A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Raf- Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors

1 The University of Texas MD Anderson Cancer Center, Houston, Texas. 2 Yale School of Medicine, New Haven, Connecticut. 3 Nektar Therapeutics, San Francisco, California. 4 Providence Cancer Institute and Earle A. Chiles Research Institute, Portland, Oregon. Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). S.-E. Bentebibel, M.E. Hurwitz, and C. Bernatchez contributed equally to this article. ABSTRACT NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor βγ to drive increased proliferation and activation of CD8 + T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this fi rst-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated 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 IL2 receptor pathway and signifi cantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.