| Title: |
Biomarker and pharmacodynamic activity of the transforming growth factor-beta (TGFβ) inhibitor SAR439459 as monotherapy and in combination with cemiplimab in a phase I clinical study in patients with advanced solid tumors |
| Authors: |
Robbrecht, Debbie; Grob, Jean-Jacques; Bechter, Oliver; Simonelli, Matteo; Doger, B.; Borbath, Ivan; Doger, B; GARRALDA, Elena |
| Contributors: |
Institut Català de la Salut; Robbrecht D Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. Grob JJ Dermatology and Oncology Service, Aix Marseille University and Timone Hospital, Marseille, France. Bechter O Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Leuven, Belgium. Simonelli M Department of Biomedical Science, Humanitas University, Milan, Italy. Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy. Doger B START Madrid-FJD, Early Phase Clinical Trials Unit, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain. Borbath I Department of Hepatogastroenterology, Cliniques Universitaires SaintLuc, Université Catholique de Louvain, Brussels, Belgium. Garralda E Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Vall d'Hebron Barcelona Hospital Campus |
| Source: |
Scientia |
| Publisher Information: |
Wiley |
| Publication Year: |
2024 |
| Subject Terms: |
Anticossos monoclonals - Ús terapèutic; Càncer - Tractament; Factors de creixement - Inhibidors; CHEMICALS AND DRUGS::Amino Acids; Peptides; and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Transforming Growth Factor beta; Other subheadings::Other subheadings::Other subheadings::/antagonists & inhibitors; DISEASES::Neoplasms; and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies; Monoclonal; COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos; péptidos y proteínas::péptidos::péptidos y proteínas de señalización intercelular::citocinas::factor de crecimiento transformador beta; Otros calificadores::Otros calificadores::Otros calificadores::/antagonistas & inhibidores; ENFERMEDADES::neoplasias; péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos monoclonales |
| Description: |
Pharmacodynamic; Transforming growth factor-beta; Advanced solid tumors ; Farmacodinámica; Factor de crecimiento transformante beta; Tumores sólidos avanzados ; Farmacodinàmica; Factor de creixement transformador beta; Tumors sòlids avançats ; SAR439459, a ‘second-generation’ human anti-transforming growth factor-beta (TGFβ) monoclonal antibody, inhibits all TGFβ isoforms and improves the antitumor activity of anti-programmed cell death protein-1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first-in-human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose-escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose-expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFβ, downregulation of TGFβ-pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from ‘immune-excluded’ to ‘immune-infiltrated’ phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFβ1 was more consistently elevated followed by TGFβ2, whereas TGFβ3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFβ alteration. However, further studies are needed to identify biomarkers of ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Clinical and Translational Science;17(2); https://doi.org/10.1111/cts.13736; https://hdl.handle.net/11351/11109 |
| DOI: |
10.1111/cts.13736 |
| Availability: |
https://hdl.handle.net/11351/11109; https://doi.org/10.1111/cts.13736 |
| Rights: |
Attribution-NonCommercial-NoDerivatives 4.0 International ; http://creativecommons.org/licenses/by-nc-nd/4.0/ ; info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.4D7262AF |
| Database: |
BASE |