Pembrolizumab Plus Entinostat for Uveal (Eye) Melanoma and Recent Developments

According to a new second-stage clinical trial, immunotherapy pembrolizumab plus an epigenetic mechanism inhibitor, entinostat, showed activity with long-lasting responses in patients with uveal (eye) melanoma, for which satisfactory treatment options are limited. An anti-PD-1 immune checkpoint inhibitor, pembrolizumab was tested alongside the histone deacetylase (HDAC) inhibitor entinostat in this study, called PEMDAC. Its results were published in Nature Communications.

What Is Uveal Melanoma?

Uveal melanoma is a rare subtype of an aggressive cancer accounting for about 5% of skin cancers: malignant melanoma. Uveal melanoma begins in the pigment cells of the eye. Most melanoma is cutaneous (arising on the skin surface), and immune checkpoint inhibitor therapies such as pembrolizumab have been effective in most cases of these types. This does not apply to intraocular (inside the eye) melanoma. Approximately 50% of patients with uveal melanoma develop metastatic (stage 4) disease, most commonly with liver metastases, which is associated with a poor prognosis (disease outlook).

Details of the PEMDAC Study

In the phase 2 PEMDAC study, 29 patients with metastatic uveal melanoma received the combination of these 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.

These results are promising for a cancer such as uveal melanoma, for which there is no approved treatment.

The study's lead author, Dr. Lars Ny, explained why they tested this combination: “Our hope was that the HDAC inhibitor would reprogram the hiding cancer cells so that they could be detected by immune system cells, thereby making immunotherapy with PD-1 inhibitors effective.”

All things considered, although this clinical trial does not appear to offer a complete cure, it meets expectations. To understand why there were such large differences in how well patients responded, the researchers performed genetic analyses. These analyses showed that the combination treatment worked better in people whose tumors had an active, undamaged BAP1 gene. This gene is generally inactive in metastases, but we have now found it to be associated with the best response to immunotherapy.

In conclusion, HDAC inhibition and anti-PD-1 immunotherapy resulted in durable responses in some patients with metastatic uveal melanoma. Longer survival was also associated with low levels of ctDNA (tumor DNA in the blood) or lactak dehydrogenase.

The research team is continuing to investigate why loss of the BAP1 gene causes resistance to immunotherapy and which other changes in blood components in patients with uveal melanoma might contribute to survival rates after immunotherapy.

Recent Developments in Uveal Melanoma Treatment: A Summary?

In uveal melanoma, more than half of which is detected at the metastatic stage at diagnosis, median survival rates of 12 months unfortunately remain disappointing, and managing metastases, particularly to the liver, remains substantially difficult. There is little agreement on how this situation should be managed. Studies suggest that liver-directed regional treatments may provide longer disease control than current systemic treatment options.

Supporting the response to another immune-system biomarker, Type 1 INF, is also viewed as a strategy to overcome immune resistance. Intratumoral approaches to support this mechanism are ongoing. Tebentafusp is a leading candidate for improving uveal melanoma survival through T-cell redirection. Studies of people who do and do not respond to this treatment will help us understand how this class of agents provides benefit, produces toxicity and redirects the immune system.

Another important development in targeted treatment strategies for uveal melanoma is the production of selective YAP/TAZ-TEAD signaling pathway inhibitors and their testing in uveal melanoma models, providing evidence that this pathway plays an important role in mutant Gαq/11 signaling. Research on targeted therapy with second-generation PKC inhibitors also continues.

There is also a study examining adenosine signaling and immune suppression in uveal melanoma and pancreatic adenocarcinoma.