Entinostat/IL-2 Combination Active in Previously Untreated Renal Cell Carcinoma

Roberto Pili, MD

More than one-third of patients with previously untreated renal cell carcinoma (RCC) responded to the combination of high-dose interleukin-2 (IL-2) and an investigational histone deacetylase (HDAC) inhibitor entinostat, according to results of a phase I/II trial presented at the 2016 AACR Annual Meeting.

High-dose IL-2 and entinostat led to an overall response rate (ORR) of 37% in 47 patients. The study population had a median progression-free survival (PFS) of more than 1 year, increasing to more than 2 years in responding patients.

“Reduced levels of regulatory T cells (Tregs) following entinostat treatment may be associated with objective responses,” said Roberto Pili, MD, a professor of Medicine at Indiana University in Indianapolis. “These results suggest that the selective class I HDAC inhibitor entinostat may increase the anti-tumor effect of high-dose IL-2 by modulating immunosuppressive cells.”

High-dose IL-2 is a treatment option for selected patients with metastatic RCC, resulting in an ORR of 15% in 255 patients treated in 7 clinical trials (J Clin Oncol. 1995;13:688-696). More recently, a prospective study involving 120 patients showed an objective response rate of 25% and median PFS of 4.2 months with high-dose IL-2 (Clin Cancer Res. 2015;21:561-568).

High-dose IL-2 and entinostat exhibited synergistic antitumor activity in a murine model of RCC (Clin Cancer Res. 2007;13 (15 Pt 1):4538-4546). Entinostat inhibits the suppressive function of Tregs (PLoS One. 2012;7:e30815), and low numbers of Tregs have been associated with better outcomes in patients receiving high dose IL-2.

“The inhibitor effect of entinostat on Tregs may increase the response rate and progression-free survival in patients receiving high-dose IL-2,” said Pili.

To evaluate the safety and estimate the efficacy high-dose IL-2 plus entinostat, investigators enrolled patients with previously untreated RCC into the phase I/II trial. A response rate of 20% or less was considered unsuccessful, while a response rate of 40% or greater was considered sufficiently active to warrant further investigation.

The 47 patients enrolled in the trial had a median age of 58, and all had undergone nephrectomy. Slightly more than half (53%) the patients met Memorial Sloan Kettering criteria for favorable risk, and the remaining patients had intermediate-risk disease status. Pili said 36 patients had lung metastases, and 26 had lymph node involvement.

Treatment consisted of 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.

Among 41 evaluable patients, 15 (37%) had objective responses, including three complete responses. An additional 18 patients (44%) had stable disease. Median PFS was 13.8 months. Responding patients had a median PFS of 28.5 months versus 5.7 months for patients who did not achieve an objective response (P = 0.0015). The cohort had a median overall survival of 65 months, and an estimated 3-year survival of 81%.

Pre- and post-treatment biopsies suggested an association between decreased Tregs and both objective response and durable stable disease. Specifically, responding patients had lower levels of Tregs on day 1 of a treatment cycle (start of high-dose IL-2). Additionally, responding patients had higher levels of antigen-presenting cells from day 7 to day 1 of cycle 1 and increasing levels from day -14 to day 1 of cycle 1.

The combination was found to be safe; however, it was associated with high rates of grade 3 hypophosphatemia and lymphopenia.

Grade 3/4 toxicities included hypophosphatemia (16.4%), lymphopenia (15.1%) hypocalcemia (7.2%), thrombocytopenia (6.4%), and hyponatremia (5.3%).

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: AACR 2016 Annual Meeting; New Orleans, Louisiana, April 16-20, 2016. Abstract CT015.

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