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Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, <jats:italic>n<\/jats:italic>\u2009=\u200916) or nivolumab\u2013relatlimab (Arm B, <jats:italic>n<\/jats:italic>\u2009=\u200916) in combination with chemoradiotherapy in 32 patients with resectable stage II\/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT03044613\">NCT03044613<\/jats:ext-link>.<\/jats:p>","DOI":"10.1038\/s41591-024-02877-z","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T11:02:05Z","timestamp":1710846125000},"page":"1023-1034","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":132,"title":["Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal\/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6446-2103","authenticated-orcid":false,"given":"Ronan J.","family":"Kelly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5235-7410","authenticated-orcid":false,"given":"Blair V.","family":"Landon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5463-2252","authenticated-orcid":false,"given":"Ali H.","family":"Zaidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipika","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna V.","family":"Canzoniero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana","family":"Balan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell K.","family":"Hales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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Cancer Inform."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-02877-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-02877-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-02877-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T12:04:22Z","timestamp":1713528262000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-02877-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,19]]},"references-count":43,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["2877"],"URL":"https:\/\/doi.org\/10.1038\/s41591-024-02877-z","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,19]]},"assertion":[{"value":"5 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"R.J.K. reports receiving advisory board\/consulting fees from Astellas, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, EMD Serono, Exact Sciences, Grail, Ipsen, Merck, Novartis, Novocure, Phillips, Takeda, Toray and grant support paid to Johns Hopkins University and Baylor University Medical Center from Bristol Myers Squibb and Eli Lilly. E.J.S. is a consultant for Boston Scientific. A.H.Z. has served in a consultant\/advisory role for Previse, has received research funding from Eli Lilly, Prognomiq, BilliontoOne, Genece Health and Tempus and has equity interest in Previse, Tg Therapeutics and Gritstone Bio. K.A.M. is a consultant for AstraZeneca, Amgen, Puma Biotechnology, Jannsen, Mirati Therapeutics, Daiichi Sankyo\/Lilly and Regeneron and receives research funding from Mirati, Bristol Myers Squibb and AstraZeneca. K.N.S. has received honoraria from Illumina and Adaptive Biotechnologies, research funding to Johns Hopkins University from Bristol Myers Squibb, AstraZeneca and Abbvie, is an inventor on a patent application related to the MANAFEST technology described herein (16\/341,862) that has been licensed to one or more entities and owns founder\u2019s equity in ManaT Bio. J.L.F. has served in a consultant\/advisory role for Genentech, Eli Lilly, AstraZeneca, Merck, Takeda, Coherus, Regeneron and Pfizer and has received research funding (directly to the institution) from AstraZeneca, Pfizer and Bristol Myers Squibb. V.L. has served in a consultant\/advisory role for Anheart Therapeutics, Takeda, Seattle Genetics, Bristol Myers Squibb, AstraZeneca and Guardant Health and has received research funding from GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Merck and Seattle Genetics. V.A. receives research funding to Johns Hopkins University from AstraZeneca and Personal Genome Diagnostics, has received research funding to Johns Hopkins University from Bristol Myers Squibb and Delfi Diagnostics in the past 5\u2009years, is an advisory board member for AstraZeneca and Neogenomics and receives honoraria from Foundation Medicine and Personal Genome Diagnostics. V.A. is an inventor on patent applications (63\/276,525, 17\/779,936, 16\/312,152, 16\/341,862, 17\/047,006 and 17\/598,690) submitted by Johns Hopkins University related to cancer genomic analyses, ctDNA therapeutic response monitoring and immunogenomic features of response to immunotherapy that has been licensed to one or more entities. Under the terms of these license agreements, the University and inventors are entitled to fees and royalty distributions. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}