Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR-255, a Novel IL-15 Receptor Agonist, in Patients with Relapsed/Refractory Hematologic Malignancies

Introduction: NKTR-255, a novel polymer-conjugated recombinant human interleukin (IL)-15 agonist, maintains the full spectrum of IL-15 biology and provides sustained pharmacodynamic (PD) responses without the need for daily dosing. NKTR-255 engages IL-15Rα and IL-2/IL-15Rβγ leading to natural killer (NK) and CD8⁺ T-cell activation, proliferation, and expansion. In preclinical studies, NKTR-255 enhanced antibody-dependent cellular cytotoxicity (ADCC) of daratumumab, rituximab, and cetuximab, resulting in synergistic antitumor effect. This ongoing Phase 1 trial (NCT04136756) evaluates safety, tolerability, pharmacokinetics (PK) and PD of NKTR-255 monotherapy and with subcutaneous (SC) Darzalex-Faspro (dara) or rituximab in patients with hematologic malignancies. Preliminary data is presented from the monotherapy and NKTR-255+dara cohorts.

Methods: Heavily pretreated patients with relapsed/refractory (r/r) multiple myeloma (MM) or non-Hodgkin lymphoma (NHL) received escalating doses of NKTR-255 intravenously every 3 weeks. A cohort of patients with MM received NKTR-255+dara (1,800 mg). Patients were observed following the first NKTR-255 dose for dose-limiting toxicity (DLT). Preliminary PK/PD analyses were conducted, including detection of chimeric antigen receptor T cells (CAR-T) in patients who received CAR-T therapy prior to enrollment. NKTR-255-mediated immune activation was assessed by flow cytometry and plasma cytokine analyses.

Results: As of June 26, 2022, 23 patients were enrolled, median age 65 (range 49-80 yrs, 61% male. Sixteen (70%) had MM and 7 (30%) had NHL. Ten (43%) of 23 pts previously received CAR-T therapy (MM=7, NHL=3). The 23 patients were dosed at 7 cohorts (NKTR-255 1.5 µg/kg: 3 pts; 3.0 µg/kg: 4 pts; 4.5 µg/kg: 4 pts; 6.0 µg/kg: 5 pts, 9.0 µg/kg: 4 pts, 12 µg/kg: 1 pt; 4.5 µg/kg+dara: 2 pts). Among the 19 response-evaluable, 10 pts (53%) reported disease stabilization (7/12 [58%] MM pts; 3/7 [43%] NHL pts). One 4L MM patient (at 4.5 µg/kg) experienced ongoing stable disease for 63+ weeks. Ongoing disease control was observed for 2/2 pts receiving NKTR-255+dara. Treatment-related AEs any grade ≥30% were pyrexia (15/23; 65%), chills (13/23; 57%), nausea (11/23; 48%), fatigue (10/23; 43%), headache (10/23; 43%), and infusion-related reaction (9/23; 39%). Most AEs were transient and resolved without intervention and were easily managed. No DLTs were observed; no patients discontinued NKTR-255 due to AEs. NKTR-255+dara was well tolerated with no overlapping toxicities. Preliminary NKTR-255 PK analyses showed target-mediated disposition at the lower dose (1.5 µg/kg) and linear PK at higher doses (≥3.0 µg/kg). The average t_1/2 of NKTR-255 was ~34-87 hours over the dose range of 3-12 µg/kg. No/minimal accumulation was observed with q3w dosing. There was expansion of NK and CD8+ T cell numbers in peripheral blood, with peak fold-changes of ~8-fold and ~2-fold respectively, in the first 2 cycles at 6.0 µg/kg. NK and CD8⁺ T cells maintained proliferative ability (Ki67) across multiple treatment cycles. Preliminary data with NKTR-255 + dara demonstrated dara administration on D1 induced rapid NK population contraction that was rescued by NKTR-255 administration on D2, with levels of total and CD56^dimCD16⁺ NK cells returning to baseline (pre-dara) by D7. Cellular expansion and proliferation of NK cells were similar to NKTR-255 monotherapy and upregulation of NK activation markers was observed. Consistent with NKTR-255 mechanism, Treg induction was minimal. NKTR-255 induced transient changes in inflammatory cytokines (INF-γ, MCP-1and IL-6) peaking at 3-6 hrs post-infusion and resolving to baseline by 24-48 hrs.

Conclusions: In heavily pretreated patients with heme malignancies NKTR-255, alone and with SC dara was well-tolerated, manageable and biologically active with sustained increases in NK and CD8⁺ T cells. NKTR-255 administration replenished dara-induced NK cell depletion. Optimal biological response of NKTR-255 monotherapy was observed between 6-9 µg/kg and will be further tested in Phase 2. NKTR-255 is being evaluated in multiple clinical studies in both heme malignancies and solid tumors as monotherapy, in combination with ADCC agents, checkpoint inhibitors, and cellular therapies (NCT03233854, NCT05359211).

Ethics approval: The study was approved by the institutional review board of each participating site.

Patel:Janssen, Celgene/BMS, Caribou Sciences, Arcellx, Cellectis, Merck, Pfizer, Karyopharm, Oncopeptides: Consultancy. Shah:Celgene/BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar, Precision Biosciences: Research Funding; AstraZeneca: Current Employment, Current equity holder in publicly-traded company; GSK, Amgen, Indapta Therapeutics, Sanofi, CareDx, Kite, Karyopharm, Oncopeptides,: Consultancy; Aztra Zeneca: Current Employment, Other: stock ownership. Cowan:Abbvie: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy; BMS: Consultancy, Research Funding; EUSA: Consultancy; GSK: Consultancy; Harpoon: Research Funding; Janssen: Consultancy, Research Funding; Nektar: Research Funding; Sanofi: Research Funding; Secura Bio: Consultancy. Turtle:Juno Therapeutics, a BMS Company: Patents & Royalties, Research Funding; Eureka Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Caribou Bioscience: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Kite Pharma, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Decheng Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Century Therapeutics: Membership on an entity's Board of Directors or advisory committees; Arsenal Bio: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Expert Connect: Consultancy; Precision Bioscience: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Prescient Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hofmeister:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; BlueBird Bio: Honoraria. Saeed:Novartis: Consultancy; Epizyme: Consultancy; Morphosys: Honoraria. Chavez:MorphoSys/Incyte: Speakers Bureau; Abbvie: Consultancy; GenMab: Consultancy; Kite Pharma: Consultancy; Adicet: Consultancy; Astrazeneca: Research Funding, Speakers Bureau; Beigene: Honoraria; TG Therapeutics: Honoraria; Epizyme: Honoraria, Speakers Bureau; ADC Therapeutics: Research Funding; Janssen: Research Funding; Merck: Research Funding. Gandhi:Karyopharm: Honoraria; TG Therapeutics: Honoraria; Janssen: Honoraria; GlaxoSmithKline: Honoraria. Chaudhry:Nektar Therapeutics: Current Employment. Lee:Nektar Therapeutics: Current Employment. Dixit:Nektar Therapeutics: Current Employment. Fanton:Nektar Therapeutics: Current Employment. Wang:Nektar Therapeutics: Current Employment. Xu:Nektar Therapeutics: Current Employment. Marcondes:Nektar Therapeutics: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Tagliaferri:Nektar Therapeutics: Current Employment. Zalevsky:Nektar Therapeutics: Current Employment. Perales:DSMB: Other; Bellicum: Honoraria; Incyte: Honoraria, Research Funding; Nektar Therapeutics: Consultancy, Honoraria; Takeda: Honoraria; MorphoSys: Consultancy, Honoraria; Orca Bio: Consultancy; Abbvie: Honoraria; Novartis: Honoraria; Cidara Therapeutics: Consultancy; Vor Biopharma: Honoraria; Karyopharm: Honoraria; Merck: Consultancy; Omeros: Consultancy; Astellas: Honoraria; Sellas Life Sciences: Consultancy; VectivBio AG: Honoraria; Servier: Consultancy; Medigene: Consultancy; Miltenyi Biotec: Consultancy, Honoraria; Kite, a Gilead Company: Honoraria, Research Funding; Bristol-Mysers Squibb: Honoraria; Celgene: Honoraria.