NKTR-214 in combination with TECENTRIQ® (atezolizumab) or KEYTRUDA® (pembrolizumab)
Research Focus: Immuno-oncology
Discovered and wholly owned by Nektar
NKTR-214 in combination with NKTR-262
Research Focus: Immuno-oncology
Discovered and wholly owned by Nektar
About NKTR-214, Nektar's Lead Immuno-oncology Candidate
NKTR-214 is a CD122-biased agonist designed to stimulate the patient's own immune system to fight cancer. NKTR-214 is designed to grow specific cancer-killing T cells and natural killer (NK) cell populations in the body which fight cancer, which are known as endogenous tumor-infiltrating lymphocytes (TILs). NKTR-214 stimulates these cancer-killing immune cells in the body by targeting CD122 specific receptors found on the surface of these immune cells, known as CD8+ effector T cells and Natural Killer (NK) cells. CD122, which is also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase proliferation of these effector T cells.1 In clinical and preclinical studies, treatment with NKTR-214 resulted in expansion of these cells and mobilization into the tumor micro-environment.2,3 NKTR-214 has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.
In preclinical studies, NKTR-214 demonstrated a mean ratio of 450:1 within the tumor micro-environment of CD8-positive effector T cells, which promote tumor destruction, compared with CD4-positive regulatory T cells, which are a type of cell that can suppress tumor-killing T cells.2 Furthermore, a single dose of NKTR-214 resulted in a 500-fold AUC exposure within the tumor compared with an equivalent dose of the existing IL-2 therapy, enabling, for the first time, an antibody-like dosing regimen for a cytokine.2 In dosing studies in non-human primates, there was no evidence of severe side effects such as low blood pressure or vascular leak syndrome with NKTR-214 at predicted clinical therapeutic doses.2 NKTR-214 has a range of potential uses against multiple tumor types, including melanoma (the most serious type of skin cancer), kidney cancer and non-small cell lung cancer (the most common form of lung cancer).
A Phase 1 study evaluating NKTR-214 as a single agent in patients with locally recurrent or metastatic solid tumors including melanoma, renal cell carcinoma (RCC), bladder, colorectal and other solid tumors is complete. Results from this Phase 1 trial were presented at the 2017 ASCO Annual Meeting and showed encouraging evidence of anti-tumor activity, and a favorable safety and tolerability profile. (Abstract 2545/Poster 37)
In February 2018, Nektar and Bristol-Myers Squibb entered into a global development and commercialization agreement to evaluate the full potential of NKTR-214 plus Opdivo® (nivolumab) in more than 20 indications in 9 tumor types including melanoma, renal cell carcinoma, non-small cell lung cancer, bladder and triple negative breast cancer.
In April 2018, Nektar announced a new clinical collaboration agreement with Takeda to evaluate NKTR-214 in combination with TAK-659, a dual SYK and FLT-3 inhibitor in liquid and solid tumors with the first of these studies expected to begin in the second half of 2018 in patients with Non-Hodgkin Lymphoma.
In May 2018, Nektar announced a clinical collaboration with Syndax Pharmaceuticals to evaluate NKTR-214 in combination with entinostat, an oral, small molecule Class 1 specific HDAC inhibitor, in patients with metastatic melanoma who have previously progressed on treatment with an anti-PD-1 agent.
Additional development plans for NKTR-214 include combination studies with additional checkpoint inhibitors, cell therapies and vaccines.
About the Phase 3, Randomized, Open-label Study of NKTR-214 Combined With Nivolumab Versus Nivolumab in Participants With Previously Untreated Unresectable or Metastatic Melanoma
The Phase 3 study will test the effectiveness (how well the drug works), safety, and tolerability of NKTR-214, when combined with nivolumab versus nivolumab given alone in participants with previously untreated melanoma skin cancer that is either unable to be surgically removed or has spread. For more information, please visit clinicaltrials.gov and search NCT03635983.
About the PIVOT Phase 1/2 Program: NKTR-214 in combination with OPDIVO® (nivolumab)
The PIVOT Phase 1/2 program is a dose escalation and expansion study of NKTR-214 when administered in combination with nivolumab in patients with melanoma, renal cell carcinoma, non-small cell lung cancer (NSCLC), urothelial carcinoma, or triple negative breast cancer. The dose escalation stage of the study enrolled 38 patients and evaluated the safety and efficacy profile of the combination and the recommended phase 2 dose was established. The expansion stage of the PIVOT program is underway to evaluate the safety and efficacy of combining NKTR-214 with nivolumab in approximately 330 patients who are either immuno-oncology (I-O) therapy naïve or anti-PD-1 or anti-PD-L1 relapsed/refractory. The expansion cohorts in the PIVOT program include five tumor types and thirteen indications, including first and second-line melanoma, first and second-line renal cell carcinoma, first and second-line NSCLC, first and third-line urothelial carcinoma, and first and second-line triple negative breast cancer. For more information, please visit clinicaltrials.gov and search NCT02983045.
About the PROPEL Phase 1/2 Program: NKTR-214 in combination with TECENTRIQ® (atezolizumab) or KEYTRUDA® (pembrolizumab)
The dose escalation stage of the PROPEL program will determine the recommended Phase 2 dose of NKTR-214 administered in combination with anti-PD-L1 agent, atezolizumab or anti-PD-1 agent, pembrolizumab. The study will evaluate the clinical benefit, safety and tolerability of combining NKTR-214 with atezolizumab or pembrolizumab and will enroll patients into two separate arms concurrently. The first arm will evaluate an every three-week dose regimen of NKTR-214 in combination with atezolizumab in up to 30 patients with urothelial bladder cancer in approved treatment settings of atezolizumab. The second arm will evaluate an every three-week dose regimen of NKTR-214 in combination with pembrolizumab in up to 50 patients with melanoma and and non-small cell lung cancer in approved treatment settings of pembrolizumab. For more information, please visit clinicaltrials.gov and search NCT03138889.
About the REVEAL Phase 1/2 Program: NKTR-214 in combination with NKTR-262
REVEAL is a Nektar-sponsored, open-label, multicenter, dose escalation and dose expansion study of NKTR-262 administered as intratumoral injections in combination with NKTR-214 administered as an IV infusion systemically (doublet). The study also may evaluate the doublet combination with nivolumab (triplet). During the dose escalation phases, recommended Phase 2 dose (RP2D) regimens of the doublet and/or triplet combinations will be established. Following dose escalation, the dose expansion phase will evaluate the doublet and/or triplet combinations in up to 350 patients who have been diagnosed with a range of locally advanced or metastatic cancers including: melanoma, Merkel cell carcinoma, triple-negative breast cancer, ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, or sarcoma. For more information, please visit clinicaltrials.gov and search NCT03435640.
1. Boyman, J., et al., Nature Reviews Immunology, 2012, 12, 180-190.
3. Diab, A., et al., Journal for ImmunoTherapy of Cancer 2016, 4(Suppl 1):P369
- Oral Abstract #O4: "Immune monitoring after NKTR-214 plus nivolumab (PIVOT-02) in previously untreated patients with metastatic Stage IV melanoma,", Diab, A., et al.
- Abstract #P424: "NKTR-214, an engineered IL-2, selectively depletes intratumoral Tregs and expands immunotherapy-induced effector T cell responses", Sharma, M., et al.
- Abstract #P368: "Combination of a Dipeptidyl Peptidase Inhibitor BXCL701 and Biased CD122 Agonist NKTR-214 with Anti-PD1 Provides Functional Immunological Memory through Inflammatory Cell Death", MacDougall, J., et al.
- Abstract #P348: "Survival and immune modulation in homologous recombination deficient murine ovarian tumors using the PARP inhibitor, rucaparib and immune agonist, NKTR-214", Charych, D., et al.
- Abstract #P419: "NKTR-214 in combination with radiation produces a potent in situ vaccine in the syngeneic B78 melanoma model", Sondel, P., et al.
- Abstract #P557: "Overcoming genetically-based resistance mechanisms to PD-1 blockade", Torrejon, D., et al.
- Abstract #P364: "Systemic anti-tumor immunity and immune memory formation by a novel TLR7/8 targeting agent NKTR-262 combined with CD122-biased immunostimulatory cytokine NKTR-214", Kivimae, S., et al.
- Abstract #P378: "NKTR-214 (CD122-biased agonist) and NKTR-262 (TLR7/8 agonist) combination treatment pairs local innate immune activation with systemic CD8+ T cell expansion to enhance anti-tumor immunity", Rolig, A., et al.
2018 ESMO Congress
- Poster 446TIP: “REVEAL: A phase 1/2, open-label, multicenter, dose escalation and dose expansion study of NKTR-262 [TLR 7/8 agonist] plus NKTR-214 [CD122-biased agonist] with or without nivolumab (nivo) in patients (pts) with locally advanced or metastatic solid tumor malignancies”, Diab, A., et al.
2018 American Conference on Pharmacometrics (ACoP), San Diego, CA
- Poster W-019: "Mechanistic modeling of receptor pharmacology of NKTR-214, a new kinetically-controlled CD122 agonist for cancer immunotherapy"
SMI Immuno-Oncology Conference, London, UK
2018 ASCO Annual Meeting
- Oral Abstract 3006: NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. Presenter: Dr. Adi Diab, MD Anderson Cancer Center
- Abstract #3085/ Poster Board #299: "Efficacy and immune modulation by BXCL701 a dipeptidyl peptidase inhibitor, NKTR-214 a CD122-biased immune agonist with PD1 blockade in murine pancreatic tumors", Rastelli, L., et al.
- Abstract #2567/Poster Board #393: "TAK-659 in Combination with NKTR-214 and anti-PD-1 Therapy Leads to Complete and Sustained Tumor Regression and Immune Memory In Pre-Clinical Syngeneic Models", Huck, J., et al.
- Abstract #TPS3115/Poster Board #322a: "PROPEL: A phase 1/2 trial of NKTR-214 (CD122-biased agonist) combined with anti-PD-1 (pembrolizumab) or anti-PD-L1 (atezolizumab) in patients (pts) with advanced solid tumors", Vaena, D., et al.
- Abstract #5582/Poster Board #309: "Efficacy and immune modulation of the tumor microenvironment in murine ovarian tumor with the PARP inhibitor rucaparib and CD122-biased immune agonist NKTR-214", Simmons, A., et al.
2018 American Association for Cancer Research (AACR) Annual Meeting
- Abstract 123/Poster 13: Enhanced anti-tumor activity of the combination of entinostat and NKTR-214 in renal and colon cancer tumor models”
- Abstract 3566/Poster 4: “Enhanced expansion and tumor targeting of adoptively transferred T cells with NKTR-214”
- Abstract 3755/Poster 5: “Comprehensive antitumor immune activation by a novel TLR7/8 targeting agent NKTR-262 combined with CD122-biased immunostimulatory cytokine NKTR-214”
Society for Immunotherapy in Cancer (SITC) 32nd Annual Meeting, National Harbor, MD
- Oral Presentation: PIVOT-02: Preliminary safety, efficacy and biomarker results from the Phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic solid tumors
Presenter: Dr. Adi Diab, Assistant Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Poster #O20: PIVOT-02: Preliminary safety, efficacy and biomarker results from the Phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic solid tumors, Diab, A., et al.
- Poster #P77: The Novel IL-2 Cytokine Immune Agonist NKTR-214 Harnesses the Adaptive and Innate Immune System for the Treatment of Solid Cancers, Bentebibel, S.E., et al.
- Poster #P275: Harnessing the innate and adaptive immune system to eradicate treated and distant untreated solid tumors, Kivimae, S., et al.
- Poster #P140: NKTR-214 enhances anti-tumor T-cell immune responses induced by checkpoint blockade or vaccination, Sharma, M., et al.
- Poster #P274: Combination of NKTR-214 and radiotherapy (RT) to reverse anergy and expand tumor-specific CD8 T-Cells, Walker, J., et al.
Presenter: Joshua Walker, Oregon Health & Science University
- Poster #434: Great apes adenoviral vaccine encoding neoantigens synergizes with immunomodulators to cure established tumors in mice, D'Alise, A.M, et al.
IASLC 18th World Conference on Lung Cancer
- Poster P2.07-062: PIVOT-02: Phase 1/2 Study of NKTR‐214 and Nivolumab in Patients with Locally Advanced or Metastatic Solid Tumor Malignancies
6th Annual Cancer Vaccines Conference 2017, London, UK
- Presentation: Enhanced Cancer Vaccine Effectiveness with NKTR-214, a CD122-Biased Cytokine, Zalevsky, J.
ESMO 2017 Congress
- Poster 1212TiP: PIVOT-02: A Phase 1/2, Open-label Multicenter, Dose Escalation and Dose Expansion Study of NKTR-214 and Nivolumab in Patients with Select Locally Advanced or Metastatic Solid Tumor Malignancies. Diab, A., et al.
2017 ASCO Annual Meeting
- Abstract 2545/Poster 37: A Novel IL-2 Cytokine Immune Agonist (NKTR-214) Increases Proliferating CD8+ T Cells and PD-1 Expression on Immune Cells in the Tumor Microenvironment in Patients with Prior Checkpoint Therapy
2017 American Association for Cancer Research (AACR) Annual Meeting
- Abstract 2671/Poster 30: Antitumor activity of NKTR-214 in combination with Adopted Cell Transfer (ACT) in an aggressive murine melanoma
- Abstract 1598/Poster 6: Single agent NKTR-214, a biased IL2 pathway agonist, increases immune cell infiltrates in brain tumors and prolongs survival in rodent (rattus) glioblastoma (GBM)
- Abstract 1604/Poster 12: NKTR-214 Synergizes with Radiotherapy to Drive Tumor Regression
- Abstract 1617/Poster 25: Mechanistic modeling of a new kinetically-controlled CD122 agonist for cancer immunotherapy: NKTR-214 pharmacokinetics, pharmacodynamics, and receptor pharmacology
2017 Genitourinary Cancers Symposium
- Abstract 454/Poster D17: A Novel Immune Agonist, NKTR-214, Increases the Number and Activity of CD8+ Tumor Infiltrating Lymphocytes in Patients with Advanced Renal Cell Carcinoma
2016 SITC Annual Meeting
- Poster: A CD122-biased agonist increases CD8+ T cells and natural killer cells in the tumor microenvironment; making cold tumors hot with NKTR-214
- Poster: Anti-tumor activity of NKTR-214; a CD122-biased agonist that promotes immune cell activation in the tumor microenvironment and lymphoid tissues
- Poster: NKTR-214, an engineered cytokine, synergizes and improves efficacy of anti-cancer vaccination in the treatment of established murine melanoma tumor
2016 ESMO Annual Meeting
- Poster: Combining Complementary Mechanisms of Immune Activation: NKTR-214, a Biased IL-2 Pathway Agonist and Immune Checkpoint Antagonists
2016 CRI-CIMT-EATI-AACR Cancer Immunotherapy Conference
- Poster Abstract #311: The CD122-biased immunostimulatory cytokine NKTR-214 combined with checkpoint blockade leads to mobilization of anti-tumor immunity and synergistic activity
2016 ASCO Annual Meeting
- Poster: Immune memory in nonclinical models after treatment with NKTR-214, an engineered cytokine biased towards expansion of CD8+ T cells in tumor
2016 AACR Annual Meeting
- Durable Antitumor Activity of the CD122-biased Immunostimulatory Cytokine NKTR-214 Combined with Immune Checkpoint Blockade
Manuscript: Clinical Cancer Research, February 2016
- NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models
Nektar Research & Development Day, October 2015
- NKTR-214: A T-Cell Growth Engine in Immuno-Oncology - Jonathan Zalevsky, Ph.D.
- Clinical and Biomarker Strategy for NKTR-214 Development Translating into the Clinic - Adi Diab, M.D.
2015 Inaugural CRI-CIMT-EATI-AACR Immunotherapy Conference
- June 2, 2018: Preliminary Data for NKTR-214 in Combination with Opdivo (nivolumab) for Patients with Stage IV Metastatic Melanoma, Renal Cell Carcinoma, and Urothelial Cancers Presented at ASCO 2018
- May 30, 2018: Syndax and Nektar Therapeutics Announce Immuno-Oncology Clinical Trial Collaboration
- April 24, 2018: New Oncology Clinical Collaboration between Nektar and Takeda to Evaluate Combination of NKTR-214, a CD122-biased Agonist, and TAK-659, a Dual SYK and FLT-3 Inhibitor, in Liquid and Solid Tumors
- April 15, 2018: Nektar Therapeutics Presents New Preclinical Data for its Immuno-Oncology Programs at the American Association for Cancer Research (AACR) Annual Meeting 2018
- February 14, 2018: Bristol-Myers Squibb and Nektar Therapeutics Announce Global Development & Commercialization Collaboration for Nektar's CD122-biased Agonist, NKTR-214
- November 11, 2017: First Data for NKTR-214 in Combination with OPDIVO® (nivolumab) for Patients with Stage IV Melanoma, Renal Cell Carcinoma and Non-Small Cell Lung Cancers, Including Patients with PD-L1 Negative Status, Revealed at SITC 2017
- September 12, 2017: Nektar Therapeutics Initiates PROPEL Clinical Study to Evaluate Combination of NKTR-214, a CD122-Biased Agonist, with TECENTRIQ® (atezolizumab) or KEYTRUDA® (pembrolizumab)
- June 5, 2017: Nektar Presents New Clinical Data from Two Studies of NKTR-214, a CD122-Biased Agonist, at 2017 American Society of Clinical Oncology (ASCO) Annual Meeting
- May 22, 2017: New Research Collaboration between Nektar and Takeda to Explore Combination Cancer Therapy Approaches with NKTR-214, a CD122-Biased Agonist, and Five Takeda Cancer Therapy Compounds
- April 4, 2017: Nektar Therapeutics Presents New Preclinical Data for its Immuno-Oncology Programs at the American Association for Cancer Research (AACR) Annual Meeting
- February 18, 2017: Clinical Data from Phase 1 Dose-Escalation Study of Single-Agent NKTR-214 in Patients with Renal Cell Carcinoma Presented at the ASCO 2017 Genitourinary Cancers Symposium
- Nektar Therapeutics Presents New Clinical Data from Ongoing Phase 1 Dose-Escalation Study of NKTR-214 at the Society for Immunotherapy of Cancer (SITC) 2016 Annual Meeting
- Bristol-Myers Squibb and Nektar Therapeutics Announce Oncology Clinical Collaboration to Evaluate the Combination of Opdivo (nivolumab) and NKTR-214
- June 6, 2016: Preclinical Data Presented at ASCO 2016 Annual Meeting Demonstrate that Single-Agent NKTR-214 Produces a Large Increase in Tumor-Infiltrating Lymphocytes to Provide Durable Anti-Tumor Activity
- April 18, 2016: Preclinical Data Presented at AACR Demonstrate that Combining NKTR-214 with Checkpoint Blockade is Superior to Dual Checkpoint Inhibition in Increasing Clonality of the T Cell Receptor (TCR) Repertoire and T Cell Tumor Infiltration
- February 1, 2016: Nektar Publishes Pre-clinical Results for NKTR-214, an Investigational CD122-Biased Immune-Stimulatory Cytokine for the Treatment of Cancer in Clinical Cancer Research
- December 8, 2015: Nektar Announces First Patient Dosed in Phase 1/2 Clinical Study of NKTR-214, a CD122-Biased Immuno-Stimulatory Cytokine
- June 2, 2015: Nektar and MD Anderson Cancer Center Announce Phase 1/2 Clinical Research Collaboration for NKTR-214, a CD122-Biased Immuno-Stimulatory Cytokine
- June 1, 2014: Nektar Presents Positive Preclinical Data for NKTR-214, a Novel Cancer Immunotherapy, at 50th ASCO Meeting
- April 9, 2014: Nektar Reports Positive Preclinical Data for Two Oncology Programs at 2014 AACR
- June 3, 2013: Nektar Presents Positive Preclinical Data for NKTR-214, a Novel Cancer Immunotherapy, At the 2013 American Society of Clinical Oncology Annual Meeting
- April 7, 2013: Positive Preclinical Data for NKTR-214, an Investigational Cancer Immunotherapy Targeting the IL-2 Receptor Complex, Presented at AACR Annual Meeting 2013