes towards SLNB are shifting among dermatologists, driven by data from landmark clinical trials and the influence of professional networks. Accordingly, interviewees adopted one of three positions in relation to SLNB: (a) believed in utility of SLNB and adhered to the guidelines; (b) were unconvinced about utility of SLNB but adhered to the guidelines; and (c) were unconvinced about utility of SLNB and did not adhere to the guidelines. Conclusion: Although most of the dermatologists surveyed were familiar with and follow the SLNB recommendations, some disagreement with and distrust of the recommendations was evident. Greater acceptance of the SLNB recommendations appeared to be driven by the improved outcomes demonstrated in stage III patients receiving adjuvant systemic therapy. [ABSTRACT FROM AUTHOR]

Keywords: Melanoma; Surgical oncology EN Melanoma Surgical oncology 208 209 2 08/17/22 20220815 NES 220815 Sentinel lymph node biopsy (SLNB) is a staging procedure for assessing metastatic spread from a primary melanoma to the draining lymph nodes. During 2018 and 2019, 892 of 1855 people diagnosed with invasive melanomas of greater than 1.0 mm thickness (48%) and 151 of 597 with melanomas of 0.8-1.0 mm thickness (25%) underwent SLNB. [Extracted from the article]

In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) than placebo in patients with resected high risk stage III melanoma. Stability of these benefits when the median follow-up was 3.5 and 5 years was published. Here we report results with a longer follow-up., Methods: We randomized 1019 patients to receive pembrolizumab 200 mg or placebo, intravenously every 3 weeks for a total of 18 doses. RFS in the overall population and in the subgroup of patients with melanoma positive for the PD-1 ligand (PD-L1) were co-primary endpoints. DMFS in these two populations was a secondary and progression/recurrence-free survival 2 (PRFS2) an exploratory endpoint., Results: The median follow-up was 6.9 years. In the overall intention-to-treat population, RFS was longer in the pembrolizumab group than in the placebo group (HR 0.63, 95 % CI 0.53 to 0.74). RFS at 7 years was 50 % (95 % CI 46 % to 55 %) in the pembrolizumab and 36 % (95 % CI 32 % to 41 %) in the placebo group. Positive effects were present both for loco-regional recurrences and distant metastases, and across substages IIIA-IIIB-IIIC, and PD-L1 positive and PD-L1 negative as well as for BRAF mutant and BRAF wild type populations. DMFS was longer in the pembrolizumab group than in the placebo group (HR 0.64, 95 % CI 0.54 to 0.76). DMFS at 7 years was 54 % (95 % CI 50 % to 59 %) in the pembrolizumab and 42 % (95 % CI 37 % to 46 %) in the placebo group. PRFS2 was longer in the pembrolizumab group than in the placebo group (HR 0.69, 95 % CI 0.57 to 0.84). PRFS2 at 7 years was 61 % (95 % CI 57 % to 66 %) in the pembrolizumab and 53 % (95 % CI 49 % to 57 %) in the placebo group., Conclusions: The 7-year analysis of adjuvant therapy with pembrolizumab demonstrated a sustained improvement in the long-term RFS, DMFS and PRFS2 compared with placebo in patients with resected stage III melanoma., Competing Interests: Declaration of Competing Interest Alexander MM Eggermont is an Editor-in-Chief for European Journal of Cancer and was not involved in the editorial review or the decision to publish this article. Susana Puig is an Editor for European Journal of Cancer Skin Cancer and was not involved in the editorial review or the decision to publish this article. Dirk Schadendorf is an Editor-in-Chief European Journal of Cancer Skin Cancer and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexander C.J. van Akkooi: advisory board/consultancy honoraria from 4SC AG, Amgen, Bristol-Myers Squibb, Merck Serono-Pfizer, MSD-Merck, Neracare, Novartis, Pierre Fabre, Sanofi, Sirius Medical, SkylineDX; research grants from Amgen, Merck Serono-Pfizer, SkylineDX. Paolo A. Ascierto: a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Boehringer-Ingelheim, Regeneron, Pfizer, Nouscom, Lunaphore, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, Erasca, Philogen, Biontech, Anaveon; research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi; travel support by Pfizer, Bio-Al Health, Replimmune, MSD, Pierre Fabre, Philogen. Victoria Atkinson: advisory board for and speeches fees from BMS, MSD, Novartis, Immunocore; travel support by Pierre Fabre. Christian U Blank: advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, Sandoz; research funding from BMS, Novartis, NanoString, 4SC; stock ownership of Flindr Therapeutics, Signature Oncology. Matteo Carlino: advisory boards or a consultant for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi; honoraria from BMS, MSD, and Novartis. Stéphane Dalle: research grants to institution from MSD, BMS, Pierre Fabre; advisory board paid to institution by MSD and BMS; spouse employment Sanofi. Alexander MM Eggermont: honoraria for scientific advisory board or data monitoring committee activities from Agenus, Bioinvent, BioNTech, Boehringer Ingelheim, Brenus, CatalYm, Eurobio, GenOway, Imcheck, IO Biotech, Ipsen, IQVIA, ISA Pharmaceuticals, Merck KGA, Merck&Co/MSD, Pfizer, Pierre Fabre, QBiotics, Regeneron, Replimune, Sairopa BV, ScanCell, Scorpion Pharmaceuticals, Secarna, Sellas, SkylineDX BV, TigaTX, Thermosome, Trained Immunotherapeutics Discovery. Stock: IO Biotech, Sairopa BV, SkylineDX. Anna Maria Di Giacomo: advisor/board member for Merck, Roche, Bristol Myers Squibb, Incyte, Pierre Fabre, Sanofi, GlaxoSmithKline, SunPharma, Immunocore; honoraria from Merck, Bristol Myers Squibb, Sanofi, Pierre Fabre, GlaxoSmithKline, SunPharma. Immunocore. Dmitri Grebennik: employee of Merck & Co. Jean-Jacques Grob: advisory boards for Novartis, BMS, MSD, Philogen, Pierre Fabr, Sanofi, Roche, Amgen. Ralf Gutzmer: honoraria for lectures and advice from BristolMyers Squibb, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron; support for participation in meetings from SUN Pharma, Boehringer Ingelheim and PierreFabre; research support (to institution) from Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Almirall Hermal, Recordati. Andrew Haydon: advisory board member for BMS, MSD and Novartis. Rahima Jamal: honoraria for presentation and advisory board with Merck. PI in Merck-sponsored trials. Adnan Khattak: speaker honoraria, advisory board, and travel sponsorship from MSD. Michal Kicinski: research funding from MSD, BMS, Pierre Fabre, Immunocore, and JnJ. Clemens Kreplere: employee and shareholder of Merck & Co. James Larkin: relationships with the following companies: iOnctura, Apple Tree, Merck, BMS, MSD, Telix, Novartis, Philogen, Pfizer, Incyte, Eisai, Debipharm, GCO, TouchIME, Immatics, Insighter, Agence Unik, VJOncology, Royal College of General Practioners, Cambridge Healthcare Research, Royal College of Physicians, TouchExperts. Georgina V Long: consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, GI Innovation, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR Ltd, Pierre Fabre, Regeneron, Scancell, SkylineDX B.V. Paul Lorigan: support for travel from MSD; research funding from Pierre Fabre and BMS; speakers bureau/consultancy for BMS and Pierre Fabre. Mario Mandala: advisory board and lectures for: MSD, BMS, Novartis, Pierre Fabre, Sanofi, Sun Pharma; research grant from Novartis. Susana Puig: speaker for Almirall, BMS, Cantabria, ISDIN, La Roche Posay, Leo Pharma, MSD, Novartis, Pfizer, Roche, Regeneron, Sanofi, Sunpharma; advisory board of Almirall, BMS, ISDIN, La Roche Posay, Regeneron, Roche, Sanofi, Sun Pharma; involvement in research and trials of Abbvie, Almirall, Amgen, BMS, Biofrontera, Canfield, Cantabria, Fotofinder, GSK, ISDIN, La Roche Posay, Leo Pharma, MSD, MEDA, Novartis, Polychem, Roche, Sun Pharma; husband has relationship with Almirall, Amgen, BMS, Biofrontera, Canfield, Cantabria, Fotofinder, GSK, ISDIN, La Roche Posay, Leo, Mavig, Nevisence, Novartis, Polychem, Roche, Sun Pharma. Educational activities for Abbie, Lilly, and ISD; ownership of Athena Tech & Dermavision Solutions. Caroline Robert: consultant/advisory board of Pierre Fabre, Sanofi, BMS, MSD, Novaris, Merck, Roche, Pfizer, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma; consultant steering committee for Novartis, Regeneron, Pfizer, IO Biotech; consultant IDMC for Ultimovacs; speaker for Pierre Fabre, Sanofi, BMS, MSD, Novaris; travel by Pierre Fabre. Piotr Rutkowski: honoraria for lectures and advisory boards from MSD, BMS, Novartis, Pierre Fabre, Genesis Pharma, Medison Pharma. Shahneen Sandhu: research funding from Novartis/AAA, AstraZeneca, Merck Sharp and Dohme, Amgen, Genentech, Senwha, Bristol-Myers Squibb, Merck Healthcare and Pfizer; participation on advisory boards for Merck Sharp and Dohme, AstraZeneca, Novartis, SkylineDx and Abbvie (fees for attending go to research funds at the institution); honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Janssen (all paid to the institution); chair of DSMB for 2 Novartis/AAA sponsored Phase III trials (no fee accepted for chair role). Dirk Schadendorf: a member of the advisory board, consultant or received speakers´ honoraria from: Astra Zeneca, BMS, CureVac, Daiichi Sankyo, Erasca, Haystack, Immatics, Immunocore, InFlarX, Lapcorp, Merck-Serono, MSD, Neracare, Novartis, Novogenix, PamGene, Philogen, Pierre Fabre, Pfizer, Regeneron, Replimune, Sanofi, Seagen, Sun Pharma, UltraVacs; research funding from BMS, Roche, MSD, Amgen & Novartis. Stefan Suciu: DSMB member of the NADINA study. Alfonsus JM van den Eertwegh: study grant from Bristol-Myers Squibb, Idera; travel expenses by Ipsen; advisory board of Bristol-Myers Squibb, MSD Oncology, Ipsen, Pierre Fabre, Janssen Cilag BV. The remaining authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Data on the efficacy and safety of anti PD-1 antibodies in children and adolescents (CA) with melanoma are lacking. The aim of this study was to determine outcomes of CA melanoma patients receiving anti PD-1 antibodies., Methods: Melanoma patients ≤18 years treated with anti PD-1 were retrospectively retrieved from 15 academic centers. Information on histopathological diagnosis, surgical treatment, systemic therapy, objective response rate (ORR), safety profile was collected. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier method., Results: Between April 2016 and March 2024, 99 patients treated with systemic therapy were retrieved, 81 treated with anti PD-1 therapy. Median age was 14 years (range 2-18 years), 37 pts were ≤12 yrs. Overall, 38 CA patients received anti PD-1 in adjuvant setting, and the 3-year PFS and OS were 70.6 % and 81.1 %, respectively. Two patients received anti-PD-1 based neoadjuvant treatment, both had a pathologic complete response and remain disease free. Fifty-six received a systemic therapy for advanced disease and among them, 43 received anti PD-1-based therapy for advanced disease in 1st line, while 12 and 5 pts received a 2nd and 3rd line, respectively. Among patients receiving a 1st line therapy with anti PD-1 monotherapy the ORR was 25 %, and the 3-year OS was 34 %. Toxicities were consistent with previous studies in adult melanoma patients., Conclusions: Our study provides the first evidence of efficacy of anti PD-1 in CA melanoma patients and supports the use of anti PD-1 therapy in pts ≤18 years, included those <12 years., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: In phase III CheckMate 238, adjuvant nivolumab significantly improved recurrence-free survival compared with ipilimumab in patients with resected stage IIIB-C/IV melanoma without a significant difference in overall survival (OS). Here, we investigate progression-free survival (PFS) and OS after postrecurrence systemic therapy., Patients and Methods: Patients 15 years or older with resected stage IIIB-C/IV melanoma were stratified by stage and tumor PD-L1 status and randomly assigned to receive nivolumab 3 mg/kg every 2 weeks, or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks for 1 year or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Patients with recurrence in each group were assessed for PFS and OS from subsequent systemic therapy (SST) initiation per recurrence timing (≤12 months [early] v >12 months [late] from initial therapy)., Results: Recurrences occurred in 198 (44%) of 453 nivolumab-treated patients (122 early, 76 late) and 232 (51%) of 453 ipilimumab-treated patients (160 early, 72 late). Median PFS on next-line systemic therapy for nivolumab-treated patients recurring early versus late was 4.7 versus 12.4 months (24-month rates, 16% v 31%); median OS was 19.8 versus 42.8 months (24-month rates: 37% v 73%). In response to subsequent therapy, patients on nivolumab with late versus early recurrence were more likely to benefit from anti-PD-1 monotherapy. Nivolumab-treated patients with either an early or late recurrence benefitted from an ipilimumab-based therapy or targeted therapy, each with similar OS., Conclusion: Postrecurrence survival was longer for patients who recurred >12 months. Patients on nivolumab who recurred early benefitted from SST but had better survival with ipilimumab-based regimens or targeted therapy compared with anti-PD-1 monotherapy.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, providing significant benefit to patients across various tumour types, including melanoma. However, around 40% of melanoma patients do not benefit from ICI treatment, and accurately predicting ICI response remains challenging. We now describe a novel and simple approach that integrates immune-associated transcriptome signatures and tumour volume burden to better predict ICI response in melanoma patients. RNA sequencing was performed on pre-treatment (PRE) tumour specimens derived from 32 patients with advanced melanoma treated with combination PD1 and CTLA4 inhibitors. Of these 32 patients, 11 also had early during treatment (EDT, 5-15 days after treatment start) tumour samples. Tumour volume was assessed at PRE for all 32 patients, and at first computed tomography (CT) imaging for the 11 patients with EDT samples. Analysis of the Hallmark IFNγ gene set revealed no association with ICI response at PRE (AUC ROC curve = 0.6404, p = 0.24, 63% sensitivity, 71% specificity). When IFNg activity was evaluated with tumour volume (ratio of gene set expression to tumour volume) using logistic regression to predict ICI response, we observed high discriminative power in separating ICI responders from non-responders (AUC = 0.7760, p = 0.02, 88% sensitivity, 67% specificity); this approach was reproduced with other immune-associated transcriptomic gene sets. These findings were further replicated in an independent cohort of 23 melanoma patients treated with PD1 inhibitor. Hence, integrating tumour volume with immune-associated transcriptomic signatures improves the prediction of ICI response, and suggest that higher levels of immune activation relative to tumour burden are required for durable ICI response., (© 2024. The Author(s).)

Immunotherapies targeting the programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) checkpoint receptors have revolutionised the treatment of metastatic melanoma. However, half of treated patients do not respond to or eventually progress on standard therapies and many experience adverse events as a result of drug toxicity. The identification of accurate biomarkers of clinical outcomes are required in order to move away from the one-size-fits-all treatment approach of standard clinical practice, and towards a more personalised approach to enable the administration of the optimal therapy for any given patient and further improve patient outcomes. Recent clinical trials have proven the potential of multi-omics analyses, including genomic, gene expression, and tumour immune profiling, of patients' tumour biopsies, to predict a patient's response to subsequently administered immunotherapies. However, reproducibility of such multi-omics analyses, tissue requirements, and clinical validation have limited the practical application of these approaches in routine clinical workflows. In this review, we discuss several pivotal tissue-based profiling techniques that can be utilised to identify potential genomic, transcriptomic and immune biomarkers predictive of clinical outcomes following treatment with immune checkpoint inhibitors in melanoma. Furthermore, we highlight the key opportunities and challenges associated with the use of each of these techniques. The development and implementation of multimodal predictive models which combine data derived from these various methods is the future for achieving precision medicine for patients with melanoma.

Background: Tumoral melanosis (TM) is a histological term to describe a nodular aggregation of macrophages containing melanin pigment (melanophages) that is devoid of viable melanocytes. It is most often identified in skin, where it may be appreciated clinically as a pigmented lesion; however, it can also be found in other organs such as lymph nodes. The presence of TM is usually thought to signify the presence of a regressed melanoma or other pigmented tumor. Until recently, it was a relatively uncommon finding; however, with the use of effective systemic therapies against melanoma, its occurrence in histological specimens is more frequent., Methods: We identified and reviewed all histopathological diagnoses of TM at any organ site reported at a single institution from 2006 to 2018. TM cases were paired with non-TM cases of cutaneous melanoma through propensity score matching at a 1:2 ratio, and their survival outcomes were compared. The clinical outcomes examined included recurrence-free survival (RFS), distant disease-free survival (DDFS), melanoma-specific survival (MSS), and overall survival (OS)., Results: TM was reported in 79 patients. Their median age was 65 years (range 22-88), with a 2:1 male predominance (51 out of 79, 65%). The most common organ involved was the skin (67%), with a third of all cases localized to a lower limb (36%). TM had a strong association with the presence of melanoma (91%) and regression at other sites of melanoma (54%), suggesting that it is part of a systemic immune response against melanoma. Most patients with TM either previously or subsequently developed histologically confirmed melanoma in the same anatomical region as the TM (89%). Thirty-five TM patients were matched with 70 non-TM cases. Patients with melanoma who developed TM without prior regional or systemic therapy showed improved MSS (p = 0.03), whereas no statistically significant differences were observed in terms of RFS, DDFS, and OS., Conclusions: TM usually occurs in the context of a previous or subsequent cutaneous melanoma and is associated with improved MSS. It is important that TM is recognized by pathologists and documented in pathology reports., (© 2024 The Author(s). Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Introduction: Approximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking., Methods: This was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected., Results: 711 patients from 17 sites were included. Median age was 60 [range 16-92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0-68.5) and median follow up time from recurrence was 19.8 months (range 0.2-73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with "second adjuvant" anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %., Conclusion: Most recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, and Qbiotics. JK has received research funding from LEO Pharma, honorium from BMS, Amgen, Janssen; and educational funding from MSD, Janssen and Astra Zeneca. RRT has served on advisory boards for BMS, MSD, Amgen, Pierre-Fabre, Astra Zeneca and Roche. CL has received research funding from BMS, Roche, consulting fees from BMS, Pierre-Fabre, Sanofi, Novartis, MSD, Amgen, Merck Serono, Roche and Iflax; speaking fees from Amgen, BMS, Pierre-Fabre, Sanofi, Novartis, MSD, Incyte, Pfizer, Roche; and travel funding from BMS, MSD, Novartis, Pierre-Fabre, Roche, Sanofi and served on advisory boards for BMS, Pierre Fabre, Sanofi, Novartis, MSD, Magen, Merck Serono, Roche and Inflax. CA has received travel funding from BMS, Roche and Amgen and speaking fees from Novartis. RJS has served on advisory boards for Merck, Novartis, Pfizer, and Replimune and receives grant funding from Merck. CR has served on advisory boards for Pierre Fabre, Sanofi, BMS, MSD, Novartis, Merck, Roche, Pfizer, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma; involved in steering committees for Novartis, Regeneron, Pfizer and IO Biotech and a consultant IDMC for Ultimovacs; received speaking fees from Pierre Fabre, Sanofi, BMS, MSD and Novartis and travel funding from Pierre Fabre. JM has intermittent project focused consultant or advisory relationships with Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Johnson & Johnson, and Pierre Fabre and has received travel support from L′ Oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. MSC has served on advisory boards or as a consultant for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi and received honoraria from BMS, MSD, and Novartis. DBJ has served on advisory boards or as a consultant for AstraZeneca, BMS, The Jackson Laboratory, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte. BN has received financial compensation from Novartis, Roche, BMS, MSD, and Pierre-Fabre for service on advisory boards and speaking engagements; and institutional research funding from Pfizer, Novartis, Roche and Merck-Serono. VR has received honoraria from AstraZeneca and has received travel and education funding from MSD and Novartis. PAA has served as a consultant for BMS, MSD, Roche-Genentech, Ventana, Novartis, Amgen and Array and received research funding from BMS, Roche-Genentech and Ventana. JW has served as a consultant for Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, EMD Serono, and Bristol Myers Squibb; has had equity roles in Biond, Evaxion, OncoC4, and Instill Bio; received institutional research support from Bristol Myers Squibb, Merck, GSK, Moderna, Pfizer, Novartis, and AstraZeneca; served in scientific advisory roles with CytomX, Incyte, ImCheck, Biond, Sellas, Instill Bio, OncoC4, and NexImmune; and holds patent agreements with Moffitt Cancer Center and Biodesix. PR has received honoraria from BMS, MSD, Novartis, Pierre-Fabre, Merck and Sanofi; and served in an advisory capacity for MSD, BMS, Sanofi, Pierre-Fabre, Blueprint Medicines and Philogen. GAM has received institutional research funding through Roche-Genentech, MSD, Roche, and BMS and other funding through Novartis and BMS. SH has served as a consultant for Amgen, Genmab, Xencor, Astellas Pharma, Regeneron, and Nektar. AA has served as a consultant for BMS, Roche, Novartis, Pierre Fabre, MSD, Merck, Sanofi; received speaking fees from Pierre Fabre, Novartis, MSD, BMS, Roche, Merck, Sanofi; institutional funding from Pierre-Fabre, Novartis, Roche, BMS, MSD, Merck and Sanofi; and travel funding from BMS, MSD, Novartis, Pierre-Fabre. AH has served on an advisory board for BMS, MSD and Novartis. RD has received honoraria from Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator Bioscience, MaxiVax, touchIME, T3 Pharmaceuticals, Pfizer; served as a consultant for Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Alligator Bioscience, touchIME, MaxiVax, Regeneron, Pfizer, T3 Pharmaceuticals and received institutional research funding from Roche, BMS, Novartis, MSD and Amgen. CUB has served as a consultant for AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Third Rock Ventures; received institutional research funding from SC, Bristol-Myers Squibb, NanoString Technologies, and Novartis; provided expert testimony for Freshfields Bruckhaus Deringer; received travel funding from BMS; and has ownership interest in Immagene and Signature Oncology. GVL has received honoraria from BMS, Pierre-Fabre and received served as a consultant for Agenus, Amgen, Array BioPharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion Biotech, Hexal AG (Sandoz Company), Highlight Therapeutics, Innovent Biologics USA Inc, Merck Sharp & Dohme, Novartis, OncoSec Medical Australia, PHMR Limited, Pierre Fabre, Provectus, QBiotics, Regeneron, and AstraZeneca. The remaining authors have nothing to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Pembrolizumab significantly improved overall survival (OS) versus ipilimumab for unresectable advanced melanoma in KEYNOTE-006 (NCT01866319); 10-year follow-up data are presented., Patients and Methods: Patients with unresectable stage III or IV melanoma were randomly assigned (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 weeks or every 3 weeks for ≤2 years (pooled), or ipilimumab 3 mg/kg i.v. every 3 weeks for four cycles. After KEYNOTE-006, patients could transition to KEYNOTE-587 (NCT03486873) for long-term follow-up. Eligible patients could receive second-course pembrolizumab. The primary endpoint was OS; modified progression-free survival (PFS; censored at date last known alive), modified PFS on second-course pembrolizumab, and melanoma-specific survival were exploratory., Results: Of 834 patients randomly assigned in KEYNOTE-006 (pembrolizumab, n = 556; ipilimumab, n = 278), 333 (39.9%) were eligible for KEYNOTE-587; 211/333 patients (25.3%) transitioned to KEYNOTE-587 (pembrolizumab, n = 159; ipilimumab, n = 52) and 122 (14.6%) did not. For patients who transitioned to KEYNOTE-587 (n = 211), median time from randomization in KEYNOTE-006 to data cut-off for KEYNOTE-587 (1 May 2024) was 123.7 months (range, 122.0-127.3 months). Median OS was 32.7 months [95% confidence interval (CI) 24.5-41.6 months] for pembrolizumab and 15.9 months (95% CI 13.3-22.0 months) for ipilimumab [hazard ratio (HR), 0.71 (95% CI 0.60-0.85)]; 10-year OS was 34.0% and 23.6%, respectively. Among patients who completed ≥94 weeks of pembrolizumab, median OS from week 94 was not reached (NR; 95% CI NR-NR); 8-year OS rate was 80.8%. Median modified PFS was 9.4 months (95% CI 6.7-11.6 months) for pembrolizumab and 3.8 months (2.9-4.3 months) for ipilimumab [HR, 0.64 (95% CI 0.54-0.75)]. Among patients who received second-course pembrolizumab, median modified PFS from start of second course was 51.8 months (95% CI 11.0 months-NR); 6-year modified PFS was 49.2%. Median melanoma-specific survival was 51.9 months (95% CI 30.0-114.7 months) for pembrolizumab and 17.2 months (13.9-25.9 months) for ipilimumab [HR, 0.66 (95% CI 0.55-0.81)]., Conclusions: These results confirm that pembrolizumab provides long-term survival benefits in advanced melanoma, supporting it as a standard of care in this setting., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions., Methods: We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to BRAF mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response., Results: With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab., Conclusions: The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Melanoma is increasingly recognized as a heterogeneous disease, with conflicting evidence regarding whether cutaneous head and neck melanoma (CHNM) represents a distinct entity., Objective: Comparison of clinicopathological features and treatment outcomes of CHNM and cutaneous melanomas of other sites (CMOS)., Methods: Patients with CHNM and CMOS diagnosed between 2000 and 2018 were included. Locoregional control, distant metastasis-free survival, melanoma-specific survival (MSS), and overall survival (OS) were described using the Kaplan-Meier method. Cox regression analyses were performed to examine associations between prognostic factors and outcomes. Additional analyses of survival from time of stage IV disease diagnosis were undertaken, stratified by receipt of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy., Results: Of 3007 CHNM and 10,637 CMOS patients, CHNM had more adverse pathological features (median age 65.9 vs 58.5, P < .001; median Breslow thickness 1.7 mm vs 1.2 mm, P < .001; and ulceration 21.2% vs 18.2%, P < .001). CHNM had worse locoregional control (hazard ratio (HR) 1.17, P < .001) and distant metastasis-free survival (HR 1.25, P < .001) but there were no significant differences in MSS or OS. Among stage IV patients who received immune checkpoint inhibitor, CHNM had better MSS (HR 0.56, P = .001) and OS (HR 0.57, P < .001) on multivariable analyses., Limitations: Retrospective study, offset by prospective data collection., Conclusion: CHNM is associated with a distinct clinicopathological and prognostic profile., Competing Interests: Conflicts of interest Dr Saw has received honoraria for advisory board participation from MSD, Novartis, and Qbiotics and speaking honoraria from BMS and Novartis. Dr Pires da Silva has received travel support from BMS and MSD and speaker fees from Roche, BMS, MSD, and Novartis. Dr Varey has received an honorarium from Novartis. Dr Akkooi has served on advisory boards and received consultancy honoraria from Amgen, Bristol Myers Squibb, Neracare, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, and 4SC. Dr Menzies has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, and QBiotics. Dr Carlino has served on advisory boards for Bristol-Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar, Eisai, Oncosec, and Qbiotics and honoraria from Bristol-Myers Squibb, MSD, and Novartis. Dr Long is 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, and Regeneron. Dr Scolyer has received fees for professional services from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, and GlaxoSmithKline. Dr Thompson has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK, and Provectus Biopharmaceuticals, and travel and conference support from GSK, Provectus Biopharmaceuticals, and Novartis. Drs Li, Xu, Blah, Lo, Shannon, and Ch'ng have no conflicts of interest to declare., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4 + T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4 + T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4 + T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events., (© 2024. The Author(s).)

Background: Melanoma is a heterogeneous cancer influenced by the plasticity of melanoma cells and their dynamic adaptations to microenvironmental cues. Melanoma cells transition between well-defined transcriptional cell states that impact treatment response and resistance., Methods: In this study, we applied single-cell RNA sequencing to interrogate the molecular features of immunotherapy-naive and immunotherapy-resistant melanoma tumours in response to ex vivo BRAF/MEK inhibitor treatment., Findings: We confirm the presence of four distinct melanoma cell states - melanocytic, transitory, neural-crest like and undifferentiated, and identify enrichment of neural crest-like and undifferentiated melanoma cells in immunotherapy-resistant tumours. Furthermore, we introduce an integrated computational approach to identify subsets of responding and nonresponding melanoma cells within the transcriptional cell states., Interpretation: Nonresponding melanoma cells are identified in all transcriptional cell states and are predisposed to BRAF/MEK inhibitor resistance due to pro-inflammatory IL6 and TNFɑ signalling. Our study provides a framework to study treatment response within distinct melanoma cell states and indicate that tumour-intrinsic pro-inflammatory signalling contributes to BRAF/MEK inhibitor resistance., Funding: This work was supported by Macquarie University, Melanoma Institute Australia, and the National Health and Medical Research Council of Australia (NHMRC; grant 2012860, 2028055)., Competing Interests: Declaration of interests JHL has received honorarium from Merck, Sharp & Dohme and AstraZeneca, received conference support from Pfizer and Merck, Sharp & Dohme, and consulting fees from Boxer Capitol. JHL is a consultant for Merck, Sharp & Dohme, Sanofi, Cancer Council and EviO. RAS has received fees for professional services from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline, IO Biotech ApS and SkylineDX B.V. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer Health Care, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IO Biotech, Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Qbiotics, Regeneron, Scancell Limited and SkylineDX B.V. GVL has received conference support from Bristol Myers Squibb and Pierre Fabre. All other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAF V600 -mutant melanoma. Sixty patients (42% females) were randomized to pembrolizumab alone (n = 20), sequential therapy (dabrafenib plus trametinib followed by pembrolizumab; n = 20) or concurrent (triple) therapy (n = 20), followed by surgery and adjuvant therapy. The primary outcome was pathological response; secondary outcomes included radiographic response, recurrence-free survival, overall survival, surgical outcomes, peripheral blood and tumor analyses and safety. The pathological response rate was 55% (11/20; including six pathological complete responses (pCRs)) with pembrolizumab, 50% (10/20; three pCRs) with sequential therapy and 80% (16/20; ten pCRs) with concurrent therapy, which met the primary outcome in each arm. Treatment-related adverse events affected 75-100% of patients during neoadjuvant treatment, with seven early discontinuations (all in the concurrent arm). At 2 years, event-free survival was 60% with pembrolizumab, 80% with sequential therapy and 71% with concurrent therapy. Recurrences after major pathological response were more common in the targeted therapy arms, suggesting a reduction in response 'quality' when targeted therapy is added to neoadjuvant immunotherapy. Risking the curative potential of immunotherapy in melanoma cannot be justified. Pending longer follow-up, we suggest that immunotherapy and targeted therapy should not be combined in the neoadjuvant setting for melanoma. ClinicalTrials.gov registration: NCT02858921 ., (© 2024. The Author(s).)

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.)

Background: Neoadjuvant therapy improves recurrence-free survival (RFS) in resectable stage III cutaneous melanoma. However, accurately predicting individual recurrence risk remains a significant challenge. We investigated circulating tumour DNA (ctDNA) as a biomarker for recurrence in measurable stage IIIB/C melanoma patients undergoing neoadjuvant immunotherapy., Methods: Plasma samples were collected pre-neoadjuvant treatment, pre-surgery and/or six weeks post-surgery from 40 patients enrolled in the OpACIN-neo and PRADO clinical trials. Patients received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before surgery. Cell free DNA (cfDNA) underwent unbiased pre-amplification followed by tumour-informed mutation detection using droplet digital polymerase chain reaction (ddPCR) with the Bio-Rad QX600 PCR system., Results: Pre-treatment ctDNA was detectable in 19/40 (48%) patients. Among these, 17/19 (89%) zero-converted within six weeks of surgery and none recurred. Positive ctDNA post-surgery (N = 4), irrespective of pre-treatment ctDNA status, was 100% predictive of recurrence (sensitivity 44%, specificity 100%). Furthermore, ctDNA cleared prior to surgery in 7/9 (78%) patients who did not recur, warranting further investigation into ctDNA-guided surgical management., Conclusion: Post-surgery ctDNA positivity and zero-conversion are highly predictive of recurrence, offering a window for personalised modification of adjuvant therapy., (© 2024. The Author(s).)