Bempegaldesleukin* (NKTR-214)

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
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 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.

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

*rINN