Combination Is Active in Checkpoint Inhibitor-Refractory Patients With Melanoma

Promising clinical activity and acceptable safety was shown when the PD-1 inhibitor Keytruda (pembrolizumab) was given with the HDAC inhibitor entinostat for patients with melanoma who were refractory to immune checkpoint inhibitors.
BY Jason M. Broderick
PUBLISHED June 27, 2017
Promising clinical activity and acceptable safety was shown when the PD-1 inhibitor Keytruda (pembrolizumab) was given with the HDAC inhibitor entinostat for patients with melanoma who were refractory to immune checkpoint inhibitors.

In the ongoing phase 2 ENCORE 601 trial, the PD-1/HDAC combination induced a response in four of 13 patients (31 percent; 95 percent CI, 9-61). The responses comprised three confirmed responses and one unconfirmed response, according to the study findings, which were presented in a poster at the 2017 ASCO Annual Meeting. An additional four patients achieved stable disease.

In an interview with CURE at the ASCO meeting, lead study author Melissa Lynne Johnson, M.D., 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 percent had an ECOG performance status (PS) of 0, and 38 percent had an ECOG performance status of 1. Forty-six percent of patients had visceral metastases. By PD-L1 expression status, 31 percent were negative, 46 percent were positive, and 23 percent were not evaluable. All patients had progressed on or following Keytruda (54 percent) or Opdivo (nivolumab; 46 percent); Yervoy (ipilimumab; 62 percent); and a BRAF inhibitor (15 percent).

Patients received oral entinostat at 5 mg weekly and Keytruda at 200 mg IV every three weeks in 21-day cycles until disease progression. Patients were assessed for response every six 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 four patients who responded had stable disease (SD) and two had progressive disease as their best response to their previous anti–PD-1 agent before progressing. At the data cutoff, three patients remained on treatment, one with a partial response (PR) and two with SD.

Three of the four 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 Yervoy in combination with their prior regimen of Opdivo or Keytruda.

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 or higher AEs occurred in eight 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 one AE–related treatment discontinuation—transaminitis, which the researchers considered to likely be related to Keytruda.

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,” Jedd D. Wolchok, M.D., Ph.D., chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, said in a 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 Keytruda /entinostat combination in three 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.
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