Pembrolizumab With Entinostat Led to Responses in Patients With Melanoma Who Progressed on Prior Checkpoint Inhibitors

Combining the PD-1 inhibitor pembrolizumab (Keytruda) with the HDAC inhibitor entinostat demonstrated promising clinical activity and acceptable safety in patients with melanoma who were refractory to immune checkpoint inhibitors. 

Melissa Lynne Johnson, MD

Pembrolizumab (Keytruda) in combination with entinostat, an HDAC inhibitor, showed clinical activity in patients with melanoma who had progressed on or following treatment with checkpoint inhibitors, as well as an acceptable safety profile.

In the ongoing phase II ENCORE 601 trial, the PD-1/HDAC combination induced a response in 4 of 13 patients (31%; 95% CI, 9-61). The responses comprised 3 confirmed responses and 1 unconfirmed response, according to the study findings, which were presented in a poster at the 2017 ASCO Annual Meeting. An additional 4 patients achieved stable disease.

In an interview withTargeted Oncologyat the ASCO meeting, lead study author Melissa Lynne Johnson, MD, Sarah Cannon Research Institute, explained the mechanism of this novel regimen.

“Myeloid-derived suppressor cells (MDSCs) are immune cells that rise as a mechanism of resistance to PD-1/PD-L1 inhibitors. Entinostat has been shown preclinically to suppress MDSCs. So, the idea here is that we are warming up cold tumors that used to be hot. And, maybe, warming up tumors that were cold to begin with.”

The median age was 62 (range, 38-86) for the 13 melanoma patients, 62% had an ECOG performance status (PS) of 0, and 38% had an ECOG performance status of 1. Forty-six percent of patients had visceral metastases. By PD-L1 expression status, 31% were negative, 46% were positive, and 23% were not evaluable. All patients had progressed on or following pembrolizumab (54%) or nivolumab (Opdivo; 46%); ipilimumab (Yervoy; 62%); and a BRAF inhibitor (15%).

Patients received oral entinostat at 5 mg weekly and pembrolizumab at 200 mg IV every 3 weeks in 21-day cycles until disease progression. Patients were assessed for response every 6 weeks.

Among the responders, the median duration of prior anti—PD-1 therapy was 4.9 months (range, 2.7-12.5). Two of the 4 patients who responded had stable disease (SD) and 2 had progressive disease as their best response to their previous anti–PD-1 agent before progressing. At the data cutoff, 3 patients remained on treatment, 1 with a partial response (PR) and 2 with SD.

Three of the 4 responders began study treatment within 10 months (range, 1.8-10.4) of their last dose of anti—PD-1 therapy. The fourth patient’s last dose occurred 28.8 months before the start of the study.

Responses were observed in patients who did and did not receive ipilimumab in combination with their prior regimen of nivolumab or pembrolizumab.

Additionally, the researchers noted in their poster that, “One patient with a confirmed PR converted from a PD-L1—negative, noninflamed gene signature in a pretreatment tumor biopsy to a PD-L1–positive, inflamed gene signature posttreatment.”

The most common all-grade treatment-related adverse events (AEs), included nausea (7 patients), diarrhea (3 patients), pruritus (3 patients), and fatigue (2 patients).

Treatment-emergent grade ≥3 AEs occurred in 8 patients. These events included ALT/AST increase, atrial flutter, blood bilirubin increased, cellulitis, fatigue, hyponatremia, hypovolemia, nausea, rash, sepsis, and urinary tract infection.

There was 1 AE—related treatment discontinuation—transaminitis, which the researchers considered to likely be related to pembrolizumab.

The researchers are continuing to conduct correlative analyses of peripheral blood and tumor tissue biomarkers the entire patient population.

“This is important data showing that with the addition of entinostat, meaningful responses can occur in patients who have progressed on an anti—PD-1 or anti–PD-1/anti–CTLA-4 regimen. This is an area of very high unmet medical need,” said Jedd D. Wolchok, MD, PhD, chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, said in statement when Syndax Pharmaceuticals, the manufacturer of entinostat, initially announced the results in May. Wolchok is a member of the Syndax Scientific Advisory Board.

Encore 601 is also exploring the pembrolizumab/entinostat combination in 3 other cohorts: patients with non—small cell lung cancer (NSCLC) with no prior anti–PD-1 treatment; patients with NSCLC who progressed on a PD-1 inhibitor; and patients with microsatellite stable colorectal cancer who have not received a PD-1 inhibitor.


Johnson ML, Gonzalez R, Opyrchal M, et al. ENCORE 601: A phase II study of entinostat (ENT) in combination with pembrolizumab (PEMBRO) in patients with melanoma.J Clin Oncol35, 2017 (suppl; abstr 9529).