NKTR-214 in combination with TECENTRIQ® (atezolizumab) or KEYTRUDA® (pembrolizumab)
Research Focus: Immuno-oncology
Discovered and wholly owned by Nektar
NKTR-214 (single agent)
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 preclinical studies, treatment with NKTR-214 results in a rapid expansion of these cells and mobilization into the tumor micro-environment. 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 ongoing with patient enrollment complete. Results from this Phase 1 trial were presented at the Society for Immunotherapy of Cancer (SITC) 2016 Annual Meeting and showed encouraging evidence of anti-tumor activity, and a favorable safety and tolerability profile. (Poster #387)
In September 2016, Nektar entered into a clinical collaboration with Bristol-Myers Squibb to evaluate NKTR-214 as a potential combination treatment regimen with Opdivo (nivolumab) in five tumor types and eight potential indications. The Phase 1/2 PIVOT clinical trials, known as PIVOT-02 and PIVOT-04 will enroll up to 260 patients and will evaluate the potential for the combination of Opdivo (nivolumab) and NKTR-214 to show improved and sustained efficacy and tolerability above the current standard of care in melanoma, kidney, triple-negative breast cancer, bladder and non-small cell lung cancer patients.
In May 2017, Nektar entered into a research collaboration with Takeda to explore the combination of NKTR-214 with five oncology compounds from Takeda's cancer portfolio including a SYK-inhibitor and a proteasome inhibitor. The collaboration will explore the anti-cancer activity of NKTR-214 combined with five different targeted mechanisms in preclinical tumor models of lymphoma, melanoma and colorectal cancer to identify which combination treatment regimens show the most promise for possible advancement into the clinic.
Under the terms of the collaboration, the companies will share costs related to the preclinical studies and each will contribute their respective compounds to the research collaboration. Nektar and Takeda will each maintain global commercial rights to their respective drugs and/or drug candidates.
Additional development plans for NKTR-214 include combination studies with additional checkpoint inhibitors, cell therapies and vaccines.
About the Excel NKTR-214 Phase 1/2 Study
The dose-escalation stage of the Excel Phase 1/2 study is designed to evaluate safety, efficacy, and define the recommended Phase 2 dose of NKTR-214 in approximately 20 patients with solid tumors. In addition to a determination of the recommended Phase 2 dose, the study will assess preliminary anti-tumor activity, including objective response rate (ORR). The immunologic effect of NKTR-214 on tumor-infiltrating lymphocytes (TILs) and other immune infiltrating cells in both blood and tumor tissue will also be assessed. Enrollment in the dose escalation study is completed. More information on the Excel Phase 1/2 study can be found on clinicaltrials.gov.
About the PIVOT Phase 1/2 Program: NKTR-214 in combination with OPDIVO® (nivolumab)
The dose escalation stage of the PIVOT program (PIVOT-02 Phase 1/2 study) is underway and will determine the recommended Phase 2 dose of NKTR-214 administered in combination with nivolumab. The study is first evaluating the clinical benefit, safety, and tolerability of combining NKTR-214 with nivolumab in approximately 30 patients with melanoma, renal cell carcinoma or non-small cell lung cancer. Once the recommended Phase 2 dose is achieved, the study will expand into additional patients for each tumor type. The second phase of the expansion cohorts in the PIVOT program (PIVOT-04 Phase 2 study) will evaluate safety and efficacy of the combination in up to 260 patients, in five tumor types and eight indications, including first and second-line melanoma, second-line renal cell carcinoma in immune-oncology therapy (IO) naïve and IO-relapsed patients, second-line non-small cell lung cancer in IO-naïve and IO-relapsed patients, first-line urothelial carcinoma, and second-line triple negative breast cancer. This study is expected to initiate in the second quarter of 2017.
Information on the PIVOT-02 study can be found on clinicaltrials.gov.
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 in approved treatment settings of atezolizumab, including patients with non-small cell lung cancer or bladder cancer. The second arm will evaluate an every three-week dose regimen of NKTR-214 in combination with pembrolizumab in up to 30 patients in approved treatment settings of pembrolizumab, including patients with melanoma, non-small cell lung cancer or bladder cancer.
Information on the PROPEL study can be found on clinicaltrials.gov.
1Boyman, J., et al., Nature Reviews Immunology, 2012, 12, 180-190.
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
- 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