{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T16:34:09Z","timestamp":1788194049042,"version":"build-2803163510"},"reference-count":33,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K07229"],"award-info":[{"award-number":["21K07229"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K06706"],"award-info":[{"award-number":["23K06706"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K10395"],"award-info":[{"award-number":["24K10395"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Thoracic Cancer"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The impact of concomitant medications on immune\u2010related adverse events (irAEs) and immune checkpoint inhibitor (ICI) efficacy in non\u2010small cell lung cancer (NSCLC) remains unclear. Benzodiazepine receptor agonists (BZRAs), commonly prescribed for anxiety and insomnia in cancer care, may influence antitumor immunity via \u03b3\u2010aminobutyric acid (GABA) signaling. Here, we retrospectively analyzed medical records of NSCLC patients treated with ICIs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In an initial exploratory analysis, BZRA use was significantly associated with a lower incidence of irAEs, prompting further evaluation. Propensity score matching (PSM) was performed to adjust for potential confounding factors. In the matched cohort, we assessed associations between BZRA use, irAE incidence, and ICI efficacy, as measured by progression\u2010free survival (PFS) and overall survival (OS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the matched cohort, BZRA use was significantly associated with a lower incidence of irAEs (OR 0.33, 95% CI: 0.13\u20130.80, <jats:italic>p<\/jats:italic>\u2009=\u20090.015). BZRA use was also linked to shorter PFS (HR 1.80, 95% CI: 1.13\u20132.86, <jats:italic>p<\/jats:italic>\u2009=\u20090.013), but not OS (HR 1.63, 95% CI: 0.95\u20132.81, <jats:italic>p<\/jats:italic>\u2009=\u20090.077). In subgroup analysis, among patients who developed irAEs, BZRA use was associated with shorter PFS (HR 2.69, 95% CI: 1.32\u20135.48, <jats:italic>p<\/jats:italic>\u2009=\u20090.007) and OS (HR 3.35, 95% CI: 1.40\u20138.04, <jats:italic>p<\/jats:italic>\u2009=\u20090.007), whereas no significant associations were observed in non\u2010irAE patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>BZRA use was associated with reduced irAE incidence and poorer ICI outcomes among patients who developed irAEs, suggesting potential immunosuppressive effects that may impair ICI efficacy in NSCLC.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1759-7714.70081","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T23:58:59Z","timestamp":1747267139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Impact of Exposure to Benzodiazepines on Adverse Effects and Efficacy of <scp>PD<\/scp>\u20101\/<scp>PD<\/scp>\u2010<scp>L1<\/scp> Blockade in Patients With Non\u2010Small Cell Lung Cancer"],"prefix":"10.1111","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2860-4163","authenticated-orcid":false,"given":"Kiyoshi","family":"Takagaki","sequence":"first","affiliation":[{"name":"Laboratory of Immunobiology School of Pharmacy, Hyogo Medical University  Kobe Japan"},{"name":"Department of Pharmacy Hyogo Medical University Hospital  Nishinomiya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9190-8424","authenticated-orcid":false,"given":"Yoshiya","family":"Ohno","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology School of Pharmacy, Hyogo Medical University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiichiro","family":"Otsuki","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and Hematology School of Medicine, Hyogo Medical University  Nishinomiya Japan"},{"name":"Department of Thoracic Oncology School of Medicine, Hyogo Medical University  Nishinomiya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aki","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and Hematology School of Medicine, Hyogo Medical University  Nishinomiya Japan"},{"name":"Department of Thoracic Oncology School of Medicine, Hyogo Medical University  Nishinomiya Japan"},{"name":"Department of Biomedical Statistics and Bioinformatics Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kijima","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and Hematology School of Medicine, Hyogo Medical University  Nishinomiya Japan"},{"name":"Department of Thoracic Oncology School of Medicine, Hyogo Medical University  Nishinomiya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology School of Pharmacy, Hyogo Medical University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423\u2010020\u201000577\u20105"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1703481"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.09.020"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12094\u2010020\u201002315\u20109"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.01.006"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102021\u2010002421"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2020.09.033"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.79.0006"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.14182"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/1759\u20107714.14001"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2021.08.036"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.22915"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2021.02.040"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881113503509"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.22106"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010021\u201003881\u2010z"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095\u20103941.2021.0052"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262\u2010020\u201002585\u2010w"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.7150\/jca.53242"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.00189"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2020.12.012"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12874\u2010017\u20100338\u20100"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2012.244"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.2925"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.5012"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl\u20102019\u2010320204"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25979"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3502"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0251632"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201004082\u20101"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010021\u201000820\u20109"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201023\u20100547"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2024.2413719"}],"updated-by":[{"DOI":"10.1111\/1759-7714.70143","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T00:00:00Z","timestamp":1754524800000}}],"container-title":["Thoracic 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