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NKTR-255 Vs Placebo to Enhance Complete Responses and Durability Following CD19-Directed CAR-T Therapy in Patients with Relapsed/ Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Year: 2025

Type: article

Study designs: Randomized Controlled Trial, Clinical Trial

Abstract: CD19-directed chimeric antigen receptor (CAR) have high response rates in refractory large B-cell lymphoma (LBCL). However, more than half of patients fail to achieve remission and/or relapse. Thus, strategies to improve efficacy of CAR-T cell products are needed. NKTR-255 is an investigational polymer-conjugated IL-15 agonist that activates, proliferates and expands CD8+T and NK cells, as well as promote creation of memory CD8+ T cells. Clinical studies with NKTR-255 have shown expansion of CAR-T and CD8+T cells in R/R NHL patients who previously received CAR-T therapy (NCT04136756), and CAR-T trafficking to the tumor microenvironment (Muffly, 2024; NCT03233854). Here, we describe results of a Phase 2 trial evaluating NKTR-255 in combination with CAR-T therapy (NCT05664217). This is a phase 2 randomized, double-blind, placebo-controlled study of NKTR-255 vs placebo following one of two FDA-approved CAR-T products (axicabtagene-ciloleucel or lisocabtagene-maraleucel). Eligible patients with R/R LBCL received study drug intravenously starting +14 days following CAR-T infusion for up to 5 months. Primary endpoint was complete response rate (CRR) by blinded independent central review (BICR) at month 6 after CD19-CAR-T cells. Efficacy was assessed by PET-CT according to Lugano. Key secondary and exploratory objectives included safety/tolerability, NKTR-255 PK and CAR-T PD quantified by flow-cytometry. 15 patients with LBCL were randomized between Mar and Dec 2023. All patients received CD19-CAR-T cell therapy and ≥1 dose of study treatment; 12/15 (80%) received axi-cel and 3/15 (20%) received liso-cel. In total, 11 were randomized to the NKTR-255 (5 at 1.5 µg/kg; 3 at 3 µg/kg; 3 at 3 µg/kg then 6 µg/kg cycle 2+) and 4 were randomized to placebo. LDH and histology were similar between both groups, except tumor burden (NKTR-255 median 1408 vs 940 mm 2 placebo). NKTR-255 following CAR-T was well-tolerated. Among 11 who received NKTR-255, infusion-related reaction (IRR) and fever were reported in 2/11 (18%) and 3/11 (27%) pts, respectively; all were grade 1/2 and resolved in 24 hrs. The most common grade ≥3 TRAEs with NKTR-255 in >1 patient was decreased neutrophil count 5/11 (46%), platelet count 2/11 (18%), and lymphocyte count 2/11 (18%); all resolved. Per intent-to-treat, the CRR at month 6 for NKTR-255 was 8/11 (73%) vs 2/4 (50%) with placebo. Per response-evaluable analysis, CRR at month 6 for NKTR-255 was 8/10 (80%) vs 2/4 (50%) with placebo. Re-expansion of CD8+CAR-T cells occurred in 8/11 (73%) for NKTR-255. Additional PD analyses will be presented. Preliminary data of NKTR-255 adjuvant to CD19-CAR-T cell therapy in LBCL was well-tolerated, safe and demonstrated superior CR rate compared to CD19-CAR-T cell therapy alone at 6-months. Confirmatory studies with NKTR-255 adjuvant to CAR-T therapy and other cellular therapies are warranted.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.021