IMMUNOTHERAPY LESS EFFECTIVE FOR OCULAR AND MUCOSAL MELANOMA

Immunotherapy Less Effective in Mucosal Melanoma

First, let's talk about mucosal melanoma. Recently there was an article published in the Journal of Clinical Oncology by D'Angelo and colleagues^[1] which represented a compilation of patients with mucosal melanoma treated either with the PD-1 antibody nivolumab alone (something like 86 patients in that group) or with the combination of ipilimumab and nivolumab (something like 35 patients in that group). It was clear that there was a significant response rate for the patients with mucosal melanoma who were getting nivolumab alone, but it was not quite as good as that seen in patients with standard cutaneous melanoma. Remember that mucosal melanoma affects perhaps 1000 patients per year in the United States. It is not a common malignancy. It represents a little more than 1% of all patients with melanoma.^[2] The response rate with nivolumab in those primarily treated front-line with mucosal melanoma was 23%, but it was 40% for those with cutaneous melanoma.

If you look at the response rate in those who got ipilimumab with nivolumab, a more potent and somewhat more toxic regimen, we are looking at a 37% response rate for the nivolumab patients versus a 60% response rate for those who had standard cutaneous melanoma. The progression-free survival was only about 5.5 months in the combination regimen versus 11-plus months for those with standard cutaneous melanoma.^[1] It seemed clear that patients will not do quite as well when they have mucosal melanoma as when they have cutaneous melanoma, when receiving either PD-1 antibodies such as nivolumab alone or in combination with ipilimumab. However, it is clear that there is benefit. Patients will respond. Some patients will have long-term survival. It remains to be seen what drugs could be added to these regimens that will bring the response rate, the progression-free survival, and the overall survival up to what we see with cutaneous melanoma patients.

Ocular Melanoma Proves Even Less Responsive

Another rare subtype of melanoma is ocular melanoma. It represents a little more than 1% of all melanomas.^[3] As you remember, we have pigment cells in the uveal tract in our eyes, so you can develop a primary ocular melanoma. Many of these are treated with radiation plaque or, in the case of more advanced disease, enucleation or even exenteration of the orbit. However, quite a few patients will go on to metastasize and require systemic therapy. There is no FDA-approved regimen at this point. No drug has been approved for the treatment of ocular melanoma that has metastasized.

A number of studies, dating from 2012, have looked at either ipilimumab, the CTLA-4 antibody, or, now, the PD-1 and PD-L1 antibodies in this relatively uncommon but difficult-to-treat disease. In 2012 there was an article about the Memorial Sloan Kettering Cancer Center [experience of uveal melanoma], suggesting that the response rate in patients who received ipilimumab was really, at most, 5%-10%, with a handful of partial responses seen in the uveal melanoma patients out of more than 20 treated.^[4] Again, a relatively short survival, a short duration of response, suggesting that the potential benefit from ipilimumab alone in ocular melanoma was fairly low and was probably not quite as good as that seen with standard cutaneous melanoma.

More recently, at ASCO 2016, there were a couple of abstracts, one of them actually a compilation of 58 patients across nine institutions who had metastatic, stage IV ocular melanoma treated with PD-1 antibodies. Treatment could have been nivolumab, pembrolizumab, both PD-1 antibodies, or atezolizumab, the PD-L1 antibody.^[5]

Unfortunately, there were only two responses seen out of the total of 58 patients, for a 3% response rate^[5] which, frankly, is pretty poor. There were some stable patients, around 10. Almost all of the patients went on to progress. Duration of response was modest. We do not know what has happened with those two partial responders yet; there has been no follow-up. This is a very difficult patient population to treat. These were data presented at ASCO by Katie Tsai from UCSF.^[5] They would suggest that the median progression-free survival was only between 2.5 and 3 months, which is considerably less than what you would see with PD-1 antibodies alone in cutaneous melanoma.

There has been yet another, smaller study of 20 patients with ocular melanoma that had metastasized, treated at the Institut Curie in Paris. Zero for 20 was the result; there were really no responders.^[6]Unfortunately, it suggests that ocular melanoma remains a very difficult tumor to treat with immunotherapy. There is some hope that we may see some responses in patients who received ipilimumab with nivolumab. Those have been anecdotal reports only. We will see how that pans out over the next year or so.