乌鸦传媒

ATLANTA -- Patients with metastatic melanoma that progressed on anti-PD-1/L1 therapy achieved durable responses with an investigational histone deacetylase (HDAC) inhibitor plus a PD-1 inhibitor, a showed.

Ten of 53 (19%) patients had confirmed responses, including one complete response, when treated with entinostat and pembrolizumab (Keytruda). An additional nine patients had stable disease for more than 6 months.

A majority of the patients had some degree of tumor shrinkage with the combination, reported Ryan J. Sullivan, MD, of Massachusetts General Hospital Cancer Center in Boston, at the American Association for Cancer Research (AACR) annual meeting.

"In patients with progressing melanoma on prior PD-1 blockade -- clearly, a group with limited treatment options -- entinostat and pembrolizumab demonstrated significant antitumor activity," said Sullivan. "The combination was safe and tolerable. In fact, the dominant toxicity was additive toxicity with entinostat, with no apparent increase in immune-related adverse events with the combination."

Use of epigenetic therapy, such as the entinostat-pembrolizumab combination, to reverse melanoma resistance has "galvanized" melanoma researchers and may represent the most important use of epigenetic therapy, said AACR invited discussant Stephen B. Baylin, MD, of Johns Hopkins University in Baltimore.

"This is an important trial," Baylin said of Sullivan's presentation. "The positive findings of this trial are pivotal at a pivotal time in the field. Reversing resistance to immune checkpoint therapy, involving RECIST criteria responses, is fantastic. The overall medical benefit is impressive. The study is very positive for seeing the overall potential role for epigenetic therapy in the setting of immunotherapy. Right now, there are no FDA-approved epigenetic therapy agents for solid tumors."

Beginning with the FDA approval of ipilimumab (Yervoy) in 2011, the treatment landscape for melanoma has changed dramatically. Long-term survival increased from about 10% with high-dose interferon to about 20% with ipilimumab alone. Data from completed and ongoing studies of immune checkpoint inhibitors, either alone or in combination, showed that long-term survival may be within reach for 30%-40% of patients with advanced melanoma.

"Maybe it's because I'm standing next to the College Football Hall of Fame, but when I'm looking at the advances in melanoma over the past decade, I sort of want to spike the football, because we've made such great progress in a short period of time," said Sullivan.

Despite the advances, most patients with advanced melanoma eventually develop resistance to treatment, and succumb to the disease, he added. Continued improvement in the long-term outlook requires better understanding of the mechanisms of therapeutic resistance in melanoma. Investigations into multiple potential mechanisms are ongoing.

Better understanding of resistance mechanisms could inform development of more effective therapy. Better front-line therapy will remain important, but with respect to clinical trial planning, "the most relevant and most unmet need is what do we do for patients who have received anti-PD-1 antibody therapy and need something else."

The rationale for evaluating entinostat in combination with anti-PD-1/L1 therapy includes evidence that the agent contributes to downregulation of immunosuppressive cells in the tumor microenvironment. Studies involving preclinical models showed evidence of synergy with anti-PD-1 drugs. A phase I study reported at AACR showed a significant decline in myeloid-derived suppressor cells within 14 days after a single dose of entinostat.

Sullivan reported findings from a phase II, open-label study evaluating entinostat and pembrolizumab in 53 patients with recurrent or metastatic melanoma and progression during or after anti-PD-1 therapy. The patients were part of a larger clinical evaluation that also included patients with non-small cell lung cancer and colorectal cancer.

About half the patients had PD-L1 positive tumors. Treatment history included the combination of ipilimumab and a PD-1 inhibitor in 37 patients and a BRAF/MEK inhibitor combination in 12. Seven patients attained objective responses to frontline therapy, including one complete response. Another 20 patients had stable disease. The median duration of prior anti-PD-1 therapy was 5.2 months.

The combination led to objective responses in 19% of the patients and clinical benefit in 36%. A majority of the patients had some degree of tumor shrinkage. After a median follow-up of 10.6 months, the study population had a median progression-free survival of 4.2 months. Ten patients remained in follow-up for more than a year, including one patient who had an early response, developed intolerance and discontinued treatment, but maintained the response during follow-up for more than 90 weeks.

The most common treatment-related adverse events (TRAEs, all grades) were nausea (47.2%), fatigue (37.7%), diarrhea (20.8%), decreased neutrophil count (18.9%), decreased platelets (17%), pruritus (17%), decreased white-cell count (17%), anemia (15.1%), arthralgia (15.1%), and vomiting (15.1%). Grade 3/4 TRAEs included neutropenia (7.5%), hyponatremia (5.7%), and fatigue (5.7%).

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