Phase II multicenter open label study of pembrolizumab and entinostat in adult patients with metastatic uveal melanoma (PEMDAC study)

Background 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 patients with metastatic uveal melanoma. Reports of treatment with immune checkpoint inhibitors in monotherapy have been disappointing. There is preclinical evidence that the effect of immunotherapy may be augmented by epigenetic therapy through mechanisms including enhanced expression of HLA class I and cancer antigens, and suppression of myeloid suppressor cells. Methods We performed a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD-1 inhibitor pembrolizumab and the HDAC inhibitor entinostat in 29 adult patients with metastatic uveal melanoma. Eligible patients had histologically confirmed metastatic uveal melanoma, ECOG performance status 0–1, and measurable disease as per RECIST 1.1. Patients received pembrolizumab 200 mg intravenously every third week in combination with entinostat 5 mg orally once weekly. Primary endpoint was objective response rate (ORR). Secondary endpoints include clinical benefit rate (CBR; CR, PR or SD) at 18 weeks, overall survival (OS), and safety assessed by adverse events (AE). Results At the data cut off of June 21, 2019, 29 patients had been enrolled and received at least one dose of treatment with a median follow up of 7.7 months. Ninety per cent had liver metastases and 59% had received previous treatment for metastatic disease. A partial response (PR) was observed in 3 patients resulting in an ORR of 10%. Nine patients (31%) had a best overall response of stable disease (SD). Clinical benefit at week 18 was observed in 7 out of 29 patients (24%). Median OS was 11.5 months. Twenty-eight patients (97%) experienced treatment related AEs, and grade 3-4 AEs were reported in 18 patients (62%). There were no treatment related deaths. Conclusions The PEMDAC study has demonstrated that combined HDAC- and PD-1-inhibition can result in clinical efficacy in metastatic uveal melanoma with manageable toxicities. The obtained data warrant further investigation to address clinical and immunological characteristics of patients achieving clinical benefit. Clinical trial identification NCT02697630 (Registered 3 March 2016). EudraCT: 2016-002114-50. Legal entity responsible for the study Sahlgrenska University Hospital, Vastra Gotaland Region. Funding Syndax Pharmaceuticals and Merck & Co. Inc. Disclosure R. Olofsson Bagge: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). G. Ullenhag: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). I. Ljuslinder: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). M. Levin: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). U. Stierner: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). L. Ny: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). All other authors have declared no conflicts of interest.