The CSF-1R inhibitor Pexidartinib impacts dendritic cell differentiation through inhibition of FLT3 signaling and may antagonize the effect of durvalumab in patients with advanced cancer – results from a phase 1 study

Tumor-associated macrophages (TAM) are critical determinant of resistance to programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade. This phase I study (MEDIPLEX, [NCT02777710][1]) investigated the safety and efficacy of pexidartinib, a CSF-1R-directed tyrosine kinase inhibitor (TKI), and durvalumab (anti-PD-L1) in patients with advanced colorectal (CRC) and pancreatic (PDAC) carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1-dependent suppressive TAM. No unexpected toxicities were observed and 2% and 15% of patients achieved partial response and stable disease respectively. Increase of CSF-1 levels and decrease of CD14lowCD16high monocytes in peripheral blood mononuclear cells (PBMC) confirmed CSF-1R engagement. Treatment significantly decreased blood dendritic cell (DC) subsets and impaired IFN-λ/IL-29 production by type-1 conventional DC in ex vivo TLR3-stimulated PBMC. Pexidartinib also targets c-KIT and FLT3, both key growth factor receptors of DC development and maturation. In patients, FLT3-L levels increased with pexidartinib treatment. In vitro , pexidartinib impaired the FLT3-L but not GM-CSF-dependent generation of DC subsets from murine bone marrow progenitors. Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has deleterious effect on DC differentiation, which may explain the limited anti-tumor clinical activity observed in this study. This study suggests that inhibition of FLT3 should be taken into account when combining TKIs with immune checkpoint blockers. One-sentence summary Pexidartinib affects the development of dendritic cells ### Competing Interest Statement P.A.C.: Honoraria: ITeos Therapeutics, Amgen, Janssen; Consulting/advisory role : OSE immunotherapeutics; Research Funding: Novartis, Roche/Genentech, Lilly, Blueprint Medicines, Bayer, Astra Zeneca, Celgene, Plexxikon, Abbvie, BMS, Merck Serono, Merck Sharp and Dohme, Taiho Pharmaceutical, Toray Industries, Transgene, Loxo, GSK, Innate Pharma, Janssen; Travel expenses: Roche, Amgen, Novartis, BMS, MSD, Netris Pharma, Bayer, Merck Serono, Astra Zeneca/MedImmune. D.P.: Consulting/advisory role : Astrazeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Eli-Lilly, Ipsen, Roche, Novartis, Merck Sharp and Dohme, Takeda. C.G.R.: Invited Speaker: BMS, Eisai, Pierre Fabre, Roche/Genentech; Coordinating PI: BMS; Steering Committee Member: BMS; Local PI: Foundation Medicine; Steering Committee Member: Genentech; Research Grant: Roche/Genentech; BMS Advisory board : Macomics ; Honoraria: BMS, Roche/Genentech, Pierre Fabre, Foundation Medicine. C.T.: Research funding GSK, travel expenses Mundipharma. J.-P.D.: Advisory Board : BMS, MSD, Pierre Fabre, Roche, invited speaker Merck Serono, Research Grant Amgen, Astra Zeneca, BMS, Genentech, MSD, Transgene. The authors declare that they have no other competing interests. ### Clinical Trial NCT02777710 ### Funding Statement The study was funded by grants of the French National Cancer Institute (INCa) and The Foundation ARC pour la recherche sur le cancer (INCa-ARC_9226) and RHU PERFUSE (ANR-17-RHUS0006) of Universite Claude Bernard Lyon 1 (UCBL) within the program Investissements d Avenir operated by the French National Research Agency (ANR). This work was also financially supported by the SIRIC project (LYRICan grant INCa-DGOS-Inserm 12563). A.V. is a recipient of a post-doctoral fellowship from Labex DEVweCAN. Study treatments were provided by AstraZeneca and Plexxikon. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethic committee named Comite de Protection des personnes - Sud EST IV gave ethical approval on 10 february 2016 for the MEDIPLEx trial (approval reference : A 16-57) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02777710&atom=%2Fmedrxiv%2Fearly%2F2023%2F02%2F23%2F2023.02.15.23285939.atom