Scientific publications

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

Aug 17, 2022 | Magazine: ESMO Open

M Simonelli  1 , E Garralda  2 , F Eskens  3 , M Gil-Martin  4 , C-J Yen  5 , R Obermannova  6 , Y Chao  7 , S Lonardi  8 , B Melichar  9 , V Moreno  10 , M-L Yu  11 , A Bongiovanni  12 , E Calvo  13 , S Rottey  14 , J-P Machiels  15 , A Gonzalez-Martin  16 , L Paz-Ares  17 , C-L Chang  18 , W Mason  19 , C-C Lin  20 , D A Reardon  21 , M Vieito  2 , A Santoro  22 , R Meng  23 , G Abbadessa  23 , F Menas  24 , H Lee  23 , Q Liu  23 , C Combeau  24 , N Ternes  24 , S Ziti-Ljajic  24 , C Massard  25

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.

CITATION  ESMO Open. 2022 Oct;7(5):100562.  doi: 10.1016/j.esmoop.2022.100562. Epub 2022 Aug 18.