A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL-2-Receptor Beta/Gamma (βγ)-Biased Cytokine, in Patients With Advanced or Metastatic Solid Tumors

NKTR-214 (bempegaldesleukin) is a novel IL-2 pathway agonist, designed to provide sustained signaling through heterodimeric IL-2-Receptor Beta/Gamma to drive increased proliferation and activation of CD8+ T and NK cells without unwanted expansion of T regulatory cells (Tregs) in the tumor microenvironment. In this first-in-human multicenter phase 1 study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily treated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL-2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase 2 dose was determined to be 0.006 mg/kg q3w.