In Refractory Melanoma, Immunotherapy plus HDAC Inhibitor Yields 'Impressive Results'

Jeffrey S. Weber, MD, PhD


April 11, 2019

This transcript has been edited for clarity.

Hello. This is Dr Jeffrey Weber, deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health in New York City. Today I want to report a very interesting abstract just presented at the 2019 AACR (American Association for Cancer Research) meeting in Atlanta, Georgia, a study presented orally by Ryan Sullivan[1] from the Massachusetts General Hospital.

In this trial, patients with PD1 refractory melanoma received the combination of the PD1 inhibitory antibody pembrolizumab plus the histone deacetylase (HDAC) inhibitor entinostat, which is an oral drug. This was a phase 2, open-label study. There were a total of 53 patients with recurrent or metastatic melanoma. All of them had ultimately progressed, but not all of them had no response to previous treatment, meaning they were not primarily refractory patients. For example, seven of the 53 had prior objective responses to frontline PD1 inhibition, including one with a complete response, and 20 of them had prior stable disease. But all of them, of course, had progressed before entering the study.

Pembrolizumab was given intravenously at the standard dose of 200 mg every 3 weeks, and entinostat was given orally at 5 mg once a week. In this trial, half of the patients had PD-L1-positive tumors, and half were PD-L1 negative. More than half of the patients had previously received the combination of ipilimumab and nivolumab, and 23% of them, or 12 of the total, had received BRAF/MEK inhibitors. So this was a heavily pretreated population. The median duration of prior PD1 antibody therapy was 5.2 months; thus, patients had generally progressed pretty quickly.

By the time of the data cutoff in January, of those 53 evaluable patients with PD1-refractory disease, nine of them had a partial response and one of them had a complete response, for a total response rate overall of 19%. An additional nine patients had stable disease for more than 6 months, which would suggest that the true clinical benefit rate was actually 36%. This is a very impressive number in a PD1-refractory population.

The median duration of response was 12.5 months, and five of the 53 patients had ongoing responses. A majority of the patients, approximately 60%, actually had some tumor shrinkage, shown in the waterfall plot. And again, with a median follow-up of 10.6 months, the median progression-free survival was a modest 4.2 months. About 10 patients remained in follow-up for more than a year, including one patient who had an early response and then discontinued treatment, but has maintained the response now for almost 2 years.

There were some significant side effects, which Dr Sullivan felt represented the additive toxicity of the immune-related adverse events of pembrolizumab plus the side effects of entinostat, which are primarily hematologic. But looking at all of the treatment-related adverse events of all grades, the most common were nausea, fatigue, diarrhea, decreased neutrophil count (which presumably was the entinostat) decreased platelets [also entinostat], pruritus, decreased white count, and anemia, which of course, were probably also from the HDAC inhibitor.

Of the grade 3/4 treatment-related adverse events, 7.5% had neutropenia and 5.7% had hyponatremia, which may well have been related to the entinostat. Fatigue, which could be seen with either drug, was present in 5.7% of all patients. Adding up the grade 3/4 treatment-related adverse event rate, it was about 18%, which is not so different from what we would see with pembrolizumab alone, with some activity from the entinostat.

All in all, these are impressive results. And again, it's not just the 19% [overall response rate]. It's the fact that you had a significant cadre of patients who had stable disease at 6 months, for a total clinical benefit rate of 36%. We hope to see more from the expansion of this initial cohort, and we look forward to seeing the updated results of this very impressive study.

This is Dr Jeffrey Weber. Please feel free to contact me with questions or comments. Thank you very much for your attention.

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