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.”
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.
OncLive: How would you describe the study with entinostat and high-dose IL-2 in RCC?
: 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.
What has been the overall significance of these findings?
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.
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.
Are there any toxicity concerns associated with this combination?
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.
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.
Could this HDAC inhibitor be combined with other agents in this space?
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.