Combining a selective class I oral histone deactylase (HDAC) inhibitor with high-dose interleukin (IL)-2 may boost the latter's antitumor effect in renal cell carcinoma (RCC).
HDAC Plus High-Dose IL-2 Improved Antitumor Activity RCC
Roberto Pili, MD
Combining a selective class I oral histone deactylase (HDAC) inhibitor with high-dose interleukin (IL)-2 may boost the latter's antitumor effect in renal cell carcinoma (RCC), according to Roberto Pili, MD.
High-dose IL-2 is an option for some patients with metastatic clear cell RCC and has been shown to be superior to low-dose IL-2, with an objective response rate (ORR) of 15% in 7 of the clinical trials that came to form the basis of approval by the FDA.2
The SELECT trial, conducted in 120 patients, demonstrated an ORR of 25%, a median progression-free survival (PFS) of 4.2 months, and a median duration of response of 20 months with high-dose IL-2 in this setting.3The combination was also found to induce minimal toxicities in patients.1
Entinostat is a class I selective oral HDAC inhibitor that is in clinical development for use in combinations for the treatment of breast and lung cancer.
“Its long half-life [140 hours] allows continuous exposure with once weekly or bi-weekly dosing,” said Pili, professor of oncology, Indiana University School of Medicine, Indianapolis, at the 2016 Genitourinary Cancers Symposium. “Several years ago, our group showed that high-dose IL-2 and entinostat had a synergistic antitumor effect in a murine model of renal cell carcinoma.”4
Entinostat downregulates Foxp3 expression in regulatory T cells (Tregs) and inhibits their suppressive function. “Interestingly, low Tregs numbers have been associated with better outcomes in patients receiving high-dose IL-2,” he explained.5,6The inhibitory effect of entinostat on Tregs may therefore increase the response rate and PFS in patients receiving high-dose IL-2.7
The phase I/II study reported here investigated entinostat administered as 3 mg or 5 mg starting 2 weeks before initiating high-dose IL-2, during IL-2 therapy, and continuing until disease progression in 47 patients with measurable or evaluable metastatic clear cell RCC who had no prior first-line systemic therapy. To be eligible, patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 and normal bone marrow, liver, and renal function. IL-2 was dosed at 600,000 U/kg every 8 hours.
All patients had prior nephrectomy. Memorial Sloan Kettering Cancer Center risk status was 0 (favorable) in 53% of the patients and 1-2 (intermediate) in 47%. Metastatic sites were lung in 36 patients, lymph nodes in 26, bone in 7, and liver in 6.
Eleven patients were treated during phase 1 (3 patients with the 3-mg dose of entinostat and 8 patients with 5 mg) with no dose-limiting toxicity observed. The most common grade ≥3 toxicity was hypophosphatemia. One patient died from malignant pericardial effusion and tamponade unrelated to the study drug regimen.
Of 37 patients with measurable disease, the ORR is 35% (13 responses). Three patients had a complete response and 10 had a partial response. Two additional patients had resolution of the target lesion but still had a subcentimeter non-target lesion present. Nineteen patients are still receiving treatment. To date, the median PFS is 16.1 months. In patients with an objective response, the median PFS is 28.5 months, compared with 5.7 months in those with a response.
The effect of the regimen on tumor metabolism was also assessed using fluorodeoxyglucose positron emission tomography (FDG-PET) in 22 patients, 11 of whom had pre- and post-scans. Treated patients who had an objective response had a greater decline in FDG-PET uptake in the target lesions compared with baseline.
Three patients had tumor biopsy pre- and post-treatment. An increase in the number of tumor infiltrating CD8+ effector cells and a decreased number of Tregs were observed in one patient with durable stable disease (16 months) and one patient with objective response.
Circulating immune cells were compared in responders and non-responders during pre-treatment with entinostat, from cycle 1, day 14 through cycle 1, day 1. Flow cytometry values for responders were likely to be lower for Tregs at cycle 1, day 1. Values for responders were also likely to be higher for antigen presenting cells at cycle 1, day 7 and cycle 1, day 1, as well as increases from baseline from cycle 1, day 14 through cycle 1, day 1 (P≤ .03).
The data suggest that entinostat may increase the antitumor effect of high-dose IL-2 by modulating immunosuppressive cells, concluded Pili.
References
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