ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.
Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%,, reported at the annual meeting of the American Association for Cancer Research.
The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.
“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.
Study participants are adults with Eastern Cooperative Oncology Groupof less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.
The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.
Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.
“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”
Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.
Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.
Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.
“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.
The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.
Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.
Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.
SOURCE: Sullivan R et al. AACR 2019, .