{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T17:43:40Z","timestamp":1778003020945,"version":"3.51.4"},"reference-count":43,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T00:00:00Z","timestamp":1623715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001171","name":"Cancer Institute NSW","doi-asserted-by":"publisher","award":["14CDF117"],"award-info":[{"award-number":["14CDF117"]}],"id":[{"id":"10.13039\/501100001171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001081","name":"Hunter Medical Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001081","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Trial data support an absence of an exposure\u2013survival relationship for pembrolizumab. As these relationships remain unexamined in a real\u2010world setting, we determined them in metastatic melanoma prospectively in an observational study. Translational objectives included identifying biomarkers of progressive disease (PD). Checkpoint blockade na\u00efve patients receiving 2\u00a0mg\/kg Q3W pembrolizumab had pharmacokinetic and clinical outcome data collected. Trough, a valid surrogate for drug exposure, was assessed using ELISA. T\u2010cell exhaustion and chemokine markers were determined using flow cytometry. Geometric means of exposures and biomarkers were tested against objective response groups using one\u2010way ANOVA. The cohort was split by the median into high versus low pembrolizumab exposure groups. Kaplan\u2013Meier progression\u2010free survival (PFS) and overall survival (OS) curves were estimated for high versus low exposure, compared using the log rank test. The high pembrolizumab exposure group (<jats:italic>n<\/jats:italic>\u00a0=\u00a014) experienced substantially longer median OS (not reached vs. 48\u00a0months, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.014), than the low exposure group (<jats:italic>n<\/jats:italic>\u00a0=\u00a014). A similar positive exposure PFS relationship was found (median not reached vs. 48\u00a0months, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.045). The frequency of TIM\u20103 expression on CD4<jats:sup>+<\/jats:sup> T cells was significantly higher in PD (mean 27.8%) than complete response (CR) (13.38%, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.01) and partial response (12.4%, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.05). There was a near doubling of CXCR6 and TIM\u20103 co\u2010expression on CD4<jats:sup>+<\/jats:sup> T cells in PD (mean 23.3%) versus CR (mean 11.4, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.003) and partial response (9.8%, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.0001). We describe positive exposure\u2010PFS and exposure\u2010OS relationships for pembrolizumab in metastatic melanoma. TIM\u20103, alongside co\u2010expression of CXCR6 and TIM\u20103 on circulating CD4<jats:sup>+<\/jats:sup> T cells are potential bio markers of treatment failure.<\/jats:p>","DOI":"10.1002\/prp2.808","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T14:50:22Z","timestamp":1623768622000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Overall survival in metastatic melanoma correlates with pembrolizumab exposure and T cell exhaustion markers"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6795-009X","authenticated-orcid":false,"given":"Vishal","family":"Navani","sequence":"first","affiliation":[{"name":"Calvary Mater Hospital Newcastle  Waratah NSW Australia"},{"name":"Centre for Drug Repurposing and Medicines Research University of Newcastle and Hunter Medical Research Institute  Callaghan NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3380-5417","authenticated-orcid":false,"given":"Moira C.","family":"Graves","sequence":"additional","affiliation":[{"name":"Centre for Drug Repurposing and Medicines Research University of Newcastle and Hunter Medical Research Institute  Callaghan NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovana Celli","family":"Marchett","sequence":"additional","affiliation":[{"name":"Calvary Mater Hospital Newcastle  Waratah NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0824-7385","authenticated-orcid":false,"given":"Hiren","family":"Mandaliya","sequence":"additional","affiliation":[{"name":"Calvary Mater Hospital Newcastle  Waratah NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6047-1694","authenticated-orcid":false,"given":"Nikola A.","family":"Bowden","sequence":"additional","affiliation":[{"name":"Centre for Drug Repurposing and Medicines Research University of Newcastle and Hunter Medical Research Institute  Callaghan NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andre","family":"van der Westhuizen","sequence":"additional","affiliation":[{"name":"Calvary Mater Hospital Newcastle  Waratah NSW Australia"},{"name":"Centre for Drug Repurposing and Medicines Research University of Newcastle and Hunter Medical Research Institute  Callaghan NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,6,15]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2018.06.001"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.162"},{"key":"e_1_2_10_4_1","unstructured":"National Comprehensive Cancer Network.Cutaneous melanoma (Version 4.2020).https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/cutaneous_melanoma_blocks.pdf. 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