1. Fuerst, Mark L.

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ATLANTA-A combination of the experimental histone deacetylase (HDAC) inhibitor entinostat with the anti-PD-1 inhibitor pembrolizumab showed significant clinical activity and acceptable safety in patients with melanoma who had progressed on prior anti-PD-1 treatment, according to a new study.

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Inhibitors of PD-1 and its PD-L1 have improved outcomes in patients with advanced melanoma, but treatment options for patients who progress are limited.


"A growing minority of melanoma patients are cured with immunotherapy. Most patients develop resistance and will still die of metastatic melanoma. Most patients are not receiving the ultimate benefit and need a better approach," said Ryan Sullivan, MD, Assistant Professor of Hematology and Oncology at Massachusetts General Hospital Cancer Center, at the American Association for Cancer Research annual meeting.


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.


"Adding HDAC inhibition to anti-PD-1 treatment against tumors that have developed resistance to checkpoint blockade immunotherapy may lead to re-recognition of the tumor by the immune system and down-modulation of immune-suppressive elements in the tumor microenvironment, thereby increasing the efficacy of anti-PD-1 therapy," said Sullivan.


Previously, researchers from Massachusetts General had reported preliminary data that entinostat, a class I selective HDAC inhibitor, in combination with pembrolizumab showed promising activity through alteration of the immunosuppressive tumor microenvironment. A phase I study reported at AACR showed in patients with solid tumors that myeloid-derived suppressor cells declined significantly within 14 days after a single dose of entinostat.


Methodology, Findings

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.


Sullivan presented the results from ENCORE 601 on patients with unresectable or metastatic melanoma who had progressed during or following treatment with the combination therapy (Abstract CT072).


"While a large group of patients have derived benefit from treatment with checkpoint inhibitors, many still develop resistance to these therapies. A number of studies, including this trial, are endeavoring to identify key immunotherapy combinations to overcome resistance to checkpoint blockade immunotherapy," said Sullivan.


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 (ORR).


The median duration of prior anti-PD-1 treatment was 4.9 months. Two-thirds of patients had no intervening therapy between prior anti-PD-1 treatment and study enrollment. Seventy percent of patients had prior treatment with the ipilimumab, a cytotoxic T-lymphocyte associated protein-4 (CTLA-4) blocker, and 23 percent of patients had prior treatment with BRAF/MEK inhibitors. The prior response rate was 13 percent.


Of the 53 evaluable patients, median age 62 years, nine patients had a partial response and one patient had a complete response following the combination therapy, resulting in an ORR of 19 percent. At the time of data cutoff in January 2019, the median duration of response was 13 months, and four patients had ongoing responses. An additional nine patients had stable disease for more than 6 months, leading to a clinical benefit rate of 36 percent. Nine of the 10 responses were observed by week 12.


The median progression-free survival is an estimated 4.2 months at a median follow-up of 10.6 months.


The predominant adverse events were nausea, fatigue, diarrhea, and myelosuppression. Six patients discontinued treatment due to adverse events. Five patients had grade 3 or 4 immune-related adverse events, including neutropenia, hyponatremia, and fatigue.


"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. A key next step will be to identify a biomarker to better determine which patients will respond to this treatment," said Sullivan.


The researchers found no significant change in T cells associated with response. Myeloid-derived suppressor cells showed significant and early reduction ongoing over time in responders, and several immune-regulated genes were upregulated in responders. "In seven patients, many immune signatures, including those associated with increased tumor-infiltrating lymphocytes and interferon signaling, increased following treatment," said Sullivan.


He 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.


In conclusion, Sullivan said: "In patients with progressing melanoma on prior PD-1 blockade, including PD-1/CTLA-4 blockade, a group with limited treatment options, entinostat plus pembrolizumab demonstrated significant anti-tumor activity. The combination was safe and tolerable."


The dominant toxicity with entinostat plus pembrolizumab appeared to be related to entinostat with no apparent increase in immune-related adverse events with the combination, he added.


"Preliminary biomarker analysis demonstrated findings consistent with the mechanism of action of entinostat, including reduction in circulating myeloid-derived suppressor cells and tumor-specific increases in enrichment in inflammatory pathways," Sullivan concluded.


Mark L. Fuerst is a contributing writer.