Bempegaldesleukin/Nivolumab Combo May Address Unmet Need in Metastatic Urothelial Carcinoma

Brandon Scalea
Published: Monday, Feb 18, 2019

Arlene O. Siefker-Radtke, MD
Arlene O. Siefker-Radtke, MD
Bempegaldesleukin (NKTR-214) combined with nivolumab (Opdivo) showed encouraging clinical activity in patients with metastatic urothelial carcinoma who were cisplatin ineligible or refused standard therapy. The benefit was also observed in those whose tumors were PD-L1 negative, said Arlene O. Siefker-Radtke, MD.

In preliminary data from the PIVOT-02 study (NCT02983045) presented at the 2019 Genitourinary Cancers Symposium, bempegaldesleukin, a novel interleukin (IL)-2 therapy, combined with the PD-1 inhibitor nivolumab in these patients resulted in an overall response rate (ORR) of 48% in the efficacy evaluable population (n = 27) and a disease control rate of 70%. Notably, the ORR was 45% in patients with PD-L1–negative tumors compared with 50% in patients who expressed PD-L1 positivity. Patients received .006 mg/kg of bempegaldesleukin plus nivolumab at 360 mg every 3 weeks.

Regarding safety, the most common (>15%) treatment-related adverse events (TRAEs) observed with the combination were flu-like symptoms (71%), fatigue (46%), pyrexia (38%), rash (46%), pruritus (32%), decreased appetite (27%), and nausea (22%). Grade ≥3 TRAEs occurred in 16% of patients, and 15% of patients discontinued therapy due to TRAEs.

In an interview with OncLive, Siefker-Radtke, a professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed the promising preliminary data with bempegaldesleukin plus nivolumab in patients with metastatic urothelial carcinoma and the next steps for this combination.

OncLive: Could you discuss bempegaldesleukin and its mechanism of action?

Siefker-Radtke: Bempegaldesleukin is a novel IL-2 therapy. “Aldesleukin” stands for IL-2 and “peg” stands for polyethylene glycol. The IL-2 has 6 polyethylene glycols attached to it. The “bem” part—well, I have been told that it does not [stand for] anything, but I [believe] it means a biologically engineered modification.

By engineering IL-2 in this fashion, it has resulted in sustained intravascular concentrations that last on the order of days rather than the typical minutes we have traditionally observed with cytokines like IL-2. This medication works through the IL-2 beta receptor, and this is important in that it stimulates the immune cells needed to enhance the immune system's effectiveness against cancer.

The signaling is specific for IL-2 beta compared with IL-2 alpha, which has been associated with regulatory T cells, which reduce the immune response. The goal of this therapy was to have a therapeutic that stimulated lymphocytes and other favorable immune cells in the hopes of enhancing the response to immune checkpoint inhibition.

What were the findings from PIVOT-02? What were the clinical implications of these preliminary data?

What we have seen is a very gratifying response rate, with ORRs ranging from 40% to 50% of patients. Complete responses were seen in 17% of patients. Not only are we seeing gratifying responses, but we are also seeing responses in PD-L1–negative tumors. PD-L1–negative tumors have long been associated with low response rates to checkpoint inhibition. In fact, the FDA recently provided guidance that patients in the frontline setting should not be treated with checkpoint inhibitors unless they have PD-L1 positivity. The finding that there is clinical activity in the PD-L1–negative tumors suggests that this therapy may meet an unmet need by currently available treatments.

What are the next steps with these data?

We need a larger sample size, because this is a small patient population. If we can confirm these findings in a larger population of patients, then moving on to phase III trials could help us get FDA approval for a novel therapeutic with a novel mechanism to stimulate the lymphocyte production needed to help improve immune response.

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