Safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activities of FL115, a novel IL-15 superagonist, from the first-in-human study in patients with locally advanced/metastatic solid tumors.

3154 Background: FL115 is an engineered IL-15/IL15Rα-Fbody fusion protein, in which Fbody is a single-chain Fc designed to eliminate classical Fc effects including ADCC/CDC/ADCP while retaining FcRn engagement. It aims to enhance anti-tumor immunity via IL-15-mediated signaling on NK and CD8+ T cells while minimizing complexity from Fc. Methods: The first-in-human, dose-escalation study of FL115 (NCT06130722) evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of FL115 in adult patients with advanced solid tumors. FL115 monotherapy was administered intravenously once weekly. Results: 11 patients (7F, 4M) were enrolled, median age 64, who had progressed on prior systemic therapies across four dose cohorts (3–60 μg/kg). MTD was not reached. No SAEs related to FL115 or DLT were observed. Most TRAEs were Grade 1–2 and aligned with the known safety profile of cytokine-based therapies and underlying conditions of patients. Only three reversible TRAEs occurred, including transient Grade 3 alanine aminotransferase elevation, Grade 3 headache, and Grade 4 neutropenia. PK was dose-dependent, with half-life at 2.1-3.1 hours. Four patients had Stable Disease per imaging (DCR 36.3%). Dose-dependent expansion of lymphocytes was observed, with average absolute lymphocyte count (ALC) of 1257 cells/μl at baseline, and peak ALC count of 2371 cells/μl post treatment, mainly from increase in NK cells and CD8+T cells. One patient (Cervical Cancer) had Stable Disease from 1st dose at July 2024 (ALC of 1100 cells/μl) to study completion (ALC of 1900 cells/μl in August 2025). FL115 treatment led to significant transient cytokine release in peripheral blood: at 3 μg/kg, peak interferon-γ level reached 3730 pg/ml with IL-6 at 0.8 pg/ml, suggesting specific targeting of NK and T cells. An essentially identical Phase 1 study of FL115 was conducted in China, in which similar trends were observed; two patients remained on treatment with confirmed partial responses lasting 32 and 24 weeks, respectively. Conclusions: FL115 is the first IL-15 superagonist as monotherapy has shown a favorable safety profile and promising signs of durable antitumor activities in heavily pretreated patients, along with significant and sustained expansion of NK and T cell population and unique robust transient induction of interferon-γ. A Phase II study of FL115 with Bacillus Calmette-Guérin in patients with nonmuscle invasive bladder cancer (NCT07122414) and a Phase Ib study of FL115 (IV) in combination with an anti-PD-1 antibody in solid tumor patients (NCT07131202) are ongoing, and a Phase I study of FL115 subcutaneous injection will be initiated soon (IND submitted). Clinical trial information: NCT # 06130722 .