{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T06:02:47Z","timestamp":1789365767350,"version":"build-2803163510"},"reference-count":34,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>\n                    Datopotamab deruxtecan (Dato\u2010DXd) is a trophoblast cell\u2010surface antigen\u20102 (TROP2)\u2010directed antibody\u2010drug conjugate (ADC) that has demonstrated clinical activity in patients with NSCLC who have received prior therapies. Exposure\u2010response (ER) analyses were conducted using Phase 1\u20133 clinical data from patients with NSCLC (efficacy and safety) or breast cancer (BC) (only safety). Parametric time\u2010to\u2010event models were developed for overall survival (OS), progression\u2010free survival (PFS), and adverse events of special interest (AESI). Logistic regression models were used for overall response rate (ORR), Grade \u2265\u20093 treatment\u2010emergent adverse events (TEAEs), serious TEAEs, and TEAEs associated dose reduction. Covariate effects were assessed using stepwise selection. A significant linear ER relationship was found between Dato\u2010DXd AUC in the first cycle (AUC\n                    <jats:sub>1<\/jats:sub>\n                    ) and OS. Drug effect on PFS and ORR was respectively described by a maximum effect (\n                    <jats:italic>E<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) relationship with Dato\u2010DXd AUC during a dosing interval (AUC\n                    <jats:sub>\u03c4<\/jats:sub>\n                    ) and Dato\u2010DXd average concentration (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>av<\/jats:sub>\n                    ), indicating near\u2010maximal efficacy at 6\u2009mg\/kg. Baseline liver metastasis, squamous histology, and lower albumin (28.0\u2009g\/L, 5th percentile) were identified as significant risk factors of shortened OS and PFS, predicted to increase mortality risk by 52%, 48%, and 84%, respectively. The exposure\u2010safety analysis identified Dato\u2010DXd or DXd exposures as statistically significant predictors for safety endpoints except adjudicated drug\u2010related interstitial lung disease (ILD)\/pneumonitis for which no ER relationship was observed. These ER analyses support that the 6\u2009mg\/kg Q3W Dato\u2010DXd regimen optimized the benefit\u2013risk profile for patients with advanced nonsquamous NSCLC and identified clinically relevant factors that influence both survival and safety outcomes.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70477","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:08:39Z","timestamp":1789362519000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exposure\u2010Response Analyses of Datopotamab Deruxtecan (Dato\u2010\n                    <scp>DXd<\/scp>\n                    ), a\n                    <scp>TROP2<\/scp>\n                    \u2010Directed Antibody\u2010Drug Conjugate, in Advanced Non\u2010small Cell Lung Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9443-3515","authenticated-orcid":false,"given":"Ying","family":"Hong","sequence":"first","affiliation":[{"name":"Quantitative Clinical Pharmacology Daiichi Sankyo, Inc.  Basking Ridge New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5936-1877","authenticated-orcid":false,"given":"Anna M.","family":"Mc Laughlin","sequence":"additional","affiliation":[{"name":"Pharmetheus AB  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzhuo","family":"Pan","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology Daiichi Sankyo, Inc.  Basking Ridge New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia Friberg","family":"Hietala","sequence":"additional","affiliation":[{"name":"Pharmetheus AB  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Peign\u00e9","sequence":"additional","affiliation":[{"name":"Pharmetheus AB  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1040-9470","authenticated-orcid":false,"given":"Michael","family":"Chargualaf","sequence":"additional","affiliation":[{"name":"Clinical Development Daiichi Sankyo, Inc.  Basking Ridge New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0945-6510","authenticated-orcid":false,"given":"Zoey","family":"Tang","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology AstraZeneca  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2673-1069","authenticated-orcid":false,"given":"Diansong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology AstraZeneca  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoyuki","family":"Tajima","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malaz","family":"Abutarif","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology Daiichi Sankyo, Inc.  Basking Ridge New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tushar","family":"Garimella","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology Daiichi Sankyo, Inc.  Basking Ridge New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S0140-6736(21)00312-3","article-title":"Lung cancer","volume":"398","author":"Thai A.A.","year":"2021","journal-title":"Lancet"},{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/S1470-2045(23)00444-8","article-title":"Global variations in lung cancer incidence by histological subtype in 2020: a population\u2010based study","volume":"24","author":"Zhang Y.","year":"2023","journal-title":"Lancet Oncol."},{"key":"e_1_2_10_3_1","first-page":"1","article-title":"Immunotherapy for advanced non\u2010small cell lung cancer: a decade of Progress","volume":"41","author":"Shields M.D.","year":"2021","journal-title":"Am. Soc. Clin. Oncol. Educ. Book Am. Soc. Clin. Oncol. Annu. 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Cancer Ther."},{"key":"e_1_2_10_9_1","unstructured":"Drugs@FDA: FDA\u2010Approved Drugs<https:\/\/www.accessdata.fda.gov\/scripts\/cder\/daf\/index.cfm?event=overview.process&ApplNo=761394>. Accessed May 20 2025."},{"key":"e_1_2_10_10_1","unstructured":"Datroway | European Medicines Agency (EMA)<https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/datroway>. January 31 2025. Accessed May 20 2025."},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"4678","DOI":"10.1200\/JCO.23.00059","article-title":"First\u2010in\u2010human, phase I dose\u2010escalation and dose\u2010expansion study of trophoblast cell\u2010surface antigen 2\u2010directed antibody\u2010drug conjugate Datopotamab Deruxtecan in non\u2010small\u2010cell lung cancer: TROPION\u2010PanTumor01","volume":"41","author":"Shimizu T.","year":"2023","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1200\/JCO-24-01349","article-title":"Datopotamab Deruxtecan in advanced or metastatic non\u2010small cell lung cancer with actionable genomic alterations: results from the phase II TROPION\u2010Lung05 study","volume":"43","author":"Sands J.","year":"2025","journal-title":"J.\u00a0Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1200\/JCO-24-01544","article-title":"Datopotamab Deruxtecan versus docetaxel for previously treated advanced or metastatic non\u2010small cell lung cancer: the randomized, open\u2010label phase III TROPION\u2010Lung01 study","volume":"43","author":"Ahn M.J.","year":"2025","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1002\/psp4.70118","article-title":"Population pharmacokinetic analysis of Datopotamab Deruxtecan (Dato\u2010 DXd), a TROP2 \u2010directed antibody\u2010drug conjugate, in patients with advanced solid tumors","volume":"14","author":"Hong Y.","year":"2025","journal-title":"CPT Pharmacometrics Syst. Pharmacol."},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1002\/psp4.12838","article-title":"Efficient and relevant stepwise covariate model building for pharmacometrics","volume":"11","author":"Svensson R.J.","year":"2022","journal-title":"CPT Pharmacometrics Syst. Pharmacol."},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/psp4.13058","article-title":"Application of the model\u2010informed drug development paradigm to datopotamab deruxtecan dose selection for late\u2010stage development","volume":"13","author":"Lu Y.","year":"2024","journal-title":"CPT Pharmacometrics Syst. Pharmacol."},{"key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jtho.2017.11.111","article-title":"Current and emergent therapy options for advanced squamous cell lung cancer","volume":"13","author":"Socinski M.A.","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13073-022-01041-x","article-title":"Variation in targetable genomic alterations in non\u2010small cell lung cancer by genetic ancestry, sex, smoking history, and histology","volume":"14","author":"Adib E.","year":"2022","journal-title":"Genome Med."},{"key":"e_1_2_10_19_1","first-page":"5590","article-title":"Clinical associations and prognostic value of site\u2010specific metastases in non\u2010small cell lung cancer: a population\u2010based study","volume":"17","author":"Xu Z.","year":"2019","journal-title":"Oncol. Lett."},{"key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.7150\/jca.30463","article-title":"Prognostic value of site\u2010specific metastases in lung cancer: a population based study","volume":"10","author":"Li J.","year":"2019","journal-title":"J. Cancer"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1186\/s12885-017-3814-3","article-title":"Serum albumin level as a potential marker for deciding chemotherapy or best supportive care in elderly, advanced non\u2010small cell lung cancer patients with poor performance status","volume":"17","author":"Ikeda S.","year":"2017","journal-title":"BMC Cancer"},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"471","DOI":"10.4149\/318_151001N512","article-title":"Serum albumin is a strong predictor of survival in patients with advanced\u2010stage non\u2010small cell lung cancer treated with erlotinib","volume":"63","author":"Fiala O.","year":"2016","journal-title":"Neoplasma"},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2024.1323192","article-title":"Predictive value of serum albumin levels on cancer survival: a prospective cohort study","volume":"14","author":"Tang Q.","year":"2024","journal-title":"Front. 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