RT Journal Article SR Electronic T1 386 Phase I/Ib first-in-human study of HEK-NIZ985, a recombinant IL-15/IL-15Rα heterodimer, alone and in combination with spartalizumab, in adults with advanced and metastatic solid tumors JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP A234 OP A235 DO 10.1136/jitc-2020-SITC2020.0386 VO 8 IS Suppl 3 A1 Rom Leidner A1 Andrea Wang-Gillam A1 Sumati Gupta A1 Robert Wesolowski A1 Douglas McNeel A1 Kevin Conlon A1 Nehal Parikh A1 Jessica O’Keeffe A1 Niladri Roy Chowdhury A1 Xiaoli Wang A1 Ryan Sullivan A1 John Thompson YR 2020 UL http://jitc.bmj.com/content/8/Suppl_3/A234.abstract AB 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.View this table:Abstract 386 Table 1 Adverse event summaryConclusions 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.