A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors

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-inhuman 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. SIGNIFICANCE: We believe that IL2-and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors. See related commentary by Sullivan, p. 694.

Role of Immunotherapy in Triple-Negative Breast Cancer

“…One such strategy is the IL-2 pathway agonist bempegaldesleukin (NKTR-214), which preferentially activates the IL-2b receptor to expand effector T cells more than regulatory T cells. [52][53][54] The phase I/II PIVOT-02 trial (ClinicalTrials.gov identifier: NCT02983045) evaluated 38 patients with mTNBC treated with bempegaldesleukin in combination with nivolumab and found an ORR of 13.2%, with durable responses regardless of PD-L1 expression ( Table 4). Future trials of bempegaldesleukin combined with anti-PD-1/L1 therapies and chemotherapy in TNBC are currently being developed.…”

Immune regulation and cytotoxic T cell activation of IL-10 agonists – Preclinical and clinical experience

“…In patients, Pegilodecakin did not induce significant changes in the overall lymphocyte counts and the number of regulatory T cells or widespread NK and T cell proliferation [52]. This is in contrast to therapies using IL-2 [100] or pegylated IL-2 [85], which induce transient lymphopenia followed proliferation and expansion of CD4 + T cells and Tregs, CD8 + T cells and NK cells. Rather, on pegilodecakin, the percentage of proliferating PD-1 + Lag-3 + CD8 + T cells increased in the peripheral blood.…”

“…In contrast, high dose IL-2 is reserved for previously not treated patients and is not expected to have responses in pretreated RCC patients. Similarly, a pegylated from of IL-2 (NKTR-214), did not have single agent objective tumor response in pretreated, advanced RCC patients [85] (established and emerging treatments for RCC are also discussed in [86]).…”

Bempegaldesleukin (NKTR-214): a CD-122-biased IL-2 receptor agonist for cancer immunotherapy

“…Despite the increases in Tregs in the periphery with bempegaldesleukin administration, expansion of these cells was limited or absent in the tumor. Preclinical evidence from mouse tumor models indicates that bempegaldesleukin limits intratumoral Treg proliferation and survival by way of promoting apoptosis, thereby polarizing the TME toward CD8 + T cells and consequently driving a very high CD8+/Treg ratio [21][22][23]. MDSC and other immunosuppressive immune subsets in the TME, which are likely not affected by bempegaldesleukin, may continue to negatively regulate anti-tumor immune responses.…”