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.

Clínica Universidad de Navarra Madrid and Program in Solid Tumors Center for Applied Medical Research Pamplona

Cliniques Universitaires Saint Luc Brussels Belgium

Dana Farber Cancer Institute Harvard University Boston

Department of Biomedical Sciences Humanitas University Pieve Emanuele Italy; Vall d'Hebron Institute of Oncology Barcelona Spain

Department of Obstetrics and Gynecology Mackay Memorial Hospital Taipei Taiwan

Department of Oncology Palacky University Olomouc Czech Republic

Department of Oncology Taipei Veterans General Hospital Taipei Taiwan

Erasmus MC Cancer Institute Rotterdam the Netherlands

Ghent University Ghent

Gustave Roussy Villejuif France

Hepatobiliary Division Department of Internal Medicine and Hepatitis Center Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Taiwan

Hospital Universitario 12 de Octubre Madrid Spain

Institut Català d'Oncologia IDIBELL L'Hospitalet Barcelona Spain

IRCCS Humanitas Research Hospital Rozzano Italy; Department of Biomedical Sciences Humanitas University Pieve Emanuele Italy

IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori Meldola Italy

Masaryk Memorial Cancer Institute Brno Czech Republic

National Cheng Kung University Tainan Taiwan

National Taiwan University Hospital Taipei Taiwan

Princess Margaret Cancer Centre Toronto Canada

Sanofi Cambridge USA

Sanofi Chilly Mazarin France

START Madrid CIOCC Centro Integral Oncológico Clara Campal Madrid Spain

START Madrid FJD Hospital Fundación Jiménez Díaz Madrid Spain

Vall d'Hebron Institute of Oncology Barcelona Spain

Veneto Institute of Oncology IOV IRCCS Padova Italy

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ClinicalTrials.gov
NCT03637764