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

Autores: Simonelli, M. (Autor de correspondencia); Garralda, E.; Eskens, F.; Gil-Martín, M.; Yen, C. J.; Obermannova, R.; Chao, Y.; Lonardi, S.; Melichar, B.; Moreno, V.; Yu, M. L.; Bongiovanni, A.; Calvo, E.; Rottey, S.; Machiels, J. P.; González Martín, Antonio; Paz-Ares, L.; Chang, C. L.; Mason, W.; Lin, C. C.; Reardon, D. A.; Vieito, M.; Santoro, A.; Meng, R.; Abbadessa, G.; Menas, F.; Lee, H.; Liu, Q.; Combeau, C.; Ternes, N.; Ziti-Ljajic, S.; Massard, C.
Título de la revista: ESMO OPEN
ISSN: 2059-7029
Volumen: 7
Número: 5
Fecha de publicación: 2022
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.