1489 REStoring lymphoCytes using NKTR-255 after chemoradiothErapy in solid tumors (RESCUE): preplanned interim safety and efficacy analysis

<h3>Background</h3> Radiation induced lymphopenia (RIL) is common after chemoradiation therapy (CRT) and can reduce efficacy of immunotherapies. IL-15 is a pleiotropic cytokine with roles in innate and adaptive immunity and is essential for lymphocyte formation, immunological memory and cell survival. NKTR-255 is an investigational polymer-conjugated rhIL-15 receptor agonist with extended exposure and sustained activation of the IL-15 pathway. Here, we present a prespecified interim analysis of a Phase II study evaluating safety and PK of NKTR-255 for restoring absolute lymphocyte count (ALC) after CRT in locally advanced non-small cell lung cancer (LA-NSCLC). <h3>Methods</h3> NKTR-255 (3µg/kg) is given after CRT (day 0), with repeat doses given every 4 weeks concurrently with durvalumab up to 1 year. This trial is designed to enroll up to 30 patients with ongoing safety and futility analysis after the first 10 evaluable patients. The primary objectives are safety of NKTR-255 after CRT, incidence of treatment-related adverse events (TRAE) of Grade 3+ (G3) radiation pneumonitis, and ALC normalization after administration of NKTR-255 and durvalumab at Day 60 after CRT (figure 1). Early stopping rules are in place to control incidence of grade 3+ radiation pneumonitis, and futility monitoring for efficacy, defined as ALC recovery &gt;1000 cells/µL. <h3>Results</h3> As of September 5th, 2024, 15 enrolled patients received at least one dose of NKTR-255. Preliminary PK analyses showed a mean half-life of 32 hours with no accumulation after repeat dosing, consistent with prior studies. One patient developed G3 pneumonitis. Two patients had transient G3 liver enzyme elevation and 1 patient had transient G3 sinus tachycardia. The most common TRAEs were fever, chills, sinus tachycardia, ALT elevation and dyspnea. Among the enrolled 15 patients, 10 patients, who completed at least 2 doses of the study treatment and reached week 8 evaluation, are evaluable for ALC assessment. At week 8, ALC recovery was met for 9 evaluable patients and 1 patient had increased ALC from G2 to G1. This finding greatly exceeds the minimal success rate futility cutoff. At Cycle 1 day 8 (C1D8), the median increase in ALC was 2.35-fold (range 1.46–4.33) and at C2D8, it was 3.57-fold (range 1.84–8.09). <h3>Conclusions</h3> NKTR-255 after CRT was safe and biologically active in reverting RIL. These preliminary findings support the MOA of reversal of lymphopenia with NKTR-255. After meeting the initial safety and efficacy threshold, the trial continues accrual at MDACC (NCT05632809). <h3>Trial Registration</h3> NCT05632809. <h3>Ethics Approval</h3> All patients are consented to an institutional review board approved clinical trial protocol.