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368 REVEAL: Phase 1 dose-escalation study of NKTR-262, a novel TLR7/8 agonist, plus bempegaldesleukin: local innate immune activation and systemic adaptive immune expansion for treating solid tumors
  1. Adi Diab1,
  2. Brendan Curti2,
  3. Mehmet Bilen3,
  4. Andrew Brohl4,
  5. Evidio Domingo-Musibay5,
  6. Erkut Borazanci6,
  7. Christie Fanton7,
  8. Cat Haglund7,
  9. Mona Vimal7,
  10. Mann Muhsin7,
  11. Mario Marcondes7,
  12. Anh Nguyen7,
  13. Mary Tagliaferri7,
  14. Wei Lin7,
  15. Jonathan Zalevsky7 and
  16. Sandra D’Angelo8
  1. 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2Providence Cancer Center and Earle A. Chiles Research Institute, Portland, OR, USA
  3. 3Winship Cancer Institute of Emory University, Atlanta, GA, USA
  4. 4H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  5. 5University of Minnesota Medical Center, Minneapolis, MN, USA
  6. 6HonorHealth Research Institute, Scottsdale, AZ, USA
  7. 7Nektar Therapeutics, San Francisco, CA, USA
  8. 8Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA


Background NKTR-262 is a small-molecule agonist of toll-like receptors (TLR) 7/8. Given by intratumoral (IT) injection, NKTR-262 is retained within the tumor microenvironment (TME) and promotes an immunostimulatory milieu and tumor antigen release. Bempegaldesleukin (BEMPEG) is a CD122-preferential IL-2 pathway agonist, which increases proliferation and tumor infiltration of CD8+ T cells and natural killer (NK) cells. Preclinically, NKTR-262 plus BEMPEG combined innate immune signaling and enhanced antigen presentation, with sustained T-cell activation, resulting in tumor growth inhibition of treated and abscopal lesions.

Methods This phase 1 dose-escalation study enrolled patients with relapsed/refractory, advanced/metastatic solid tumors (REVEAL; NCT03435640). Patients received escalating doses of NKTR-262 (0.03 mg to 3.84 mg IT) followed 3 weeks‘ later by BEMPEG (0.006 mg/kg IV) q3wk utilizing a 3+3 design. The primary endpoint was safety and tolerability, including definition of the recommended phase 2 dose (RP2D). Other endpoints included antitumor activity, pharmacodynamics, and pharmacokinetics.

Results As of June 15, 2020, 36 patients were enrolled. One dose-limiting toxicity, transient transaminase elevation, was observed at the highest NKTR-262 dose (3.84 mg). The most frequent treatment-related adverse events were flu-like symptoms, fatigue, nausea, and pruritus, consistent with the known profile of BEMPEG. Early evidence of clinical activity was observed in patients with metastatic melanoma, with a disease control rate (partial response [PR] + stable disease) of 41.2% (7/17 patients), including two patients with PRs after progression on two prior immunotherapy regimens. Preliminary analyses showed dose-dependent induction of CXCL10 and type 1 interferon genes, consistent with TLR7/8 engagement. CD11c+ target cells were significantly more abundant in baseline melanoma biopsies than other tumor types (p<0.001). Induction of TLR7/8-responsive genes correlated with CD11c+ baseline density (p<0.05). Minimal TLR7/8-dependent changes in immune cell subsets or inflammatory cytokines were observed in peripheral blood, reflecting favorable TME modifications driven by retention of NKTR-262. Increased activation of CD4+, CD8+, and NK cells in blood were observed, consistent with BEMPEG mechanism of action.

Conclusions NKTR-262 plus BEMPEG led to engagement of the entire immune activation cascade required for systemic tumor clearance. Robust TLR7/8 engagement supported the NKTR-262 mechanism of action, while the minimal toxicity profile underscored the benefit of local delivery of NKTR-262, and the BEMPEG combination induced systemic activation of T and NK cells. These data support the RP2D of NKTR-262 (3.84 mg IT) plus BEMPEG (0.006 mg IV) q3w, and the initiation of the phase 1b dose-expansion phase, which is exploring concurrent dosing, with or without nivolumab, in relapsed/refractory metastatic melanoma patients.

Trial Registration NCT03435640

Ethics Approval The study was approved by the institutional review board of each participating site.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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