1. Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study
- Author
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M. Simonelli, E. Garralda, F. Eskens, M. Gil-Martin, C.-J. Yen, R. Obermannova, Y. Chao, S. Lonardi, B. Melichar, V. Moreno, M.-L. Yu, A. Bongiovanni, E. Calvo, S. Rottey, J.-P. Machiels, A. Gonzalez-Martin, L. Paz-Ares, C.-L. Chang, W. Mason, C.-C. Lin, D.A. Reardon, M. Vieito, A. Santoro, R. Meng, G. Abbadessa, F. Menas, H. Lee, Q. Liu, C. Combeau, N. Ternes, S. Ziti-Ljajic, C. Massard, Medical Oncology, Institut Català de la Salut, [Simonelli M] IRCCS Humanitas Research Hospital, Rozzano, Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy. [Garralda E] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Eskens F] Erasmus MC Cancer Institute, Rotterdam, the Netherlands. [Gil-Martin M] Institut Català d’Oncologia-IDIBELL, L’Hospitalet, Barcelona, Spain. [Yen CJ] National Cheng Kung University, Tainan, Taiwan. [Santoro A] Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, and UCL - (SLuc) Service d'oncologie médicale
- Subjects
atezolizumab ,Cancer Research ,anti-PD-L1 ,Carcinoma, Hepatocellular ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Quimioteràpia combinada ,B7-H1 Antigen ,neoplasias [ENFERMEDADES] ,Càncer de fetge ,SDG 3 - Good Health and Well-being ,anti-CD38 ,Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Medicine and Health Sciences ,Tumor Microenvironment ,Humans ,Tumors ,Càncer - Tractament ,Cell Physiological Phenomena::Cellular Microenvironment::Tumor Microenvironment [PHENOMENA AND PROCESSES] ,fenómenos fisiológicos celulares::microambiente celular::microambiente tumoral [FENÓMENOS Y PROCESOS] ,Liver Neoplasms ,terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Forkhead Transcription Factors ,solid tumors ,Neoplasms [DISEASES] ,Oncology ,Liver cancer ,isatuximab - Abstract
Atezolizumab; Isatuximab; Solid tumors Atezolizumab; Isatuximab; Tumores sólidos Atezolizumab; Isatuximab; Tumors sòlids 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. This work was sponsored by Sanofi (no grant number).
- Published
- 2022