Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells.,We report the results of the PEMDAC phase 2 clinical trial (n = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM).,The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%.,The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months.,Toxicities were manageable, and there were no treatment-related deaths.,Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature.,Longer survival also correlated with low baseline ctDNA levels or LDH.,In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM.,Trial registration ClinicalTrials.gov registration number: NCT02697630 (registered 3 March 2016).,EudraCT registration number: 2016-002114-50.,The authors report the results of the phase II PEMDAC clinical study testing the combination of the HDAC inhibitor entinostat with the anti- PD-1 antibody pembrolizumab in uveal melanoma.,Low tumor burden, a wildtype BAP1 gene in the tumor or iris melanoma correlates with response and longer survival.
While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma.,Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need.,Reports of treatment with immune checkpoint inhibitors have thus far been disappointing.,Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy.,Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells.,The PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma.,Primary endpoint is objective response rate.,Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0-1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy.,Twenty nine patients will be enrolled.,Patients receive pembrolizumab 200 mg intravenously every third week in combination with entinostat 5 mg orally once weekly.,Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24 months.,The PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM.,ClinicalTrials.gov registration number: NCT02697630.,(Registered 3 March 2016).,EudraCT registration number: 2016-002114-50.