PIVOT-02 Trial

Arlene O. Siefker-Radtke, MD:Recently, it was my pleasure to present the first results of the expansion cohort from PIVOT-02. This clinical trial combined bempegaldesleukin with nivolumab in multiple tumor types. Bempegaldesleukin is a pegylated modifier of the IL-2 receptor. And using these pegylations—it actually contained 6 of them—they developed a therapeutic cytokine that remains in the circulation longer, which has been 1 of the limitations with the use of cytokine-directed therapies. Not only does it remain around longer, but it showed preferential expansion of the immune infiltration that’s needed to induce the immune response without upregulation of the T-cell regulatory subset that’s been associated with a lack of immune response.

As a result of the phase I trial, a 3-week schedule combining bempegaldesleukin with nivolumab was utilized and 27 patients were treated with metastatic urothelial cancer in the frontline setting. The majority of them were considered cisplatin ineligible by a variety of factors, including poor kidney function, being hard of hearing, and having neuropathy.

When we look at the response rates, there was a gratifying objective response rate of around 48%, which included CRs [complete responses] and PRs [partial responses], and additional patients achieving disease control with a disease control rate of around 70%. Not only did we see partial responses, but we saw complete responses occurring in 19% of patients, which is a much higher complete response rate compared with what’s been observed with single-agent immune checkpoint inhibition.

Not only did we see a great response rate, we’re also seeing evidence of durability of responses. I have several patients who are still ongoing with their treatment for more than a year from when the trial opened.

On the basis of these results, we are moving forward with several clinical trials testing the combination of bempegaldesleukin with nivolumab in patients with metastatic urothelial cancer, but also in patients needing neoadjuvant chemotherapy for their bladder cancer. With a complete response rate of 19%, I think it is truly an option that we can consider for neoadjuvant treatment. When you look at systemic chemotherapy, which has curative potential in the neoadjuvant setting, the best complete response rate was 21%. So my hope is that we may be able to provide an alternative for patients with muscle-invasive disease who are not candidates for curative cisplatin-based chemotherapy.

This outpatient regimen of bempegaldesleukin with nivolumab not only had an excellent response rate, but we also saw responses in PD-L1 [programmed death-ligand 1]—low tumors and in patients with visceral metastases, including liver metastases. And both of these situations, PD-L1–low and visceral metastases, remain an unmet need for our patients given the low response rates observed with single-agent immunotherapy. This additional evidence, I believe, supports the development of this therapy both in the frontline treatment of metastatic urothelial cancer and as a neoadjuvant strategy for patients who are not candidates for curative cisplatin-based chemotherapy.

When you look at the adverse-effect profile of this combination, overall it has been very well tolerated by our patients. We do see a lot of the typical immune checkpoint inhibitor—mediated adverse effects, including the thyroiditis, the myositis. But what’s unusual about this combination is we also see the cytokine-related adverse effects. Typically, patients experience flu-like symptoms for approximately 5 days to 1 week following their dose of treatment. They can have myalgias and muscle aches in addition to having their fever. And we’ve been able to control this well for the majority of patients with the use of Tylenol and other anti-inflammatory agents.

We also see some hypotension, which has observed with high-dose IL-2. Usually this has been well controlled with modification of their blood pressure medication strategy, and also with hydration, giving IV [intravenous] fluids on the day that they receive their bempegaldesleukin and encouraging oral fluid hydration with additional IV hydration if indicated.

The majority of patients have been able to tolerate their treatment well, which has been shown by the durability of responses and the ability of patients to continue on this treatment for a long period of time.

As part of this clinical trial, biopsies were performed both pre- and post treatment to get an idea of how this impacts PD-L1 expression on the tumor and other markers associated with the immune response. PD-L1 was shown to be low in approximately half the patients who were reported on at GU ASCO [Genitourinary Cancers Symposium]. Despite low PD-L1 expression, we saw a similar objective response rate with the use of bempegaldesleukin plus nivolumab as compared with those who were high expressers for PD-L1. We also saw conversion of PD-L1—low tumors, then displaying PD-L1 positivity after they received treatment with the combination. That occurred in 7 of 10 patients. So it does appear that this combination can induce an immune response, which is associated with an inflammatory infiltrate, creating an impact against their disease.

Transcript edited for clarity.