{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T04:54:55Z","timestamp":1784782495419,"version":"3.55.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"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><jats:title>Background<\/jats:title><jats:p>Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become a standard first-line treatment for advanced non-small cell lung cancer (NSCLC). However, the optimal sequence of administrating the two treatments remains controversial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study included advanced NSCLC patients who received ICIs combined with chemotherapy at Renmin Hospital of Wuhan University and Xiangyang Hospital, Hubei University of Chinese Medicine between 1st September 2020 and 30th September 2024. Patients were categorized into the concurrent, immune-chemo, and chemo-immune groups based on different sequences of treatment administration. The primary endpoints evaluated were survival and treatment efficacy. The secondary endpoint assessed was treatment-related adverse events (TRAEs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This two-center, retrospective study included 270 NSCLC patients who received ICIs plus chemotherapy. Survival analysis revealed statistically significant differences across treatment groups. The median overall survival (mOS) durations were 636 days (concurrent group), 615 days (immune-chemo group), and 749 days (chemo-immune group), with a log-rank test demonstrating significant intergroup differences (<jats:italic>P<\/jats:italic> = 0.0017). Similarly, median progression-free survival (mPFS) showed distinct patterns at 178 days, 180 days, and 216 days for the respective groups (log-rank <jats:italic>P<\/jats:italic> = 0.0134). Additionally, the objective response rates (ORRs) for the three groups were 55.82% (72\/129), 58.21% (39\/67), and 68.92% (51\/74), respectively. The incidence of TRAEs of any grade in the concurrent, the immune-chemo, and the chemo-immune groups was 77.52% (100\/129), 65.67% (44\/67), and 59.46% (44\/74) rates, respectively, which was a significant difference (\u03c7\u00b2=7.91, <jats:italic>P<\/jats:italic>=0.019). Despite patients experiencing Grade 3 or higher TRAEs had extremely poor prognoses, overall, patients who developed any grade of TRAEs had better survival outcomes, particularly those with skin or endocrine toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings suggest that the administration sequence of chemotherapy followed by ICIs may yield the greatest clinical benefit, providing a basis for clinical decision-making.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1579420","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T05:31:29Z","timestamp":1745818289000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The administration sequences of immune checkpoint inhibitors and chemotherapy cause discrete efficacy when treating non-small cell lung cancer: a retrospective study"],"prefix":"10.3389","volume":"16","author":[{"given":"Bicheng","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiao","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Min","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiting","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00577-5","article-title":"The cutting-edge progress of immune-checkpoint blockade in lung cancer","volume":"18","author":"Zhou","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00794-7","article-title":"Immune-checkpoint inhibition for resectable non-small-cell lung cancer - opportunities and challenges","volume":"20","author":"Mountzios","year":"2023","journal-title":"Nat Rev Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s12964-022-00854-y","article-title":"Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons","volume":"20","author":"Naimi","year":"2022","journal-title":"Cell Commun Signal"},{"key":"B5","doi-asserted-by":"publisher","first-page":"a037895","DOI":"10.1101\/cshperspect.a037895","article-title":"Tumor immunology and immunotherapy of non-small-cell lung cancer","volume":"12","author":"Cascone","year":"2022","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12327","article-title":"Kras-G12d mutation drives immune suppression and the primary resistance of anti-PD-1\/PD-L1 immunotherapy in non-small cell lung cancer","volume":"42","author":"Liu","year":"2022","journal-title":"Cancer Commun (Lond)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1177\/17588359241255613","article-title":"First-line treatments for advanced non-squamous non-small cell lung cancer with immune checkpoint inhibitors plus chemotherapy: A systematic review, network meta-analysis, and cost-effectiveness analysis","volume":"16","author":"Tian","year":"2024","journal-title":"Ther Adv Med Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-023-01740-y","article-title":"Lung cancer immunotherapy: progress, pitfalls, and promises","volume":"22","author":"Lahiri","year":"2023","journal-title":"Mol Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1200\/jco.21.01497","article-title":"First-line immunotherapy for non-small-cell lung cancer","volume":"40","author":"Reck","year":"2022","journal-title":"J Clin Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800275","article-title":"Chemotherapy combines effectively with anti-PD-L1 treatment and can augment antitumor responses","volume":"201","author":"Cubas","year":"2018","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001392","article-title":"Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy","volume":"8","author":"Lu","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-19-0433","article-title":"The folate pathway inhibitor pemetrexed pleiotropically enhances effects of cancer immunotherapy","volume":"25","author":"Schaer","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.06.020","article-title":"Outcomes with pembrolizumab plus platinum-based chemotherapy for patients with NSCLC and stable brain metastases: pooled analysis of KEYNOTE-021, -189, and -407","volume":"16","author":"Powell","year":"2021","journal-title":"J Thorac Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1200\/jco.22.01989","article-title":"Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 Study","volume":"41","author":"Garassino","year":"2023","journal-title":"J Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.07.009","article-title":"IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC","volume":"16","author":"Socinski","year":"2021","journal-title":"J Thorac Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.12.013","article-title":"Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up","volume":"34","author":"Hendriks","year":"2023","journal-title":"Ann Oncol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.annonc.2019.10.026","article-title":"Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: A KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS","volume":"31","author":"Park","year":"2020","journal-title":"Ann Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2021.12.022","article-title":"Rational administration sequencing of immunochemotherapy elicits powerful anti-tumor effect","volume":"341","author":"Zhu","year":"2022","journal-title":"J Control Release"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-024-00920-9","article-title":"Targeting immunogenic cell stress and death for cancer therapy","volume":"23","author":"Galluzzi","year":"2024","journal-title":"Nat Rev Drug Discov"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202201734","article-title":"Immunogenic cell death activates the tumor immune microenvironment to soost the immunotherapy efficiency","volume":"9","author":"Li","year":"2022","journal-title":"Adv Sci (Weinh)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1038\/s41419-020-03221-2","article-title":"Detection of immunogenic cell death and its relevance for cancer therapy","volume":"11","author":"Fucikova","year":"2020","journal-title":"Cell Death Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/s41571-021-00564-3","article-title":"tumour burden and efficacy of immune-checkpoint inhibitors","volume":"19","author":"Dall\u2019Olio","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-23-1316","article-title":"Platinum-based chemotherapy attenuates the effector response of CD8 T cells to concomitant PD-1 blockade","volume":"30","author":"Mariniello","year":"2024","journal-title":"Clin Cancer Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.97828","article-title":"Cx3cr1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy","volume":"3","author":"Yan","year":"2018","journal-title":"JCI Insight"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.15_suppl.4051","article-title":"The sequence of chemotherapy and anti-PD-1 antibody influence the efficacy of neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell cancer: A phase II study","volume":"39","author":"Zhao","year":"2021","journal-title":"J Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2021.100094","article-title":"Impact of the combined timing of PD-1\/PD-L1 inhibitors and chemotherapy on the outcomes in patients with refractory lung cancer","volume":"6","author":"Yao","year":"2021","journal-title":"ESMO Open"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.18632\/aging.205328","article-title":"The efficacy of immune checkpoint inhibitors is limited in elderly NSCLC: a retrospective efficacy study and meta-analysis","volume":"15","author":"Yin","year":"2023","journal-title":"Aging (Albany NY)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e2352302","DOI":"10.1001\/jamanetworkopen.2023.52302","article-title":"Immune-related adverse events and survival among patients with metastatic NSCLC treated with immune checkpoint inhibitors","volume":"7","author":"Cook","year":"2024","journal-title":"JAMA Netw Open"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-021-03115-y","article-title":"The prognostic impact of mild and severe immune-related adverse events in non-small cell lung cancer treated with immune checkpoint inhibitors: a multicenter retrospective study","volume":"71","author":"Wang","year":"2022","journal-title":"Cancer Immunol Immunother"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.6449","article-title":"Immune-related adverse events and outcomes among pan-cancer patients receiving immune checkpoint inhibitors: a monocentric real-world observational study","volume":"12","author":"Ge","year":"2023","journal-title":"Cancer Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.4143\/crt.2023.1118","article-title":"Association of immune-related adverse events and the efficacy of anti-PD-(L)1 monotherapy in non-small cell lung cancer: adjusting for immortal-time bias","volume":"56","author":"Yu","year":"2024","journal-title":"Cancer Res Treat"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.976224","article-title":"Patients with melanoma treated with immune checkpoint inhibitors who had non-thyroid endocrine and skin immune-related adverse events have better prognosis: a systematic review and meta-analysis","volume":"12","author":"Sun","year":"2022","journal-title":"Front Oncol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1190001","article-title":"Association between immune-related adverse events and immunotherapy efficacy in non-small-cell lung cancer: a meta-analysis","volume":"14","author":"Lin","year":"2023","journal-title":"Front Pharmacol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1402017","article-title":"Association between immune-related adverse events and prognosis in patients with advanced non-small cell lung cancer: a systematic review and meta-analysis","volume":"14","author":"Ma","year":"2024","journal-title":"Front Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1579420\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T05:31:30Z","timestamp":1745818290000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1579420\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,28]]},"references-count":34,"alternative-id":["10.3389\/fimmu.2025.1579420"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1579420","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,28]]},"article-number":"1579420"}}