Biomarker and pharmacodynamic activity of the transforming growth factor-beta (TGF) inhibitor SAR439459 as monotherapy and in combination with cemiplimab in a phase I clinical study in patients with advanced solid tumors

SAR439459, a 'second-generation' human anti-transforming growth factor-beta (TGF beta) monoclonal antibody, inhibits all TGF beta 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 TGF beta, downregulation of TGF beta-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 TGF beta 1 was more consistently elevated followed by TGF beta 2, whereas TGF beta 3 was only measurable (lower limit of quantitation >= 2.68 pg/mg) in tumors. SAR439459 +/- cemiplimab showed expected peripheral PD effects and TGF beta alteration. However, further studies are needed to identify biomarkers of response.