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Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4\u2009weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline &amp; on-treatment tumor and blood samples to identify immune correlates of efficacy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A total of 12\/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200\u2009mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1\u20132 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7\u2009months (95%CI: 5.55\u201340.5). Three patients developed a partial response (PR) (ORR\u2009=\u200925%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD)\u2009\u2265\u20096\u2009months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4<jats:sup>+<\/jats:sup> PD1<jats:sup>+<\/jats:sup> OX40<jats:sup>+<\/jats:sup> T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP<jats:sup>+<\/jats:sup> dendritic cells, CD3<jats:sup>+<\/jats:sup> T cells and FOXP3<jats:sup>+<\/jats:sup> Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4<jats:sup>+<\/jats:sup> CXCR3<jats:sup>+<\/jats:sup> CXCR5<jats:sup>\u2212<\/jats:sup> memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Nintedanib 150\u2009mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib &amp; pembrolizumab therapy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>ClinicalTrials.gov, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02856425?term=PEMBIB&amp;draw=2&amp;rank=1\">NCT02856425<\/jats:ext-link>. Registered August 4, 2016 \u2014 Prospectively registered.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13046-022-02423-0","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T02:03:29Z","timestamp":1657159409000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Safety, recommended dose, efficacy and immune correlates for nintedanib in combination with pembrolizumab in patients with advanced 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They had a right of first glance at the data reported but could not modify or influence the results reported in the manuscript neither their interpretation. Gustave Roussy as the sponsor and his investigators remain independent from BI & MSD for the data analysis, interpretation, and publication of the PEMBIB trial. Over the last 5\u2009years, AM provided consulting work to BI for a project not related to the PEMBIB trial, participated to a scientific advisory board with MSD on a topic not related to the PEMBIB trial, has been a principal investigator for MSD-sponsored clinical trials not related to the PEMBIB trial and received a research grant from Fondation MSD Avenir that was partly funding some lab technician time and biological assays that were used for the ancillary analysis of the PEMBIB trial. JCS have shares in Gritstone bio and Relay Therapeutics, is Board of Director at Hookipa Pharmaceuticals and is Full time employee at Amgen since August 2021. As part of members of the DITEP CB, AV, SC, PV, PM-R, J-MM, RB, AG, VR, SP-V, AH and CM are Principal\/sub-Investigator of Clinical Trials for Abbvie, Adaptimmune, Adlai Nortye USA Inc., Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd., Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Curevac, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd., Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Seattle Genetics, Sotio A. S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Turning Point Therapeutics, Xencor. They benefit from research Grants from Astrazeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi and non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, GSK, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. The other authors declare no conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"217"}}