Bempegaldesleukin in combination with TECENTRIQ® (atezolizumab) or KEYTRUDA® (pembrolizumab)
Research Focus: Immuno-oncology
Discovered and wholly owned by Nektar
Bempegaldesleukin in combination with NKTR-262
Research Focus: Immuno-oncology
Discovered and wholly owned by Nektar
About Bempegaldesleukin (NKTR-214), Nektar's Lead Immuno-oncology Candidate
Bempegaldesleukin is a CD122-biased agonist designed to stimulate the patient's own immune system to fight cancer. Bempegaldesleukin 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). Bempegaldesleukin 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 bempegaldesleukin resulted in expansion of these cells and mobilization into the tumor micro-environment.2,3 Bempegaldesleukin has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.
In preclinical studies, bempegaldesleukin 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 bempegaldesleukin 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 bempegaldesleukin at predicted clinical therapeutic doses.2 Bempegaldesleukin 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 bempegaldesleukin 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 First-in-Human trial were published in Cancer Discovery and showed encouraging evidence of anti-tumor activity, and a favorable safety and tolerability profile. (Cancer Discov 2019;9:1–11)
In February 2018, Nektar and Bristol-Myers Squibb entered into a global development and commercialization agreement to evaluate the full potential of bempegaldesleukin 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 clinical collaboration agreement with Takeda to evaluate bempegaldesleukin in combination with TAK-659, a dual SYK and FLT-3 inhibitor in liquid and solid tumors. The first of these studies, a Phase 1b dose-escalation and safety expansion study of TAK-659 in combination with bempegaldesleukin in patients with Non-Hodgkin Lymphoma, initiated in December 2018.
In November 2018, Nektar announced a clinical collaboration with Pfizer to evaluate bempegaldesleukin in combination with avelumab and talazoparib or enzalutamide in multiple cancer settings including metastatic castration-resistant prostate cancer (mCRPC) and squamous cell carcinoma of the head and neck (SCCHN).
Additional development plans for bempegaldesleukin include combination studies with additional checkpoint inhibitors, cell therapies and vaccines.
About the Phase 3, Randomized, Open-label Study of Bempegaldesleukin 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 bempegaldesleukin, 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 Phase 3, Randomized, Open-label Study to
Compare Bempegaldesleukin Combined With Nivolumab to the
Investigator's Choice of Sunitinib or Cabozantinib in
Patients With Previously Untreated Advanced Renal
The Phase 3 study will compare the overall response rate (ORR) and overall survival (OS) of
bempegaldesleukin combined with nivolumab to that of a tyrosine kinase inhibitor (TKI)
monotherapy (sunitinib or cabozantinib) in intermediate and poor-risk participants with
previously untreated advanced renal cell carcinoma (RCC). For more information, please
visit clinicaltrials.gov and search NCT03729245.
About PIVOT-10, a Phase 2, Randomized, Non-Comparative, Open-Label Study of Bempegaldesleukin in Combination With Nivolumab and of Chemotherapy in Cisplatin Ineligible, Locally Advanced or Metastatic Urothelial Cancer Patients With Low PD-L1 Expression
The Phase 2 study will evaluate the anti-tumor activity of bempegaldesleukin in combination with nivolumab by assessing the objective response rate (ORR) in approximately 165 cisplatin ineligible, locally advanced or metastatic urothelial cancer patients with low PD-L1 expression. The efficacy will be assessed within the experimental Arm A (bempegaldesleukin + nivolumab), while Arm B will receive a combination of gemcitabine and carboplatin and will serve as a reference arm. Secondary outcome measures include Duration of Response (DOR) and incidence of treatment-related Adverse Events (AEs). For more information, please visit clinicaltrials.gov and search NCT03785925.
About the PIVOT Phase 1/2 Program: Bempegaldesleukin in combination with OPDIVO® (nivolumab)
The PIVOT Phase 1/2 program is a dose escalation and expansion study of bempegaldesleukin 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 bempegaldesleukin 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: Bempegaldesleukin in combination with TECENTRIQ® (atezolizumab) or KEYTRUDA® (pembrolizumab)
The dose escalation stage of the PROPEL program will determine the recommended Phase 2 dose of bempegaldesleukin 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 bempegaldesleukin 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 bempegaldesleukin 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 bempegaldesleukin 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: Bempegaldesleukin 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 bempegaldesleukin 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
2019 ASCO Annual Meeting
- Abstract #2623/Poster Board #267: "Baseline tumor-immune signatures associated with response to bempegaldesleukin (NKTR-214) and nivolumab", Hurwitz, M., et al.
- Abstract #2584/Poster Board #228: "Overcoming genetically-based resistance mechanisms to PD-1 blockade", Torrejon, D., et al.
- Abstract #11010: "Pilot study of bempegaldesleukin (NKTR-214) and nivolumab in patients with sarcomas", D’Angelo, S., et al.
- Abstract TPS9601/Poster Board #168b (Trials in progress (TiP) abstract): "CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL)", Khushalani, N., et al.
- Abstract TPS4595/Poster Board #416b (Trials in progress (TiP) abstract): "A phase III randomized open label study comparing bempegaldesleukin (NKTR-214) plus nivolumab to sunitinib or cabozantinib (investigator's choice) in patients with previously untreated advanced renal cell carcinoma", Tannir, N., et al.
- A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors
- Abstract 3210/Poster Board 20: “A potential immunotherapeutic approach for the treatment of osteosarcoma”, Wahba, A., et al.
- Abstract 2256/Poster Board 15: “Combination of neoantigen DNA plasmid vaccine VB10.NEO and NKTR-214, a CD122-biased immunostimulatory cytokine, induces strong neoantigen-specific T cell responses and sustained tumor regression in pre-clinical models”, Granum, S., et al.
2019 ASCO-SITC Clinical Immuno-Oncology Symposium
- Oral presentation/Abstract #28: “Phase Ib: Preliminary clinical activity and immune activation for NKTR-262 [TLR 7/8 agonist] plus NKTR-214 [CD122-biased agonist] in patients (pts) with locally advanced or metastatic solid tumors (REVEAL Phase Ib/II Trial).”, Diab, A.
2019 Genitourinary Cancers Symposium (ASCO-GU)
- Abstract #388: “Bempegaldesleukin (NKTR-214) + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): Updated results from PIVOT-02”, Siefker-Radtke, A., et al.
- 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: “Bempegaldesleukin (NKTR-214) + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): Updated results from PIVOT-02”, Siefker-Radtke, A., et al.
- 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”
- 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