Findings from the ENCORE-601 trial's melanoma cohort show that the experimental HDAC inhibitor entinostat is well tolerated and, together with pembrolizumab, induces durable responses in patients whose disease has progressed on PD-1 blockade alone.

Findings from ENCORE-601, a phase Ib/II trial, suggest that patients with inoperable or metastatic melanoma whose disease has progressed on a PD-1 inhibitor may benefit from the addition of entinostat (Syndax Pharmaceuticals), an experimental HDAC inhibitor, to their treatment regimen. The data were presented by Ryan Sullivan, MD, of Massachusetts General Hospital Cancer Center in Boston, during the American Association for Cancer Research (AACR) Annual Meeting 2019 in Atlanta, GA, on April 1 (Proceedings of the 110th Annual Meeting of the AACR, 2019, abstract CT072).

“Exactly what constitutes resistance to anti–PD-1 therapy is still up for debate, but for now, as good a definition as any would be physicians deciding their patients need something more,” Sullivan said. That's “a significant number of patients when it comes to melanoma, and we don't yet have a great sense of what the right approach might be for them. So, it can't be overstated that there's a huge unmet need here.”

Preclinically, “there's a large body of work suggesting the benefits of administering epigenetic modifiers alongside immunotherapy,” noted Antoni Ribas, MD, PhD, of the University of California, Los Angeles, who was not involved in the research. HDAC inhibition is thought to have a wide array of effects, he said, including increased antigen presentation on tumor cells. It may also keep myeloid-derived suppressor cells and regulatory T cells in check, Sullivan added, which—with PD-1 blockade in the picture—“should allow for cytotoxic T cells to be more effective at tumor eradication.”

Such potential synergy prompted the launch of ENCORE-601 to assess entinostat combined with pembrolizumab (Keytruda; Merck) in melanoma, nonsmall cell lung cancer (NSCLC), and mismatch repair–proficient colorectal cancer. Sullivan reported that of 53 evaluable patients in the melanoma cohort, the objective response rate to this combination was 19%, including one complete response. The median duration of response was 13 months; four responses are ongoing. Nine other patients experienced stable disease for more than 6 months, resulting in a clinical benefit rate of 36%, “which is not insignificant,” he said.

In addition, Sullivan noted that responses were observed regardless of treatment history—patients had previously received pembrolizumab, nivolumab (Opdivo; Bristol-Myers Squibb), or ipilimumab (Yervoy; Bristol-Myers Squibb), as well as BRAF/MEK inhibitors in some cases. The combination was also well tolerated overall, with nausea and fatigue being the main side effects.

“Continuing with PD-1 blockade alone upon disease progression would be expected to induce delayed responses in 5% to 7% of patients, at most,” Ribas pointed out. “Therefore, this study strongly suggests that adding entinostat can overcome primary resistance to immune checkpoint inhibition in a significant subset of patients with metastatic melanoma. An important next step will be defining the mechanism underlying this benefit.”

Also at AACR, Suresh S. Ramalingam, MD, deputy director of the Winship Cancer Institute in Atlanta, reported findings from gene expression analyses of patients in the NSCLC cohort of ENCORE-601 (Proceedings of the 110th Annual Meeting of the AACR, 2019, abstract CT041). Upregulated Myc and E2F signaling, as well as oxidative phosphorylation, were among the top signatures associated with response to entinostat plus pembrolizumab. These correlations add to data presented during the 2018 World Conference on Lung Cancer in Toronto, Canada, where a high baseline level of peripheral classic monocytes was linked with improved response in this patient population.

Similar exploratory biomarker studies are ongoing for the trial's melanoma arm, Sullivan said. Given that various other combinations with PD-1 blockade are being evaluated in this disease—direct intratumoral injection of TLR9 agonists, for instance, as well as oncolytic viruses—“it will be interesting to sort out whether it's always the same patient characteristics that determine benefit, or if it's different with each of these approaches,” he noted.

In the latter scenario, “you could imagine largely nonoverlapping treatment strategies where 20% of patients respond to this combination, 25% to another, and you end up with a clearer idea of what to do for the majority of patients after disease progression on PD-1 blockade alone,” Sullivan added. “I think that's where we should head next.” –Alissa Poh

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