Simonelli, M.Garralda, ElenaEskens, FerryGil Martin, M.Yen, C. J.Obermannova, R.Chao, Y.Lonardi, S.Melichar, B.Moreno, V.Yu, M. L.Bongiovanni, A.Calvo, E.Rottey, SylvieMachiels, J. P.Gonzalez Martin, A.Paz-Ares, LuisChang, C. L.Mason, W.Lin, C. C.Reardon, David A.Vieito, M.Santoro, A.Meng, R.Abbadessa, G.Menas, F.Lee, H.Liu, Q.Combeau, C.Ternes, N.Ziti Ljajic, S.Massard, C.2022-10-252022-10-252022-10-012059-7029https://hdl.handle.net/2445/190195Background: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced >= 1 treatment-emergent adverse event (TEAE), with <= 48.5% being grade >= 3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.8 p.application/pdfengcc by (c) Simonelli, M. et al., 2022http://creativecommons.org/licenses/by/3.0/es/TumorsCàncer de fetgeTumorsLiver cancerinfo:eu-repo/semantics/article2022-10-20info:eu-repo/semantics/openAccess35987165