{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T15:27:00Z","timestamp":1790954820408,"version":"4.1.0"},"reference-count":48,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000},"content-version":"unspecified","delay-in-days":24,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Bristol Myers Squibb","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,12,2]]},"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Some patients with melanoma experience disease progression during immunotherapy (IO) and may benefit from novel combinations of immune checkpoint inhibitors (ICIs). We report results from exploratory biomarker analyses to characterize the responses of patients with advanced melanoma to treatment with nivolumab (anti-programmed cell death-1 (PD-1)) and relatlimab (anti-lymphocyte-activation gene 3 (LAG-3)) combination therapy in RELATIVITY-020 (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT01968109\">NCT01968109<\/jats:ext-link>).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Tumor biopsies collected at baseline and \u22644 weeks after treatment initiation were evaluated for % LAG-3-positive and % CD8-positive immune cells and % programmed death-ligand 1 (PD-L1) expression on tumor cells. Baseline biomarker expression was compared among patients with IO-refractory melanoma based on last prior therapy and IO-resistance type, and between patients with IO-refractory and IO-na\u00efve melanoma. Change in biomarker expression after treatment was evaluated in patients with IO-refractory and IO-na\u00efve melanoma. Immune-related gene expression was compared among resistance groups and by the last prior treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Among patients with IO-refractory melanoma (N=505), elevated baseline LAG-3, PD-L1, and CD8 expression (p\u22640.01, p\u22640.05, p\u22640.001, respectively) was observed in patients whose last prior therapy was IO versus non-IO, and in those who responded (complete\/partial per Response Evaluation Criteria in Solid Tumors V.1.1) to nivolumab and relatlimab combination therapy versus those who did not (stable\/progressive disease). Inflammation-related gene expression was significantly higher (p&lt;0.05) in patients with secondary versus primary resistance to prior IO treatment, and in those whose last prior therapy was IO versus non-IO. IO-refractory patients whose tumors responded to nivolumab and relatlimab combination therapy had higher inflammation-related gene expression than non-responders (p&lt;0.05); proliferation and hypoxia-related gene expression were enriched in non-responders. During treatment with nivolumab and relatlimab combination therapy, LAG-3 expression increased significantly in patients with IO-refractory (p\u22640.01) and IO-na\u00efve melanoma (p\u22640.001), and PD-L1 and CD8 increased significantly (p\u22640.01 and p\u22640.05, respectively) in patients with IO-na\u00efve melanoma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Nivolumab and relatlimab combination therapy can modulate the tumor microenvironment in patients with both IO-refractory and IO-na\u00efve melanoma. Further research is needed to identify patients who will most benefit from anti-LAG-3\/PD-(L)1 agents, and to elucidate the mechanisms of action of, and resistance to, this combination therapy in patients with advanced melanoma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT01968109\">NCT01968109<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-009773","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T01:30:15Z","timestamp":1740533415000},"page":"e009773","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Effect of prior and first-line immunotherapy on baseline immune biomarkers and modulation of the tumor microenvironment in response to nivolumab and relatlimab combination therapy in patients with melanoma from RELATIVITY-020"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct01968109","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01968109","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01968109","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01968109","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8322-475X","authenticated-orcid":false,"given":"Paolo A","family":"Ascierto","sequence":"first","affiliation":[{"name":"Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Tang","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Dolfi","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Nyakas","sequence":"additional","affiliation":[{"name":"Department of Oncology, Oslo University Hospital, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge","family":"Marie Svane","sequence":"additional","affiliation":[{"name":"Department of Oncology, Copenhagen University Hospital, Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Mu\u00f1oz-Couselo","sequence":"additional","affiliation":[{"name":"Oncology Department, Vall d\u2019Hebron Barcelona Hospital Campus, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Jacques","family":"Grob","sequence":"additional","affiliation":[{"name":"Dermatology Department, Aix-Marseille Universite, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Alberto","family":"Gomez-Roca","sequence":"additional","affiliation":[{"name":"Department of Medicine & Clinical Research Unit, Institut Universitaire du Cancer de Toulouse Oncopole CHU Toulouse, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanna","family":"Chiarion-Sileni","sequence":"additional","affiliation":[{"name":"Clinical Oncology, Veneto Institute of Oncology Institute for Hospitalization and Care Scientific, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katriina","family":"Peltola","sequence":"additional","affiliation":[{"name":"Helsinki University Central Hospital Department of Oncology, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Larkin","sequence":"additional","affiliation":[{"name":"The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1360-348X","authenticated-orcid":false,"given":"Ignacio","family":"Melero","sequence":"additional","affiliation":[{"name":"Departments of Immunotherapy and Oncology, Cl\u00ednica Universidad de Navarra, Pamplona, Navarre, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9087-0012","authenticated-orcid":false,"given":"Margaret","family":"Callahan","sequence":"additional","affiliation":[{"name":"Immunotherapeutics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2279-6906","authenticated-orcid":false,"given":"Reinhard","family":"Dummer","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Z\u00fcrich, Zuerich, 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