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Optimal systemic therapy for high-risk resectable melanoma

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.

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Acknowledgements

The work of G.V.L. is supported by an Australian National Health and Medical Research Council Investigator Grant and the University of Sydney Medical Foundation. J.J.L. acknowledges grant support from the US Department of Defense (W81XWH-17-1-0265), the NIH (UM1CA186690-06, P50CA254865-01A1 and P30CA047904-32), State of Pennsylvania Tobacco Phase 20 Formula Funds, as well as the UPMC Hillman Cancer Center via the Sy Holzer Endowed Immunotherapy Research Fund Award and as a Hillman Senior Faculty Fellow for Innovative Cancer Research.

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Authors

Contributions

A.M.M.E. is a Full Professor of Clinical & Translational Immunotherapy at the University of Utrecht, Chief Scientific Officer of the Princess Máxima Center for Paediatric Oncology, both in Utrecht, Netherlands, and is Chair of the Board of the Comprehensive Cancer Center Munich, Germany. He is a leading investigator in immunotherapy trials in oncology, in particular in the field of melanoma.

O.H. is the Chief of Translational Research and Immuno-Oncology at The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate, in Los Angeles, CA, USA, where he serves as Co-Director of the Melanoma and Director of the Phase I Programs. His areas of expertise include immunotherapy and phase I drug development. He is recognized as one of the pre-eminent immuno-oncologists and melanoma specialists in the world and has published extensively on and been at the forefront of paradigm-shifting breakthrough treatments, including BRAF/MEK-targeted agents, anti-CTLA4, anti-PD-1 and anti-PD-L1 therapies. His current research interests include next-generation immunotherapeutic agents, including novel immune-checkpoint inhibitors, bispecific antibodies, adoptive T cell therapies and oncolytic therapies, with a focus on combinatorial approaches.

G.V.L. is Professor of Melanoma Medical Oncology and Translational Research at the Melanoma Institute Australia, The University of Sydney, Sydney, Australia. She leads an extensive clinical trials team and translational laboratory, with a focus on targeted therapies and immuno-oncology in melanoma. She is a Clarivate highly cited Researcher for 2017–2021 and is ranked the world’s second, and Australia’s first, melanoma expert in all fields and disciplines (http://expertscape.com/ex/melanoma), with over 400 peer-reviewed publications in clinical and translational research in melanoma. In recognition of her ground-breaking research and work, she has received multiple awards, and she holds many leadership and advisory positions in the field of melanoma.

J.J.L. is Associate Professor of Medicine at the University of Pittsburgh and Director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center in Pittsburgh, PA, USA. His laboratory studies correlates of immunotherapy outcomes, and he is a leading investigator in the fields of melanoma and novel drug development in oncology.

Corresponding authors

Correspondence to Alexander M. M. Eggermont, Omid Hamid, Georgia V. Long or Jason J. Luke.

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Competing interests

A.M.M.E. has served on data safety monitoring boards for Biocad, BioNTech, GlaxoSmithKline (GSK), Novartis and Pfizer; and has served on scientific advisory boards for Agenus, Biocad, BioInvent, CatalYm, Clover, Ellipses, Galecto, GSK, IO Biotech, Merck, Nektar, Sairopa, Sellas, SkylineDx, TigaTx and TTxDiscovery. O.H. has received speaker’s bureau from Bristol Myers Squibb (BMS), Novartis, Pfizer and Sanofi/Regeneron; is a consultant for Aduro, Akeso, Alkermes, Amgen, Beigene, Bioatla, BMS, GSK, lmmunocore, ldera, lncyte, lnstilBio, lovance, Janssen, Merck, NextCure, Novartis, Pfizer, Roche/Genentech, Sanofi/Regeneron, Seattle Genetics, Tempus and Zelluna; and is at a contracted research institution for Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, GSK, lmmunocore, ldera, lncyte, lovance, Merck, Moderna, Merck-Serono, NextCure, Novartis, Pfizer, Roche/Genentech, Rubius, Sanofi/Regeneron, Seattle Genetics, Taiga, Torque and Zelluna. G.V.L. is a consultant/adviser for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, BMS, Evaxion Biotech, Hexal AG (Sandoz Company), Highlight Therapeutics, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, Provectus, Qbiotics and Regeneron. J.J.L. has served on data safety monitoring boards for Abbvie, Immutep and Evaxion. He has served on scientific advisory boards without equity consideration for 7 Hills, Bright Peak, Exo, Fstar, Inzen, RefleXion and Xilio, and with equity consideration for Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Stipe and Tempest. He has held consultancy roles with compensation for Abbvie, Alnylam, Bayer, BMS, Castle, Checkmate, Codiak, Crown, Day One, Duke St, EMD Serono, Endeavor, Flame, Genentech, Gilead, HotSpot, Ikena, Immunocore, Incyte, Janssen, Kadmon, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Regeneron, Servier, STINGthera, Synlogic and Synthekine. He has received research support (all to his institution for clinical trials unless noted) from AbbVie, Astellas, AstraZeneca, BMS (for both investigator-initiated and industry trials), Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, NextCure, Numab, Palleon, Pfizer (investigator-initiated and industry trials), Replimmune, Rubius, Servier (investigator-initiated trials), Scholar Rock, Synlogic, Takeda, Tizona, Trishula and Xencor. He holds intellectual property on the following patents: Serial #15/612,657 (Cancer Immunotherapy); PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof).

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Eggermont, A.M.M., Hamid, O., Long, G.V. et al. Optimal systemic therapy for high-risk resectable melanoma. Nat Rev Clin Oncol 19, 431–439 (2022). https://doi.org/10.1038/s41571-022-00630-4

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