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

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• dc.contributor.author Robbrecht, Debbie
• dc.contributor.author Rodriguez-Vida, Alejo
• dc.contributor.author Wang, Rui
• dc.date.accessioned 2024-10-11T06:19:36Z
• dc.date.available 2024-10-11T06:19:36Z
• dc.date.issued 2024
• dc.description.abstract 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 response.
• dc.format.mimetype application/pdf
• dc.identifier.citation Robbrecht D, Grob JJ, Bechter O, Simonelli M, Doger B, Borbath I, et al. 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. Clin Transl Sci. 2024 Feb;17(2):e13736. DOI: 10.1111/cts.13736
• dc.identifier.doi http://dx.doi.org/10.1111/cts.13736
• dc.identifier.issn 1752-8054
• dc.identifier.uri http://hdl.handle.net/10230/61373
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof Clin Transl Sci. 2024 Feb;17(2):e13736
• dc.rights © 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.other Tumors
• dc.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
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion