Bempegaldesleukin (NKTR-214)

About Bempegaldesleukin (NKTR-214), Nektar's Lead Immuno-oncology Candidate

Bempegaldesleukin is a CD122-preferential IL-2 pathway 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 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.

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 (CRC) 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) The agreement includes 7 indications in 4 tumor types including melanoma, renal cell carcinoma, non-small cell lung cancer and bladder cancer.

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 (PIVOT-IO-001)

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 Cell Carcinoma

The Phase 3 study will compare the overall response rate (ORR) and overall survival (OS) of bempegaldesleukin combined with nivolumab to that of tyrosine kinase inhibitor (TKI) monotherapy (sunitinib or cabozantinib) in IMDC intermediate- or poor-risk patients with previously untreated advanced RCC. For more information, please visit clinicaltrials.gov and search NCT03729245.

 

A Phase 3, Randomized, Study of Neoadjuvant and Adjuvant Nivolumab Plus NKTR-214, Versus Nivolumab Alone Versus Standard of Care in Participants With Muscle-Invasive Bladder Cancer (MIBC) Who Are Cisplatin Ineligible (PIVOT-IO-009)

The purpose of this Phase 3 study is to see if treatment with bempegaldesleukin (BEMPEG: NKTR-214) in combination with nivolumab (NIVO) or NIVO alone, before and after surgery to remove the bladder, is more effective than surgery alone in participants with muscle-invasive bladder cancer who are not able to receive cisplatin chemotherapy.  The co-primary endpoints will be pathologic complete response (pCR) rate and event-free survival (EFS) of BEMPEG plus NIVO versus surgery alone. Secondary outcome measures include pCR and EFS of monotherapy NIVO versus surgery, overall survival and incidence of adverse events. For more information, please visit clinicaltrials.gov and search NCT04209114.

 

 

A Phase 3, Randomized, Open-label Study to Compare Adjuvant Immunotherapy of Bempegaldesleukin Combined With Nivolumab Versus Nivolumab After Complete Resection of Melanoma in Patients at High Risk for Recurrence (PIVOT-12)

This phase 3 study will evaluate the efficacy, safety and tolerability of adjuvant bempegaldesleukin (BEMPEG) and nivolumab versus nivolumab in approximately 950 patients in who have had their melanoma surgically removed but who have a high risk of recurrence.  The primary endpoint of the trial is recurrence-free survival (RFS) and secondary endpoints include overall survival (OS) and other measures of disease progression. For more information on the study, please visit clinicaltrials.gov and search NCT04410445.
 

About the Phase 2 Study of the Triplet Combination of Bempegaldesleukin with Nivolumab and Cabozantinib as Compared to Nivolumab plus Cabozantinib for the Treatment of Renal Cell Carcinoma that is Advanced or has Spread (PIVOT-IO-011)

The Phase 2, open-label, randomized trial is designed to assess the efficacy of the triplet combination of bempegaldesleukin (BEMPEG) plus nivolumab and cabozantinib versus the doublet of nivolumab and cabozantinib for patients with previously untreated advanced or metastatic renal cell carcinoma. The first stage of the study will include a dose-finding component for the triplet combination. The trial will assess the safety and tolerability of the triplet combination and will also measure progression-free survival (PFS) and overall survival (OS). The trial is expected to enroll more than 100 patients. For more information, please visit clinicaltrials.gov and search NCT04540705.
 

About PIVOT-10, a Phase 2, Single-Arm Study of Bempegaldesleukin in Combination With Nivolumab in Cisplatin Ineligible, Locally Advanced or Metastatic Urothelial Cancer Patients

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 205 cisplatin-ineligible, locally advanced or metastatic urothelial cancer patients (mUC). The primary endpoint will be ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 per Blinded Independent Central Review (BICR) in patients whose tumors have low programmed cell death ligand (PD-L1) expression. Secondary outcome measures include ORR by RECIST 1.1 per BICR in all treated patients, Duration of Response (DOR) by RECIST 1.1 per BICR in all treated patients and patients whose tumors have low PD-L1 expression, ORR and DOR by RECIST 1.1 per Investigator assessment in all treated patients and in patients whose tumors have low PD-L1 expression and incidence of treatment-related Adverse Events (AEs). For more information, please visit clinicaltrials.gov and search NCT03785925.

 

About the DIRECT-01 Phase 1/2a Study to Evaluate Safety and Efficacy of Multiple Dosing With VB10.NEO and Bempegaldesleukin (NKTR-214) Immunotherapy in Patients With Locally Advanced or Metastatic Cancer

This Phase 1/2a study sponsored by Vaccibody (in collaboration with Nektar) will evaluate the safety, tolerability and efficacy of the combination of VB10.NEO and bempegaldesleukin in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). For more information, please visit clinicaltrials.gov and search NCT03548467.
 

 

About the PROPEL Phase 1/2 Program: Bempegaldesleukin in combination with KEYTRUDA^® (pembrolizumab)

The PROPEL study will evaluate the clinical benefit, safety and tolerability of combining bempegaldesleukin (BEMPEG) with pembrolizumab in approximately 100 patients and is comprised of two groups: dose optimization and dose expansion cohorts. The dose optimization cohort will evaluate BEMPEG in combination with pembrolizumab in approximately 40 patients with solid tumors. The dose expansion cohort will evaluate BEMPEG in combination with pembrolizumab in approximately 58 patients with first-line NSCLC. 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 intra-tumoral 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, TNBC, RCC, CRC, SCCHN, or sarcoma. For more information, please visit clinicaltrials.gov and search NCT03435640.
 

About the Phase 1b, Randomized, Double-Blind, Placebo-Controlled Study of Bempegaldesleukin as a Treatment for Mild COVID-19

The Phase 1b trial is designed to assess the safety, tolerability, and pharmacokinetic/pharmacodynamic profile of bempegaldesleukin (BEMPEG) in adult patients with mild COVID-19. Eligibility criteria include symptoms such as fever, cough, sore throat, malaise, headache, and muscle pain without evidence of severe dyspnea or acute respiratory distress syndrome. Patients who meet the eligibility criteria will be randomized and treated with either a single dose of BEMPEG or placebo in combination with current standard of care treatment for patients with mild COVID-19. Primary and secondary endpoints include change over time in absolute lymphocyte counts and measurements of clinical progression based upon the WHO Clinical Progression Scale. The trial will enroll up to three cohorts of ten patients each, who will receive increasing doses of BEMPEG with the aim of evaluating safety and tolerability and to identify the recommended dose for future studies.

*Planned registrational study

References

1.     Boyman, J., et al., Nature Reviews Immunology, 2012, 12, 180-190.

2.     Charych, D., et al., Clin Can Res; 22(3) February 1, 2016

3.     Diab, A., et al., Journal for ImmunoTherapy of Cancer 2016, 4(Suppl 1):P369