CSF1R Inhibition in Patients with Advanced Solid Tumors or Tenosynovial Giant Cell Tumor: A Phase I Study of Vimseltinib

作者：Hans Gelderblom, Albiruni Abdul Razak, Matthew H. Taylor, Todd M. Bauer, Breelyn A. Wilky, Javier Martín‐Broto, Alejandro Falcón, Piotr Rutkowski, Bartłomiej Szostakowski, Thierry Alcindor, Ramy Saleh, Sofia Genta, Silvia Stacchiotti, Michiel A. J. van de Sande, Andrew J. Wagner, Nicholas M. Bernthal, Lara E. Davis, Jacqueline Vuky, Christopher Tait, Bahar Matin, Supraja Narasimhan, Maitreyi G. Sharma, Rodrigo Ruiz‐Soto, Matthew L. Sherman, William D. Tap · 发表于：Clinical Cancer Research · 年份：2024 · DOI：10.1158/1078-0432.ccr-24-0103 · 被引用次数：29 · 研究领域：Musculoskeletal synovial abnormalities and treatments、Bone Tumor Diagnosis and Treatments、Sarcoma Diagnosis and Treatment

PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. PATIENTS AND METHODS: This first-in-human, multicenter, open-label phase I/II study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase II dose, and characterize the pharmacokinetics; exploratory objectives included pharmacodynamics and efficacy. RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were of grade 1/2 severity. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The recommended phase II dose was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7-46.9), and the objective response rate as assessed by independent radiological review using RECIST ...