A combination of the experimental histone deacetylase (HDAC) inhibitor entinostat with the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab showed clinical responses in patients with melanoma that had progressed on prior anti–PD-1 treatment, according to results from the phase Ib/II ENCORE 601 trial presented by Sullivan et al at the American Association for Cancer Research (AACR) Annual Meeting 2019 (Abstract CT072).
“Although a large group of patients have derived benefit from treatment with checkpoint inhibitors, many still develop resistance to these therapies,” said presenting author Ryan Sullivan, MD, Assistant Professor of Hematology and Oncology at Massachusetts General Hospital Cancer Center, Boston, in a statement. “A number of studies, including this trial, are endeavoring to identify key immunotherapy combinations to overcome resistance to checkpoint blockade immunotherapy.”
HDAC inhibitors can modulate the immune system by suppressing regulatory cells (such as myeloid-derived suppressor cells and regulatory T cells) and by increasing antigen expression on cancerous cells, two mechanisms that may counteract resistance to checkpoint inhibition, explained Dr. Sullivan.
“Adding HDAC inhibition to anti–PD-1 treatment against tumors that have developed resistance to checkpoint blockade immunotherapy may lead to rerecognition of the tumor by the immune system and downmodulation of immune-suppressive elements in the tumor microenvironment, thereby increasing the efficacy of anti–PD-1 therapy,” he added.
The purpose of the phase II ENCORE 601 trial was to assess the effectiveness of entinostat and pembrolizumab in patients with non–small cell lung cancer, melanoma, and mismatch repair–proficient colorectal cancer. This substudy reports on patients with unresectable or metastatic melanoma that progressed during or following treatment with anti–PD-1 immunotherapy.
In this single-arm trial, patients were treated with 5 mg of entinostat once per week in conjunction with 200 mg of pembrolizumab every 3 weeks until disease progression. The primary endpoint of the study was objective response rate, as measured by immune-related Response Evaluation Criteria in Solid Tumors.
Fifty-three patients were enrolled in the trial by data cutoff (January 2019). The median duration of prior anti–PD-1 treatment was 4.9 months; 66% of patients had no intervening therapy between prior anti–PD-1 treatment and study enrollment. Seventy percent of patients had prior treatment with ipilimumab, and 23% of patients had prior treatment with BRAF/MEK inhibitors.
Of the 53 evaluable patients, 9 had a partial response and 1 had a complete response following the combinatorial treatment, resulting in an objective response rate of 19%. At the time of data cutoff, the median duration of response was 12.5 months; 5 patients had ongoing responses.
“Our results suggest that this combination may be an active regimen for patients who never responded to or progressed during treatment with PD-1 inhibitors,” said Dr. Sullivan. “A key next step will be to identify a biomarker to better determine which patients will respond to this treatment.”
Dr. Sullivan noted that prolonged delays and/or intervening therapy between prior anti–PD-1 treatment and trial enrollment may have influenced treatment response, representing a key limitation in the study.
Disclosure: This study was sponsored by Syndax. The study authors’ full disclosures can be found at abstractsonline.com.
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