Uveal Melanoma: Current Treatment Approaches

Richard D. Carvajal, MD: Hello, my name is Richard Carvajal. I'm a medical oncologist at Columbia University Irving Medical Center in New York, New York. I'm here today with Dr Orloff, who's an associate professor of medicine at Thomas Jefferson University Hospital. Today, we want to spend some time talking about some really exciting data and some major advances in the field of uveal melanoma, namely the data surrounding a new drug called tebentafusp. Marlana, to start us off, let's set the stage with an overview of uveal melanoma. How would you describe the current state of the field?

Marlana M. Orloff, MD: For some of our viewers who may not be as familiar with uveal melanoma, it's important to start off by explaining that although uveal melanoma has melanoma in its name, it is very different from cutaneous melanoma. And as many people know, there have been tons of advancements in cutaneous melanoma in the last decades that have totally changed the way in which we treat the disease. Unfortunately, though, that has taught us a lot about the differences with uveal melanoma and the mutations that drive it. Whereas with cutaneous we have BRAF mutations, in uveal we have different mutations like GNAQ and GNA11. The metastatic patterns in uveal are different; we don't see the lymph node metastasis that you see traditionally early on in cutaneous—rather, we see liver first. What has been most notable is that the immune checkpoint inhibitors have just changed the way we treat cutaneous melanoma; they have not been as effective as they are in uveal. I would say that the current treatment landscape in uveal has to do with 2 major approaches: one being local-regional approaches, liver-directed approaches, because like I said, we do see this disease go into the liver and the liver becoming in many patients, the life-threatening thing, as well as systemic therapies. And in the systemic therapy bucket, immune checkpoint inhibitors are there, things like Opdivo and Yervoy, but we've relied a lot on clinical trials for trying to find effective systemic therapies, whether it's different approaches in immunotherapies or even other types of targeted therapies, again, given the fact that we see those unique G-protein-coupled receptors (GPCR) mutations in uveal melanoma.

Richard D. Carvajal, MD: In the field outside of clinical trials, I tend to fall back on combination checkpoint blockade with ipilimumab and nivolumab as the frontline of protocol option if we're not going to do regional therapy. And if we look at the 2 prospective phase 2 clinical trials that have been conducted as well—retrospective data—the best outcomes we see are response rates on the order of 15% to 20% overall survival in the order of 18 to 19 months. And that is just dramatically not as good as what we see with cutaneous disease. I guess the question is: Why do you think that is?

Marlana M. Orloff, MD: In the simplest way, I like to think of uveal melanoma as just being not easily seen by the immune system. For some reasons when you send these mutational reports on cutaneous melanoma, you'll often get back a number of mutations, a high tumor mutational burden (TMB). We see PDL1 expression, and we just don't see that in uveal. It's typical to just get back a handful of mutations, TMB, tumor mutational burden is often 0 or low, really a lack of PDL1 expression, especially when our metastatic site is the liver. And this has been shown even across other tumor types. I think immune checkpoint inhibitor therapy attacking liver dominant tumors—the liver is a harder organ to crack, if you will. Even in cutaneous, there are patients who have bad liver-dominant disease, and sometimes they may not be the ones that respond best to immune checkpoint inhibition. Unfortunately, there are a lot of cards stacked against us in uveal, but there are probably also mechanisms that we aren't even aware of yet. But certainly, like you said, when you look, compare response rates, durability of response, it's not as good as it is in cutaneous.

Richard D. Carvajal, MD: Yes, and when we started doing single-agent checkpoint blockade—now that we have the data with combination checkpoint blockade—even though we do it, for a while we were saying this is a nonimmune-responsive disease. For a while many of us thought maybe this is just one of those tumors that is an immune desert. Then, over time, with the collection of biopsies that we've done, work from The University of Texas MD Anderson Cancer Center and elsewhere, just looking at the microenvironment, it just turns out that there are immune cells there, and it's not a desert, but the immunological milieu is just not sufficient or not adequate to engender a response, and maybe that's particularly true in the liver, which is just an immunosuppressive organ.

Marlana M. Orloff, MD: Yes, and you're right; even when you look at primary uveal melanoma in enucleated specimens, you can see T cells there. When I said before that the immune system is just not as attracted to uveal melanoma in the most kind of endgame sense, it may be that there are just other things, like you said, in the tumor microenvironment that just kind of set the immune system up for failure, that even if it gets there, there are these other resistance mechanisms that we've yet to overcome with traditional immune checkpoint inhibition.

Richard D. Carvajal, MD: Yes, and then looking at the data, for instance with TILs (tumor-infiltrating lymphocytes), those are early data that suggested to me that maybe it's not immune resistant, but maybe we're just targeting uveal the wrong way in terms of trying to manipulate the immune system.

Marlana M. Orloff, MD: Yes, I was trying to simplify it in my head that if standard immune checkpoint inhibition isn't going to get the job done, it's about either making the tumor more of a target to the immune system or somehow forcing the immune system over to the target that it otherwise wouldn't be able to get to. And that's certainly—which I know we'll talk about in a minute—one of the really unique things about the drug tebentafusp and acknowledging that mechanism of resistance and trying to do essentially what we haven't been super-successful with yet with immune checkpoint inhibition.

Transcript Edited for Clarity