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782-I Phase I dose escalation of SAR445710, a PDL1-IL15 targeted cytokine in metastatic and/or advanced solid tumors
  1. Jason Luke1,
  2. Anthony J Olszanski2,
  3. Lee Rosen3,
  4. Ahmad A Tarhini4,
  5. Adyb Baakili5,
  6. Timothy Wagenaar6,
  7. Chen Zhu6,
  8. Helene Guillemin-Paveau7,
  9. Meijing Wu6,
  10. Raymond Perez8,
  11. Giovanni Abbadessa6 and
  12. Christos Fountzilas9
  1. 1UPMC Hillman Cancer Center, Pittsburgh, PA, USA
  2. 2Fox Chase Cancer Center, Philadelphia, PA, USA
  3. 3UCLA Division of Hematology-Oncology, Los Angeles, CA, USA
  4. 4H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  5. 5Sanofi-Aventis, Vitry-sur-Seine, France
  6. 6Sanofi, Cambridge, MA, USA
  7. 7Sanofi, Paris, Chilly-Mazarin, France
  8. 8Sanofi, Pennington, NJ, USA
  9. 9Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background SAR445710 is a targeted cytokine comprised of a fusion antibody combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL-15Rα) sushi domain and human IL-15. SAR445710 and its mouse cross-reactive surrogate molecule have been extensively characterized by in vitro and in vivo studies and demonstrated robust efficacy and therapeutic benefits compared to IL-15 alone. Specifically, SAR445710, potentially leverages PD-L1 targeting to deliver IL-15 to the tumor microenvironment.

Methods This was a phase 1, open-label, multiple ascending dose, multi-center study in patients with metastatic or locally advanced solid tumors (NCT04242147). Dose escalation followed a ‘3+3’ design with the occurrence of dose limiting toxicity (DLT) evaluated over the first 28 days. Bi-weekly (Q2W) and weekly (QW) dosing schedules were evaluated at doses ranging from 3–400 μg/kg (Q2W) and 50–300 μg/kg (QW). The primary objective was to assess the safety and tolerability of SAR445710 monotherapy.

Results As of July 31, 2023, 39 patients (median age, 61.5 years, and 46.15% females) were treated in dose escalation with 27 patients on Q2W schedule and 12 on QW schedule. There were three DLTs in the Q2W dose escalation, two Grade 3 cytokine release syndrome at 400 μg/kg and one Grade 3 pneumonitis at 200 μg/kg. No DLTs were observed in the QW schedule. The maximum tolerated dose (MTD) in the Q2W schedule was 200 μg/kg. Pyrexia (57.1%) and chills (42.9%) were the most common treatment-related adverse events. These were mostly Grade 1–2 that resolved with supportive management. Best overall response achieved among the Q2W and QW schedules was stable disease. On-target and expected pharmacodynamics for IL-15 agonisms were observed. SAR445710 had a potent effect on peripheral NK and CD8 T cell expansion. Ki67 expression in NK and T cells peaked on day 2 to day 3 post-treatment. There was no clear sign that T cells developed an exhaustion phenotype after repeated SAR445710 dosing. SAR445710 showed a non-linear pharmacokinetic profile from 3–400 µg/kg (Q2W), as expected for targeted antibodies. Enrolment continues in the QW schedule.

Conclusions SAR445710 demonstrated a manageable toxicity profile with on-mechanism pharmacodynamics consistent with IL-15 agonism.

Acknowledgements This study is funded by Sanofi. Medical writing support was provided by Latika Saxena of Sanofi.

Trial Registration NCT04242147

Ethics Approval This study obtained ethics approval from WIRB.

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