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957 NKTR-255+cetuximab in patients with solid tumors: interim safety and efficacy results from the phase 1b dose-escalation study
  1. Mehmet Altan1,
  2. Amita Patnaik2,
  3. Minal Barve3,
  4. Lara Dunn4,
  5. Patrick Cobb5,
  6. Ari Rosenberg6,
  7. Sunil Sharma7,
  8. Ammar Sukari8,
  9. Manish Patel9,
  10. Xiaoli Wang10,
  11. Haijun Ma10,
  12. Neha Dixit10,
  13. Wildaliz Nieves11,
  14. Christie Fanton10,
  15. Sue Currie10,
  16. Zachary Lee10,
  17. Mario Marcondes10,
  18. Johnathan Zalevsky10,
  19. Mary Tagliaferri10 and
  20. Assuntina Sacco12
  1. 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA
  3. 3Mary Crowley Cancer Research Center, Dallas, TX, USA
  4. 4Memorial Sloan Kettering Cancer Center, New York, NY, USA
  5. 5St. Vincent Frontier Cancer Center, Billings, MT, USA
  6. 6University of Chicago, Chicago, IL, USA
  7. 7HonorHealth Research Institute, Scottsdale, AZ, USA
  8. 8Karmanos Cancer Center, Detroit, MI, USA
  9. 9University of Minnesota Medical Center, Rochester, MN, USA
  10. 10Nektar Therapeutics, San Francisco, CA, USA
  11. 11Nektar Therapeuitcs, San Francisco, CA, USA
  12. 12University California San Diego, La Jolla, CA, USA


Background NKTR-255 is an investigational IL-15Rα-dependent, polymer-conjugated, recombinant human IL-15 agonist designed to provide sustained pharmacodynamic (PD) responses without the need for daily dosing. NKTR-255 engages all IL-15 receptor binding complexes to expand, proliferate and activate natural killer (NK) and CD8+ T-cells. This Phase 1b/2 trial (NCT04616196) evaluates NKTR-255+cetuximab in highly refractory patients with head-and-neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC).

Methods Successive cohorts received escalating doses of NKTR-255 (q3w) +cetuximab (250mg/m< sup >2</sup > weekly), 1 week after a loading dose of cetuximab alone. Safety (CTCAEv5.0; MTD/recommended Phase 2 dose [RP2D]) and efficacy (RECISTv1.1) were measured. PK/PD analyses were conducted, including assessment by flow cytometry/plasma cytokine analysis. Fold-change was calculated as treatment over baseline for NKTR-255 (baseline=1).

Results As of August 15, 2021, 12 patients had received ≥1 dose of NKTR-255+cetuximab; (37–70 years; 92% male; HNSCC n=4, CRC n=8; NKTR-255 1.5µg/kg n=7, NKTR-255 3.0µg/kg n=5). Patients had received a median 3.5 lines of prior therapy for metastatic disease. 11 patients had no response to the most recent prior therapy. Of the 12 patients, seven remain on treatment, with five not yet reaching first scan. RP2D has not yet been reached; dose escalation is ongoing.

10 patients experienced an AE; one G5 AE occurred (due to progression). Seven patients reported NKTR-255-related AEs (all G1-2, except one G3 [which resolved in 24 hours]). Any-cause AEs in ≥20% were acneiform dermatitis, fatigue, and infusion-related reaction.

Treatment-induced transient changes in inflammatory cytokines, including IFNy, MCP-1 and IL-6, at 1.5µg/kg (n=3) peaked 4 hours post-infusion and resolved by 24-48 hours. Mean T1/2 of NKTR-255 (1.5µg/kg dose, first cycle) was 27.8 hours.

Dose-dependent expansion of NK and CD8+ T-cells was observed in peripheral blood. For NK cells, mean peak fold-change was ~4-fold and ~6-fold, and for CD8+ T-cells was ~2-fold and ~3-fold (1.5µg/kg and 3µg/kg dose levels, respectively). NK and CD8+ T-cells demonstrated increased Ki67+ proliferative ability.

As of August 15, four patients in the 1.5µg/kg NKTR-255 dose cohort were response-evaluable: one CRC patient (4 prior metastatic treatment lines) reported a confirmed PR (–52%) after 3 cycles; two HNSCC patients reported SD.

Conclusions NKTR-255 was biologically active and led to expansion and proliferation of NK and CD8+ T-cells. Early dose-escalation data suggest that NKTR-255+cetuximab is safe and tolerable with preliminary anti-tumor activity. Updated data will be presented. NKTR-255, alone and in combination with daratumumab and rituximab, is also being evaluated in liquid tumors.

Acknowledgements The authors thank the patients and their families involved in the trial.

Trial Registration NCT04616196

Ethics Approval The study was approved by site IRBs.

Consent N/A

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