In the phase II PEMDAC study, researchers showed that the combination of the PD-1 inhibitor pembrolizumab and the histone deacetylase (HDAC) inhibitor entinostat resulted in durable responses in a small group of patients with metastatic uveal melanoma. These findings were published by Ny et al in Nature Communications.
Uveal melanoma, a rare type of malignant melanoma, starts in the pigment cells of the eye. For cutaneous melanoma, immunotherapy using checkpoint inhibitors has proved effective in many cases, but this has not applied to intraocular melanoma. Up to 50% of patients with uveal melanoma develop metastatic disease, which is most commonly localized to the liver and is associated with poor prognosis.
PEMDAC
In the phase II PEMDAC trial, 29 patients with metastatic uveal melanoma received a combination of two inhibitor drugs. The objective response rate was 14%; the clinical benefit rate at 18 weeks was 28%; and median progression-free and overall survival were 2.1 and 13.4 months, respectively.
“Our hope was that the HDAC inhibitor would reprogram hidden cancer cells so that they could be detected by the immune cells, thus making the immunotherapy with PD-1 inhibitors effective,” explained first study author Lars Ny, MD, PhD, senior lecturer at the University of Gothenburg and an oncologist at Sahlgrenska University Hospital.
“On the whole, the clinical trial met our expectations, although this doesn’t seem to be a curative treatment either. To find out why there were such major differences in how well patients responded, we performed genetic analyses. These showed that the treatment worked better against the tumors where the BAP1 gene was active and intact. This gene is often inactivated in metastases, but now we find that it’s associated with a better response to immunotherapy,” said corresponding author Jonas Nilsson, PhD, Professor at Sahlgrenska Academy at the University of Gothenburg, who is active at both the Sahlgrenska Center for Cancer Research and the Harry Perkins Institute of Medical Research in Perth, Australia.
Longer survival was also correlated with low baseline ctDNA levels or lactate dehydrogenase.
The research team is now continuing to investigate why loss of the BAP1 gene causes resistance to immunotherapy, and what other changes in blood components may predict improved survival after immunotherapy in patients with uveal melanoma.
The research team concluded, “In conclusion, HDAC inhibition and anti–PD-1 immunotherapy results in durable responses in a subset of patients with metastatic uveal melanoma.”
Disclosure: For full disclosures of the study authors, visit nature.com.
