2026-04-13T06:39:21Zhttps://recercat.cat/oai/requestoai:recercat.cat:11351/111092024-06-06T08:40:35Zcom_2072_378070com_2072_378040col_2072_378092
RECERCAT
author
Robbrecht, Debbie
author
Grob, Jean-Jacques
author
Bechter, Oliver
author
Simonelli, Matteo
author
Doger, B.
author
Borbath, Ivan
author
Doger, B
author
GARRALDA, Elena
2024-06-06T08:40:35Z
2024-06-06T08:40:35Z
2024-02-23T12:40:45Z2024-02-23T12:40:45Z2024-02
http://hdl.handle.net/11351/11109
Pharmacodynamic; Transforming growth factor-beta; Advanced solid tumorsFarmacodinámica; Factor de crecimiento transformante beta; Tumores sólidos avanzadosFarmacodinàmica; Factor de creixement transformador beta; Tumors sòlids avançatsSAR439459, 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 response.This study was sponsored by Sanofi.
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess
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
CHEMICALS AND DRUGS::Amino Acids, Peptides, 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
COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos monoclonales
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
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion