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2068 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)

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase Clinical Trials and Toxicities: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Sairah Ahmed, MD1, John F. DiPersio, MD, PhD2, James H Essell, MD3, Catherine S. Diefenbach4, Miguel Angel Perales, MD5, Cristina Castilla-Llorente, MD6*, Saurabh Dahiya, MD7, Sohail Chaudhry, MD, PhD8*, Heng Xu, PhD8*, Yi Liu, PhD8*, Christie Fanton, PhD8*, Zachary Lee, PharmD8*, Mario Q. Marcondes, MD, PhD9, Mary Tagliaferri, MD8*, Jonathan Zalevsky, PhD8*, David B. Miklos, MD, PhD7, Cameron J. Turtle, MBBS, PhD10,11* and Joseph P. McGuirk, DO12

1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
2Division of Oncology, Washington University School of Medicine, Saint Louis, MO
3Oncology/Hematology Care, Cincinnati, OH
4Perlmutter Cancer Center, NYU Langone Health, New York, NY
5Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
6Gustave Roussy Cancer Campus, Villejuif, France
7Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Palo Alto, CA
8Nektar Therapeutics, San Francisco, CA
9Nektar Therapeutics, Millbrae, CA
10Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA
11University of Sydney, Sydney, NSW, Australia
12Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS

Background: Autologous T cells engineered to express CD19-directed chimeric antigen receptor (CAR) have shown high overall response rates in treatment-refractory large B-cell lymphoma (LBCL). However, more than half of patients fail to achieve remission or will eventually relapse. Thus, strategies to improve long-term efficacy of CAR-T cell products are needed. NKTR-255 is an investigational polymer-conjugated IL-15 agonist, that activates, proliferates and expands natural killer and CD8+ T-cells in vivo, as well as promote the survival and expansion of memory CD8+ T cells. Preclinical data in B-cell lymphoma xenograft models have shown that NKTR-255 enhanced proliferation, survival, and anti-tumor activity of human CD19 CAR-T cells (Hirayama, 2023). Further, clinical studies have shown that NKTR-255 expanded CAR-T and CD8+ T cells in patients with R/R NHL who previously received CAR-T therapy (NCT04136756), and enhanced CAR-T cell trafficking to the tumor microenvironment (Muffly, 2024; NCT03233854). Here, we describe results of the Phase 2 dose exploration trial evaluating NKTR-255 to enhance complete responses and durability of CD19 CAR-T therapy (NCT05664217).

Methods: This is a phase 2 randomized, double-blind, placebo-controlled, multicenter study of NKTR-255 vs placebo following CD19 CAR-T therapy. Eligible patients with R/R LBCL were treated with one of two FDA-approved CAR-T products (axicabtagene ciloleucel or lisocabtagene maraleucel). Patients received study drug intravenously starting +14 days following CAR-T infusion, with continued dosing every 21 days for up to 5 months. The primary endpoint was complete response rate (CRR) by blinded independent central review (BICR) at month 6 after CD19 CAR-T cells with NKTR-255 compared with placebo. Efficacy was assessed by PET-CT reported according to Lugano Response Criteria 2014. Key secondary and exploratory objectives included safety/tolerability, NKTR-255 PK and CAR-T PD. CAR-T cells were quantified by flow and ddPCR. Treatment related adverse events (TRAEs) were reported from the start of NKTR-255 treatment.

Results: A total of 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 preceding NKTR-255 or placebo. In total, 11 were randomized to the NKTR-255 group (5 at 1.5 µg/kg; 3 at 3.0 µg/kg; 3 at 3 µg/kg then 6 µg/kg cycle 2+) and 4 were randomized to placebo. LDH and histology was similar between the NKTR-255 and placebo groups, with the exception of tumor burden (NKTR-255 group median 1408 vs 940 mm2 for placebo). Treatment with NKTR-255 following CAR-T was well-tolerated. Among the 11 who received NKTR-255, infusion-related reaction (IRR) and fever was reported in 2/11 (18%) and 3/11 (27%) pts, respectively; these occurred ~6-8 hrs after infusion, all were grade 1/2 and resolved within 24 hrs with supportive care alone. No IRR or fever was reported with placebo. The most common grade ≥3 TRAEs reported with NKTR-255 in >1 patient was neutrophil count decrease 5/11 (46%), platelet count decrease 2/11 (18%), and lymphocyte count decrease 2/11 (18%); all resolved with no clinical sequelae. One patient had a grade 5 event of Guillain-Barré-syndrome on axi-cel with symptoms beginning prior to NKTR-255 and was deemed not related to study treatment by an independent DMC. Per intent-to-treat and BICR efficacy, the CRR at month 6 for the NKTR-255 group was 8/11 (73%) vs 2/4 (50%) with placebo. Per investigator, the conversions rate from SD/PR to CR at month 6 for the NKTR-255 group was 2/8 (25%) vs 0/2 (0%) with placebo. Per response-evaluable population by Investigator assessment, CRR at month 6 for the NKTR-255 group was 8/10 (80%) vs 2/4 (50%) with placebo. Notable re-expansion of CD8+ CAR-T cells occurred in 8/11 (73%) for NKTR-255 group vs 0/4 (0%) with placebo. NKTR-255 PK results were consistent with prior reported data. Additional longitudinal correlative analyses will be presented at the meeting.

Conclusions: Preliminary data from the randomized, double-blind, placebo-controlled study showed NKTR-255 adjuvant to CD19 CAR-T cell therapy in LBCL was well-tolerated, safe and efficacious to enhance the CR rate of CD19 CAR-T cell therapy alone at month 6. Additional confirmatory studies with NKTR-255 as adjuvant treatment to CAR-T therapy and other cellular therapies are warranted.

Disclosures: Ahmed: Janssen: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Nektar: Research Funding; Myeloid Therapeutics: Consultancy; Merck: Research Funding; Xencor: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Consultancy. DiPersio: NeoImmune Tech: Research Funding; Macrogenics: Research Funding; Bioline Rx: Research Funding; hC Bioscience, Inc.: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy; SPARC: Consultancy; RiverVest Venture Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Current equity holder in private company, Research Funding; Magenta Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Essell: Canopy Care: Current equity holder in private company; Genmab: Speakers Bureau; AbbVie: Speakers Bureau; Kite: Speakers Bureau; BMS: Consultancy, Speakers Bureau. Diefenbach: NYU Grossman School of Medicine/Perlmutter Cancer Center at NYU Langone Health: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company; OverT Therapeutics: Current equity holder in private company; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Celgene: Consultancy; FATE Therapeutics: Research Funding; Genentech/Roche: Consultancy, Research Funding; Genmab: Consultancy; I MAB: Consultancy; Incyte: Consultancy, Research Funding; MEI Pharma: Research Funding; Merck: Consultancy, Research Funding; Millenium: Research Funding; MorphoSys: Consultancy; Seattle Genetics: Consultancy, Research Funding. Perales: Omeros: Consultancy, Current equity holder in publicly-traded company; Merck: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Vor Biopharma: Consultancy; AbbVie: Honoraria; Sanofi: Consultancy; Allogene: Consultancy, Research Funding; Syncopation: Consultancy; Allovir: Consultancy; Nektar Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Sellas: Other: DSMB member; Cidara Therapeutics: Other: DSMB member; Caribou Biosciences: Consultancy; Adicet: Consultancy; OrcaBio: Consultancy, Current holder of stock options in a privately-held company; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; VectivBio AG: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Astellas: Honoraria; Karyopharm: Honoraria; MorphoSys: Honoraria; Takeda: Honoraria; Medigene: Other: DSMB member; Servier: Other: DSMB member. Dahiya: Kite/Gilead, BMS, Incyte, Adaptive biotechonologies: Consultancy. Chaudhry: Nektar Therapeutics: Current Employment, Current equity holder in publicly-traded company. Xu: Nektar Therapeutics: Current Employment, Current equity holder in publicly-traded company. Liu: Nektar Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fanton: Nektar Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lee: Nektar Therapeutics: Current Employment, Current equity holder in publicly-traded company. Marcondes: Nektar Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tagliaferri: Nektar Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zalevsky: Nektar Therapeutics: Current Employment, Current equity holder in publicly-traded company. Miklos: Fosun Kite Biotechnology: Honoraria; Janssen: Consultancy, Patents & Royalties; Adaptive Biotechnologies: Research Funding; Allogene: Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel Support, Research Funding; Juno Therapeutics: Consultancy; 2SeventyBio: Research Funding; Novartis: Consultancy; Miltenyi: Consultancy, Research Funding; Galapagos: Consultancy; Adicet: Research Funding; Bristol Myers Squibb: Consultancy. Turtle: ArsenalBio: Current holder of stock options in a privately-held company; Cargo Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Kyverna: Membership on an entity's Board of Directors or advisory committees; Advesya: Membership on an entity's Board of Directors or advisory committees; Celgene, a BMS company: Membership on an entity's Board of Directors or advisory committees; Boxer Capital: Consultancy; Prescient Therapeutics: Consultancy; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Juno Therapuetics, a BMS company: Research Funding; Abbvie: Consultancy; Myeloid Therapeutics: Current holder of stock options in a privately-held company; Nektar Therapeutics: Research Funding; IGM Biosciences: Consultancy; eGlint: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ArsenalBio: Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Current holder of stock options in a privately-held company; Differentia Bio: Membership on an entity's Board of Directors or advisory committees; Century Therapeutics: Consultancy. McGuirk: CRISPR therapeutics: Consultancy; Sana technologies: Consultancy; Caribou bio: Consultancy; Legend biotech: Consultancy; Autolus: Consultancy; NEKTAR therapeutics: Consultancy; Envision: Consultancy; Allo Vir: Consultancy; Novartis: Consultancy; Kite: Consultancy; BMS: Consultancy.

*signifies non-member of ASH