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

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.

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

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.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.

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

What are the next steps with these data?

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 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.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.

What is the safety profile of this combination?

Could you comment on the response rate drop from the earlier report from this trial at the 2018 ASCO Annual Meeting, in which the ORR was 60%?

Where do you ultimately see this combination fitting in to the treatment paradigm?

In fact, when I look at this therapy, it is more like a miniature chimeric antigen receptor T-cell therapy that you can give every time you give a dose to a patient. This [approach] allows for patients to continue to receive treatment over time, and, perhaps, respond to new antigens from tumors that develop in the setting of immune resistance.In looking at this combination, we found it to be very safe and tolerable. Only 4 patients came off therapy due to grade ≥3 AEs, and there were no grade 4 or 5 AEs observed. The AEs noted are events we typically see with single-agent immune checkpoint inhibitors at a similar frequency. We do see grade 1/2 AEs that are probably related to the mechanism of action, where stimulating of the immune system causes an inflammatory response. Typically, these AEs improve, and the patients are feeling much better after a shorter interval than what we typically see with combination chemotherapy.The ASCO data were based upon 10 patients, so the error bars are high. These data are a larger sample size from the expansion cohort. There are plans to do a much larger phase II trial which will provide the best data.At the moment, we are exploring frontline strategies, looking specifically at PD-L1—low tumors. With response rates in PD-L1–low tumors that are still in the 40% to 50% range, similar to PD-L1–positive tumors, I would argue this should be studied even in PD-L1–positive disease. It may be an attractive option for patients who are not able to tolerate or do not wish to tolerate the aggressive AEs often associated with chemotherapy combinations.

Among the other encouraging data presented in this setting was sacituzumab govitecan (IMMU-132). What are your thoughts on this agent?

What is your take-home message on the current state of urothelial cancer based on the data presented at the 2019 Genitourinary Cancers Symposium?

For the long-term, however, this has potential to serve as a baseline therapeutic where you can combine even novel agents to bempegaldesleukin and a checkpoint inhibitor; this could increase immune response across several different urothelial cancers with different mechanisms of resistance.Sacituzumab govitecan is certainly an intriguing treatment option using an antibody-drug conjugate (ADC) targeting Trop-2, which is frequently expressed on urothelial cancer cells. What we are seeing are response rates that appear reasonable and show evidence of activity in previously treated patients. Response rates were in the range of 30%. It is an ADC, so there is some toxicity associated with it. When you compare it with enfortumab vedotin, it does appear to have a higher rate of neutropenia [associated with it]; however, other ADCs have toxicity as well. Therefore, both of these agents are good candidates for our armamentarium.For over 20 years, we have relied heavily on the use of chemotherapy agents that are typically considered poisons in some other settings. We are now moving toward personalized medicine, where, based on targets that tumors may have, we are able to target them more directly. My hope is that we will continue to move in this direction and be able to find treatments that are better for our patients. Furthermore, with the use of the immune system and our ability to modulate the immune system with novel agents, my hope is that we will see more durable responses.

Siefker-Radtke A, Fishman MN, Balar AV, et al. NKTR-214 + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. J Clin Oncol. 2019;37(suppl 7; abstr 388).

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