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2022-10-01

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cc by (c) Simonelli, M. et al., 2022
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/190195

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study

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https://doi.org/10.1016/j.esmoop.2022.100562

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Background: 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.

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Tumors, Càncer de fetge

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Tumors, Liver cancer

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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SIMONELLI, M., GARRALDA, Elena, ESKENS, Ferry, GIL MARTIN, M., YEN, C. j., OBERMANNOVA, R., CHAO, Y., LONARDI, S., MELICHAR, B., MORENO, V., YU, M. l., BONGIOVANNI, A., CALVO, E., ROTTEY, Sylvie, MACHIELS, J. p., GONZALEZ MARTIN, A., PAZ-ARES, Luis, CHANG, 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.. Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study. _ESMO Open_. 2022. Vol. 7, núm. 5, pàgs. 100562. [consulta: 27 de gener de 2026]. ISSN: 2059-7029. [Disponible a: https://hdl.handle.net/2445/190195]

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