{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:35:42Z","timestamp":1790354142513,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bristol Myers Squibb"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Immunotherapy (IO) has demonstrated survival benefits in metastatic gastroesophageal cancers, and current data supports perioperative IO in localized adenocarcinomas. Radiation may further enhance IO response through immunologic priming. This study evaluates the feasibility, safety, and preliminary efficacy of incorporating IO into a chemoradiation-based perioperative strategy for resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma. Methods: This single-arm, phase I\/II study enrolled adults with untreated, locally advanced, resectable gastric or GEJ adenocarcinoma between February 2019 and June 2023. The treatment protocol consisted of induction chemotherapy (oxaliplatin + 5-fluorouracil), induction IO (nivolumab + ipilimumab), concurrent immune-chemoradiation (nivolumab, 5-fluorouracil, and 45 Gy IMRT\/VMAT), surgical resection, and adjuvant nivolumab for residual disease. Primary endpoints were safety and feasibility; secondary endpoints included the pathologic complete response (pCR), R0 resection rate, disease-free survival (DFS), overall survival (OS), and biomarker analysis. Results: In total, 30 patients were enrolled, and 23 underwent resection. Grade 4 treatment-related toxicities occurred in three patients (10%), including acute kidney injury, myocarditis\/myositis\/myasthenia gravis overlap syndrome, and neutropenia. Among surgical patients, the pCR rate was 39.1% (95% CI: 19.7\u201361.5%), and the intention-to-treat pCR rate was 30% (95% CI: 14.7\u201349.4%). R0 resection was achieved in 87% of cases. Median DFS among resected patients was 40.2 months (95% CI: 21.6\u2013NE). Median OS was 43.7 months (95% CI: 30.7\u2013NE), with 2-, 3-, and 5-year OS rates of 73.3%, 57.5%, and 47.9%, respectively. Conclusions: This multimodality approach incorporating IO with chemotherapy and chemoradiation demonstrated a manageable safety profile and an encouraging pCR rate, supporting further evaluation.<\/jats:p>","DOI":"10.3390\/cancers18142198","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:40:09Z","timestamp":1783525209000},"page":"2198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Perioperative Nivolumab and Ipilimumab with Chemotherapy and Chemoradiation for Resectable Gastric and Gastroesophageal Junction Adenocarcinoma: A Phase 1\/2 Non-Randomized Clinical Trial"],"prefix":"10.3390","volume":"18","author":[{"given":"Mariela A.","family":"Blum Murphy","sequence":"first","affiliation":[{"name":"Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianchun","family":"Xiao","sequence":"additional","affiliation":[{"name":"Departments of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4804-1891","authenticated-orcid":false,"given":"Matheus","family":"Sewastjanow-Silva","sequence":"additional","affiliation":[{"name":"Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xumei","family":"Wang","sequence":"additional","affiliation":[{"name":"Departments of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9915-8355","authenticated-orcid":false,"given":"Brian D.","family":"Badgwell","sequence":"additional","affiliation":[{"name":"Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6166-8061","authenticated-orcid":false,"given":"Paul F.","family":"Mansfield","sequence":"additional","affiliation":[{"name":"Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naruhiko","family":"Ikoma","sequence":"additional","affiliation":[{"name":"Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9755-9374","authenticated-orcid":false,"given":"Cindy M.","family":"Pabon","sequence":"additional","affiliation":[{"name":"Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey H.","family":"Lee","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1489-5947","authenticated-orcid":false,"given":"Manoop S.","family":"Bhutani","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Weston","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Coronel","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3171-2911","authenticated-orcid":false,"given":"Grace L.","family":"Smith","sequence":"additional","affiliation":[{"name":"Departments of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma B.","family":"Holliday","sequence":"additional","affiliation":[{"name":"Departments of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie","family":"Tian","sequence":"additional","affiliation":[{"name":"Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2871-676X","authenticated-orcid":false,"given":"Anas M.","family":"Barabrah","sequence":"additional","affiliation":[{"name":"Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prajnan","family":"Das","sequence":"additional","affiliation":[{"name":"Departments of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Minsky","sequence":"additional","affiliation":[{"name":"Departments of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca E.","family":"Waters","sequence":"additional","affiliation":[{"name":"Departments of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3705-5964","authenticated-orcid":false,"given":"Jeannelyn S.","family":"Estrella","sequence":"additional","affiliation":[{"name":"Departments of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0882-9860","authenticated-orcid":false,"given":"Jenny J.","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaffer A.","family":"Ajani","sequence":"additional","affiliation":[{"name":"Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.3748\/wjg.v28.i12.1187","article-title":"Epidemiology of Stomach Cancer","volume":"28","author":"Ilic","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_2","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","unstructured":"U.S. Department of Health and Human Services, and National Cancer Institute (2026, May 25). Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Stomach Cancer, Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/stomach.html."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.6004\/jnccn.2016.0137","article-title":"Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology","volume":"14","author":"Ajani","year":"2016","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1056\/NEJMoa010187","article-title":"Chemoradiotherapy after Surgery Compared with Surgery Alone for Adenocarcinoma of the Stomach or Gastroesophageal Junction","volume":"345","author":"Macdonald","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1016\/S0140-6736(18)32557-1","article-title":"Perioperative Chemotherapy with Fluorouracil plus Leucovorin, Oxaliplatin, and Docetaxel versus Fluorouracil or Capecitabine plus Cisplatin and Epirubicin for Locally Advanced, Resectable Gastric or Gastro-Oesophageal Junction Adenocarcinoma (FLOT4): A Randomised, Phase 2\/3 Trial","volume":"393","author":"Homann","year":"2019","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1056\/NEJMoa072252","article-title":"Adjuvant Chemotherapy for Gastric Cancer with S-1, an Oral Fluoropyrimidine","volume":"357","author":"Sakuramoto","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0140-6736(11)61873-4","article-title":"Adjuvant Capecitabine and Oxaliplatin for Gastric Cancer after D2 Gastrectomy (CLASSIC): A Phase 3 Open-Label, Randomised Controlled Trial","volume":"379","author":"Bang","year":"2012","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0140-6736(21)00797-2","article-title":"First-Line Nivolumab plus Chemotherapy versus Chemotherapy Alone for Advanced Gastric, Gastro-Oesophageal Junction, and Oesophageal Adenocarcinoma (CheckMate 649): A Randomised, Open-Label, Phase 3 Trial","volume":"398","author":"Janjigian","year":"2021","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s10388-022-00970-1","article-title":"First-Line Nivolumab plus Ipilimumab or Chemotherapy versus Chemotherapy Alone in Advanced Esophageal Squamous Cell Carcinoma: A Japanese Subgroup Analysis of Open-Label, Phase 3 Trial (CheckMate 648\/ONO-4538-50)","volume":"20","author":"Kato","year":"2023","journal-title":"Esophagus"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"943","DOI":"10.2217\/fon-2018-0581","article-title":"KEYNOTE-585: Phase III Study of Perioperative Chemotherapy with or Without Pembrolizumab for Gastric Cancer","volume":"15","author":"Bang","year":"2019","journal-title":"Future Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41586-021-04161-3","article-title":"The KEYNOTE-811 Trial of Dual PD-1 and HER2 Blockade in HER2-Positive Gastric Cancer","volume":"600","author":"Janjigian","year":"2021","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1080\/14737140.2022.2139241","article-title":"Nivolumab with or without chemotherapy for metastatic gastroesophageal cancers and future perspectives","volume":"22","author":"Yamashita","year":"2022","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.immuni.2015.11.024","article-title":"Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy","volume":"44","author":"Pfirschke","year":"2016","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1056\/NEJMoa2032125","article-title":"Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer","volume":"384","author":"Kelly","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/nature10803","article-title":"Expression of Tumour-Specific Antigens Underlies Cancer Immunoediting","volume":"482","author":"DuPage","year":"2012","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1200\/JCO.1996.14.1.296","article-title":"New Statistical Strategy for Monitoring Safety and Efficacy in Single-Arm Clinical Trials","volume":"14","author":"Thall","year":"1996","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Weng, J., Ajani, J.A., Murphy, M.B., Badgwell, B.D., Tchakarov, A.S., Mamlouk, O., and Das, P. (2022). Immunotherapy Recall: Chemoradiation-Induced Reactivation of Immune Checkpoint Inhibitor Nephritis. JCO Precis. Oncol.","DOI":"10.1200\/PO.22.00049"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1200\/JCO.23.00975","article-title":"Perioperative Atezolizumab Plus Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel for Resectable Esophagogastric Cancer: Interim Results From the Randomized, Multicenter, Phase II\/III DANTE\/IKF-S633 Trial","volume":"42","author":"Lorenzen","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1056\/NEJMoa2503701","article-title":"Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer","volume":"393","author":"Janjigian","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"LBA246","DOI":"10.1200\/JCO.2024.42.3_suppl.LBA246","article-title":"Pathological Complete Response (PCR) to 5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel (FLOT) with or without Durvalumab (D) in Resectable Gastric and Gastroesophageal Junction Cancer (GC\/GEJC): Subgroup Analysis by Region from the Phase 3, Randomized, Double-Blind MATTERHORN Study","volume":"42","author":"Janjigian","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4000","DOI":"10.1200\/JCO.2024.42.16_suppl.4000","article-title":"A Phase II\/III Study of Peri-Operative Nivolumab (Nivo) and Ipilimumab (Ipi) in Patients (Pts) with Locoregional Esophageal (E) and Gastroesophageal Junction (GEJ) Adenocarcinoma: Results of the Neoadjuvant Pathologic Complete Response (PCR) Rate (ECOG-ACRIN EA2174)","volume":"42","author":"Eads","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1200\/JCO.20.03611","article-title":"Randomized Phase II Study of PET Response\u2013Adapted Combined Modality Therapy for Esophageal Cancer: Mature Results of the CALGB 80803 (Alliance) Trial","volume":"39","author":"Goodman","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"381","DOI":"10.3748\/wjg.v28.i3.381","article-title":"Postoperative mortality and morbidity after D2 lymphadenectomy for gastric cancer: A retrospective cohort study","volume":"28","author":"Brisinda","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.rgmx.2020.11.004","article-title":"Risk factors associated with postoperative morbidity and mortality in D2 radical gastrectomy for gastric cancer","volume":"87","author":"Passiuri","year":"2022","journal-title":"Rev. Gastroenterol. M\u00e9xico (Engl. Ed.)"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ijsu.2018.04.034","article-title":"Severity of complications and long-term survival after laparoscopic total gastrectomy with D2 lymph node dissection for advanced gastric cancer: A propensity score-matched, case\u2013control study","volume":"54","author":"Li","year":"2018","journal-title":"Int. J. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1002\/onco.13931","article-title":"Immune Checkpoint Inhibitor\u2013Induced Myocarditis with Myositis\/Myasthenia Gravis Overlap Syndrome: A Systematic Review of Cases","volume":"26","author":"Pathak","year":"2021","journal-title":"Oncologist"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"251","DOI":"10.21037\/atm-21-7006","article-title":"Immune checkpoint inhibitors and adrenal insufficiency: A large-sample case series study","volume":"10","author":"Cui","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41571-019-0218-0","article-title":"Adverse effects of immune-checkpoint inhibitors: Epidemiology, management and surveillance","volume":"16","author":"Martins","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103967","DOI":"10.1016\/j.esmoop.2024.103967","article-title":"PD-L1 thresholds predict efficacy of immune checkpoint inhibition in first-line treatment of advanced gastroesophageal adenocarcinoma. A systematic review and meta-analysis of seven phase III randomized trials","volume":"9","author":"Formica","year":"2024","journal-title":"ESMO Open"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"78","DOI":"10.21147\/j.issn.1000-9604.2024.01.08","article-title":"Clinicopathological significance and immunotherapeutic outcome of claudin 18.2 expression in advanced gastric cancer: A retrospective study","volume":"36","author":"Qi","year":"2024","journal-title":"Chin. J. Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2198\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:19:02Z","timestamp":1783657142000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":31,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cancers18142198"],"URL":"https:\/\/doi.org\/10.3390\/cancers18142198","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,8]]}}}