Overview of Metastatic Uveal Melanoma

Ryan Sullivan, MD: Hello, my name is Dr Ryan Sullivan. I’m a medical oncologist at Massachusetts General Hospital Cancer Center, and I focus on the treatment of melanoma. I’m joined by Dr Omid Hamid from the Angeles Clinic and Research Institute, who’s also a medical oncologist and an expert in taking care of patients with melanoma. We’re here to discuss new updates in uveal melanoma and some exciting new therapies available for our patients.

I’d like to start by giving a very brief overview of the field. Then Dr Hamid is going to talk to us about a new agent called tebentafusp, which was FDA approved in January 2022 specifically to treat patients with uveal melanoma. Then we’ll have a back-and-forth conversation about some of the clinical trial data, how we treat patients on this therapy, and future directions. Welcome, Dr Hamid. I’m glad we’re able to do this.

Omid Hamid, MD: I’d like to thank you and the organizers for allowing us to educate our colleagues about this amazing drug for patients with metastatic uveal melanoma.

Ryan Sullivan, MD: Absolutely. It’s important to set the stage for why we’re here to talk about metastatic uveal melanoma. Uveal melanoma is the most common tumor of the eye in adults. In the United States, there are only a few thousand cases per year, but it has a very high rate of metastatic spread. Probably at least a third of our patients who are diagnosed with a primary uveal melanoma will at some point progress to metastatic disease. There’s a predilection for hepatic metastases in patients. As a result, patients generally present with fairly advanced metastatic disease.

In a bygone era when we rarely imaged patients, patients would present with early satiety, abdominal discomfort, abdominal girth, and ascites. They’d be on the brink of hepatic failure and generally lived a very short time despite our best efforts to treat this disease. Over the past decade and a half, there has been a tremendous improvement in the treatment of melanoma. We have a number of new therapies. We have therapies that target various immune regulatory components as well as therapies that target BRAF for cutaneous melanoma. In uveal melanoma, BRAF mutations aren’t seen, so these therapies aren’t an option.

Immunotherapy can be used, but it’s generally less effective in patients with uveal melanoma than other subtypes of melanoma—specifically cutaneous melanoma—likely because there isn’t the same tumor mutational burden that we see in cutaneous melanoma related to UV exposure and UV damage. Probably as a consequence of that, there isn’t the same robust immune response in the tumor microenvironment, thus likely driving the tumor to utilize things like PD-L1 and PD-L2 to defend itself against immune response. In blocking PD-1 or even CTLA4, we don’t get the same response rates that we see in patients with uveal melanoma.

We’ve seen great advances in melanoma, but we didn’t see great advances in uveal melanoma. To give a bit of context, the standard-of-care therapy for patients with metastatic cutaneous melanoma over the past 5 or 6 years has been either single-agent anti–PD-1 therapy with pembrolizumab or nivolumab, or combination immune checkpoint inhibitor therapy with ipilimumab and nivolumab. The response rates that we see with single-agent therapy range between 35% and 45% with single-agent anti–PD-1 therapy in cutaneous melanoma. With combination therapy, it exceeds 55% to 60%.

In uveal melanoma, using those same therapies, the single-agent anti–PD-1 response rate is 5% or less. When we give combination immune checkpoint inhibitor therapy, the response rates are between 15% and 20%. That isn’t nothing—certainly with combination therapy—but it’s far less than we see in cutaneous melanoma, so there’s a great need to develop better therapies for this disease. Until recently, no therapy had been developed and approved specifically for uveal melanoma.

Transcript edited for clarity.