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

• Published in: Journal for immunotherapy of cancer Vol. 8; no. Suppl 3; pp. A224 - A225
• Main Authors: Diab, Adi, Curti, Brendan, Bilen, Mehmet, Brohl, Andrew, Domingo-Musibay, Evidio, Borazanci, Erkut, Fanton, Christie, Haglund, Cat, Vimal, Mona, Muhsin, Mann, Marcondes, Mario, Nguyen, Anh, Tagliaferri, Mary, Lin, Wei, Zalevsky, Jonathan, D’Angelo, Sandra
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 01.11.2020; BMJ Publishing Group
• Subjects: Antigens; Immunotherapy; Melanoma; Metastasis; Tumors
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2020-SITC2020.0368

BackgroundNKTR-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.MethodsThis 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.ResultsAs 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.ConclusionsNKTR-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 RegistrationNCT03435640Ethics ApprovalThe study was approved by the institutional review board of each participating site.