Expert Shares Insight on Promising Entinostat/IL-2 Results in RCC

Roberto Pili, MD

The combination of the HDAC inhibitor entinostat and high-dose interleukin-2 (IL-2) demonstrated an overall response rate of 37% in patients with previously untreated metastatic renal cell carcinoma (RCC) of clear cell histology, according to results of a phase I/II study.

In the study, which was presented during the 2016 AACR Annual Meeting, patients were treated with entinostat at a dose of 3 mg or 5 mg every 14 days (beginning 14 days before the start of IL-2) and IL-2 at a dose of 600,000 u/kg every 8 hours for a maximum of 14 doses. One treatment cycle lasted 85 days.

“This is a small-site, single-arm study, but these preliminary data are encouraging,” says lead study author Roberto Pili, MD. “It suggests that this combination of an HDAC inhibitor can induce a greater benefit with an immunotherapy—in this case, IL-2.”

OncLive: How would you describe the study with entinostat and high-dose IL-2 in RCC?

What has been the overall significance of these findings?

In an interview with OncLive, Pili, professor of Medicine and Robert Wallace Miller Professor of Oncology at Indiana University School of Medicine and a researcher at the Indiana University Melvin and Bren Simon Cancer Center, discusses the results and significance of this early-phase trial and how it could shake up the treatment paradigm for RCC.Pili: This was a multicenter trial for patients with metastatic clear cell RCC who had no prior therapies and were eligible to receive high-dose IL-2 and we combined the standard regimen of IL-2 with entinostat, a class I selective HDAC inhibitor. Based on preclinical data, we suggested that this combination could synergize and have a greater clinical benefit in patients.In this phase I/II study, we have accrued 47 patients in total—among these 4 were not evaluable. Two patients were evaluable but with no measurable disease.

Out of the 41 patients with measurable disease, we observed a 37% ORR, with 3 patients achieving complete remissions and 12 patients achieving objective response—so a total of 15 patients.

These are encouraging results, based on the historical data with high-dose IL-2 as a single agent. The reported ORR is between 20% and 25%. The recent SELECT trial showed an ORR of 25%, but with a median progression-free survival (PFS) of 4.2 months.

Are there any toxicity concerns associated with this combination?

To date, in our patients treated with our combination of entinostat and IL-2, we observed a median PFS of 16.1 months and an overall survival of 65.3 months.Overall, we have not seen an increase in toxicity. We know that high-dose IL-2 induces severe side effects, so that’s why the treatment is only for select patients and is given in a hospital setting, where patients can receive proper care. However, we haven’t really seen an increase of the severe side effects we see with IL-2.

Could this HDAC inhibitor be combined with other agents in this space?

The most common side effect was hypophosphatemia, which is recognized as a side effect from HDAC inhibitors, but it was not really associated with electrolytes. The second side effect was a decrease in lymphocytes; however, this is a commonly reported side effect of IL-2 and was deemed to not be clinically significant.We are particularly excited about these data because this is really the first, to my knowledge, clinical trial that really showed that an epigenetic agent in clinical development could enhance immunotherapy. We already have preclinical data suggesting that HDAC inhibitors, in particular entinostat, can modulate immune response.

In the case of high-dose IL-2, we believe the synergy is really from reducing regular T cells. This plays a role in the response to high-dose IL-2, but preclinical data suggest that if we combine entinostat with PD-1 inhibitors, we have the synergy to have that immune effect.

There are ongoing studies looking at the combination of HDAC inhibitors with PD-1 inhibitors. This is really the first layer of research that will show the combinatorial effect of epigenetic drugs with immunotherapy. What setting(s) do you envision this being treated in? Currently, high-dose IL-2 is approved as a first-line treatment for select patients. We envision that this type of combination should be available in the first-line setting. However, PD-1 inhibitors or other immune checkpoint inhibitor combinations will become more available for our patients with clear cell RCC.

Looking ahead in the field of kidney cancer, where are we going?

We still believe that this type of combination with high-dose IL-2 and epigenetic drugs can also be offered in the second-line setting in a selection of patents who can tolerate this toxic regimen. It is toxic for only a short period of time, and only when patients are in the hospital. When they go home, they do fine. They don’t have that chronic toxicity we’re starting to see with immune checkpoint inhibitors.We are very excited about the availability of these immune checkpoint inhibitors. We have nivolumab (Opdivo) already approved for second-line. We are awaiting the results of other combination strategies with other immune checkpoint inhibitors. They will likely become available in the first-line setting.

With all of these therapies available, will there be any challenges with sequencing?

I believe the antiangiogenic drugs such as sunitinib (Sutent) and pazopanib (Votrient) will stay and will still be resourceful to our patients. Unfortunately, even the combinations of immune checkpoint inhibitors don’t show a clinical benefit in every patient. We are excited to have new tools available for our patients with kidney cancer, which, historically, has been an orphan disease.As we get more drugs approved, the challenge is going to be the right sequence. Time will tell as to how we are going to be able to figure out how to use these agents. I think back to 10 years ago, when we started having the first TKIs available. Now that we have more drugs, this will be something that can challenge us to find the right sequence.

What are some other ongoing trials you are excited to see the results of?

From a patient perspective, it does provide additional treatments that are not necessarily curative, but can increase the lifespan of our patients with kidney cancer. It is a challenge but, hopefully, some of the clinical trials will help us to end up with the right sequence and the right approach.We are waiting to see the results of the combination of CTLA-4 and PD-1 inhibitors as a first-line approach. There is also a combination of a PD-L1 agent with an antiangiogenic therapy.

As other agents are coming down the pipeline, there are more molecules targeting the pathway than just VEGF. This will provide additional tools for our patients.

Pili R, Quinn DI, Hammers HJ, et al. Results from a phase I/II study with the HDAC inhibitor entinostat in combination with high-dose interleukin 2 in renal cell carcinoma patients (CTEP#7870). Presented at: 2016 AACR Annual Meeting; April 16-20, 2016; New Orleans, Louisiana. Abstract CT015.