Background HEK-NIZ985 (NIZ985) is a recombinant heterodimer of IL-15/IL-15Rα that expands effector lymphocytes and antitumor activity in animal models and a human clinical trial. We report interim data from the first-in-human study of NIZ985.

Methods CNIZ985X2102J is an open-label Phase I/Ib dose-escalation/expansion trial evaluating the safety of subcutaneous NIZ985 three-times-weekly (TIW; 2-weeks-on/2-weeks-off) or once-weekly (QW; 3-weeks-on/1-week-off) as a single agent (SA) or in combination (CM) dosing with 400 mg of the PD-1 inhibitor spartalizumab every 4 weeks, in adults with metastatic/unresectable solid tumors. SA dosing was 0.25–4 µg/kg TIW or 2–10 µg/kg QW; CM dosing was 1 µg/kg TIW or 2–4 µg/kg QW. The primary objective was to characterize the safety and tolerability of NIZ985 ± spartalizumab. Data are presented for dose escalation, and CM-TIW expansion.

Results Overall, 83 patients entered dose escalation (n=47) or CM-TIW expansion (n=36), of whom 63.8% (30/47) and 69.4% (25/36), respectively, had received ≥3 prior lines of antineoplastic treatment. At data cut-off (March 2, 2020), 91.6% (76/83) had discontinued study treatment. Adverse events (AEs) are summarized below (table 1). There were no dose-limiting toxicities during the first 28-day cycle in any cohort. Systemic skin AEs (Cycle 2) occurred in three SA-TIW patients receiving 2 or 4 µg/kg (bullous pemphigoid, purpura, vasculitis), limiting TIW escalation and initiating QW dose exploration; these were not observed at 1 µg/kg TIW (± spartalizumab) or for QW doses up to 10 µg/kg. CM-TIW dose expansion was therefore at 1 µg/kg; the recommended QW expansion dose is currently undetermined. For SA NIZ985, best overall response (RECIST 1.1) was stable disease (SD; 8/27 patients [29.6%]). Objective responses for NIZ985 plus spartalizumab (3/56 partial response [PR; 5.3%], 15/56 SD [26.8%]) occurred in both immuno-oncology treatment (IO)-naïve and IO-experienced patients, including 5/8 IO-experienced melanomas (cutaneous: 3 SD, 1 PR; uveal: 1 SD). Systemic NIZ985 exposure was approximately dose-proportional after first dose for ≥1 µg/kg TIW and <10 µg/kg QW, with time-dependent clearance without accumulation. Proliferation of peripheral CD8+ and NK lymphocytes, and increased inflammatory cytokines, were observed for both dosing schedules.

Conclusions NIZ985 is safe and tolerable at both TIW and QW dosing ± spartalizumab. It displays approximately dose-proportional, time-dependent PK, and a biomarker and lymphocyte response profile consistent with target engagement. Limited antitumor activity was reported during dose escalation; however, preliminary responses in both IO-experienced and IO-naïve patients were seen in combination with spartalizumab that warrant further investigation.

Ethics Approval The study was approved by an independent ethics committee and/or institutional review board at each participating site.