{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:16:07Z","timestamp":1788419767584,"version":"build-2803163510"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>To quantify overall-survival effects of immune-checkpoint-inhibitor (ICI)-containing regimens by treatment line and to evaluate whether clinical characteristics or PD-L1 definitions modify relative treatment benefit in advanced esophageal squamous cell carcinoma (ESCC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched from inception through 1 August 2026. Two reviewers independently screened records, assessed full texts, extracted data, and evaluated risk of bias. Reports were linked to their parent randomized trial family. First-line single-checkpoint blockade plus chemotherapy and later-line checkpoint monotherapy were synthesized separately using REML random-effects models and modified Hartung-Knapp inference. Treatment-effect modification was quantified using within-trial ratios of hazard ratios (RHRs). Twenty-one interactions with at least two independent trial families entered Holm correction; Bonferroni correction was used as a sensitivity analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 14 independent randomized trial families represented by 31 reports. The primary overall-survival analysis included 7 first-line trials (\n                      <jats:italic>N<\/jats:italic>\n                      = 4,151; pooled HR 0.70, 95% CI 0.64\u20130.77; P &amp;lt; 0.001;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 0%) and 5 later-line trials (\n                      <jats:italic>N<\/jats:italic>\n                      = 1,970; pooled HR 0.74, 95% CI 0.64\u20130.85; P = 0.004;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 0%). Of 30 post hoc line-specific interaction hypotheses, 28 had at least one eligible trial-family contrast: 21 met the k \u2265 2 pooling threshold and were included in multiplicity-adjusted analyses, 7 were single-trial descriptive contrasts, and 2 had no eligible estimate. None of the 21 pooled interactions remained significant after Holm correction; all Holm- and Bonferroni-adjusted P values were 1.000. The smallest unadjusted P value was 0.092 for first-line CPS \u2265 1 versus &amp;lt; 1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>ICI-containing regimens improved overall survival in both first- and later-line settings, but aggregate within-trial interaction analyses did not identify a reliable clinical or PD-L1-defined treatment-effect modifier. Sparse subgroup reporting and the predominantly Asian evidence base limit the precision and generalizability of these findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/<\/jats:ext-link>\n                      , identifier CRD42024551725.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1901673","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:43:36Z","timestamp":1788417816000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Overall survival with immune checkpoint inhibitors across treatment settings and clinical and PD-L1-defined subgroups in advanced esophageal squamous cell carcinoma: a systematic review and 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