{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:57:18Z","timestamp":1790618238727,"version":"4.1.0"},"reference-count":17,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Reports"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Immune checkpoint blockade has changed the first\u2010line treatment landscape for advanced esophageal squamous cell carcinoma (ESCC), but the magnitude and consistency of benefit across phase III trials require careful synthesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a PRISMA 2020\u2010guided systematic review of PubMed, Embase, CENTRAL, and Web of Science (January 1, 2015 to April 30, 2025) for phase III randomized trials comparing first\u2010line PD\u20101 inhibitor\u2010based therapy with chemotherapy in advanced\/metastatic ESCC. The primary endpoint was overall survival (OS). Secondary endpoints were safety and prespecified subgroup outcomes. RoB 2 was used for risk\u2010of\u2010bias assessment; certainty of evidence was judged with GRADE. A fixed\u2010effect inverse\u2010variance model was prespecified for the primary common\u2010effect analysis, with random\u2010effects and sensitivity analyses performed secondarily.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Six eligible phase III trials were included in the primary analysis (KEYNOTE\u2010590 ESCC subgroup, CheckMate\u2010648 nivolumab\u2010plus\u2010chemotherapy arm, ESCORT\u20101st, JUPITER\u201006, ORIENT\u201015, and RATIONALE\u2010306). Across the six parent\u2010trial reports, 4137 patients were randomized overall; for pooling, KEYNOTE\u2010590 was restricted to the prespecified ESCC subgroup and CheckMate\u2010648 to the nivolumab\u2010plus\u2010chemotherapy comparison. PD\u20101 inhibitor\u2010based therapy significantly improved OS versus chemotherapy alone (pooled HR 0.68, 95% CI: 0.63\u20130.74;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20090%, interpreted as low statistical heterogeneity with caution because only six studies were pooled). Qualitative assessment indicated that the treatment effect was generally larger in PD\u2010L1\u2010high populations; however, biomarker\u2010defined subgroup data were not sufficiently harmonized for formal pooling, and the magnitude of benefit in very low or PD\u2010L1\u2010negative disease remains uncertain. Grade \u2265\u20093 treatment\u2010related adverse events were common in both arms, whereas immune\u2010related toxicities were more frequent with PD\u20101 inhibitor\u2010based therapy and required active monitoring.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>First\u2010line PD\u20101 inhibitor\u2010based therapy confers a robust OS benefit in advanced\/metastatic ESCC and supports chemoimmunotherapy as a contemporary standard of care. Remaining uncertainties relate mainly to biomarker\u2010negative disease, assay heterogeneity, and cross\u2010trial differences in chemotherapy backbone and geographic composition.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cnr2.70660","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:21:08Z","timestamp":1788754868000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["First\u2010Line\n                    <scp>PD<\/scp>\n                    \u20101 Inhibitor\u2010Based Therapy for Advanced or Metastatic Esophageal Squamous Cell Carcinoma: A Revised Systematic Review and Meta\u2010Analysis of Phase\n                    <scp>III<\/scp>\n                    Trials"],"prefix":"10.1002","volume":"9","author":[{"given":"Vincent","family":"Rothweiler","sequence":"first","affiliation":[{"name":"Medical School of Heinrich Heine University D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Roderburg","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital D\u00fcsseldorf Heinrich Heine University D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8210-0894","authenticated-orcid":false,"given":"Muemtaz","family":"Koeksal","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology University Hospital OWL, Klinikum Bielefeld  Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1626-4855","authenticated-orcid":false,"given":"Bj\u00f6rn Erik Ole","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital D\u00fcsseldorf Heinrich Heine University D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6755-4492","authenticated-orcid":false,"given":"Torsten","family":"Feldt","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital D\u00fcsseldorf Heinrich Heine University D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilyas","family":"Gencer","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology University Hospital OWL, Klinikum Bielefeld  Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2079-1845","authenticated-orcid":false,"given":"Johannes C.","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institute for Transplantation Diagnostics and Cellular Therapeutics Heinrich Heine University D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfried","family":"Budach","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology University Hospital OWL, Klinikum Bielefeld  Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfram Trudo","family":"Knoefel","sequence":"additional","affiliation":[{"name":"Department of Surgery Heinrich Heine University D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2568-7091","authenticated-orcid":false,"given":"Guangyu","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences &amp; School of Public Health, Faculty of Medicine Yangzhou University  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9112-1024","authenticated-orcid":false,"given":"Edwin","family":"B\u00f6lke","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology University Hospital OWL, Klinikum Bielefeld  Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)02226-8"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.07.003"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2021.100380"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2022.5816"},{"issue":"10314","key":"e_1_2_11_7_1","first-page":"1874","article-title":"Pembrolizumab Plus Chemotherapy Versus Chemotherapy Alone for First\u2010Line Treatment of Advanced Oesophageal Cancer (KEYNOTE\u2010590): A Randomised, Placebo\u2010Controlled, Phase 3 Study","volume":"398","author":"Sun J. 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