دورية أكاديمية
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
| العنوان: | 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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| المؤلفون: | Debbie Robbrecht, Jean‐Jacques Grob, Oliver Bechter, Matteo Simonelli, Bernard Doger, Ivan Borbath, Marcus O. Butler, Tina Cheng, Patricia Martin Romano, Elvire Pons‐Tostivint, Massimo Di Nicola, Giuseppe Curigliano, Min‐Hee Ryu, Alejo Rodriguez‐Vida, Dirk Schadendorf, Elena Garralda, Giovanni Abbadessa, Brigitte Demers, Amele Amrate, Hong Wang, Joon Sang Lee, Robert Pomponio, Rui Wang |
| المصدر: | Clinical and Translational Science, Vol 17, Iss 2, Pp n/a-n/a (2024) |
| بيانات النشر: | Wiley, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Therapeutics. Pharmacology LCC:Public aspects of medicine |
| مصطلحات موضوعية: | Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1752-8062 1752-8054 28412427 |
| العلاقة: | https://doaj.org/toc/1752-8054Test; https://doaj.org/toc/1752-8062Test |
| DOI: | 10.1111/cts.13736 |
| الوصول الحر: | https://doaj.org/article/28412427e6174db093de8737922fa32aTest |
| رقم الانضمام: | edsdoj.28412427e6174db093de8737922fa32a |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17528062 17528054 28412427 |
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| DOI: | 10.1111/cts.13736 |