Chapters Transcript Video Breakthroughs in Care of Ocular Melanoma The infrastructure of which we can use to think about the talks that are here, how we care for our patients and ourselves if we are the patients, um, but also, uh, it cannot be, uh, minimized how important the work that has been done in melanoma in the first line has contributed to, uh, other solid tumor care, all of the checkpoints and the targeted agents, the BRAF agents. But also how it has translated into the care of other types of melanoma, including ocular melanoma. Here at the Auss Clinic and Research Institute, the ocular melanoma guru is Doctor Anddujit Mami, who's been here for half a decade. Yeah, seems like just yesterday, so I will hand off to the young doctor Memmi. Thank you very much, Dr. Hamid. Um, yes, it's been about 5 years since, uh. I started and it's my 3rd or 4th presentation, uh, then, uh. Really good experience so far. So today I'm gonna take some time, um. And uh walk everybody through uh current care of ocular melanoma and what are some of the upcoming. Um, Therapeutic options uh for our patients. So this is just uh my roadmap for this presentation, background, pronois staging, uh, and what's missing from there is the talk on adjuvant and neoadjuvant approach, um, and then subsequently metastatic is the management. So these are some of the spaces where ocular melanoma or u melanoma develop. And um as you know that this is not the most common malignancy, but it is one of the or the most common malignancy FBI in adult population, about 2000 cases in the US each year and about 8000 cases globally. Um, as we know, the risk factors of, uh, The sun exposure for cutaneous melanoma, that's not the case for nal melanoma. Those risks are still being looked at, uh, but other risk factors that we know are the, the nevus and the parroidal space, um, melanocytosis, any family history of uveal melanoma, um, some of the other germline mutations can also. So once a patient is diagnosed with primary ocular melanoma, it's important to look at their staging, their primary melanoma staging, because that Informs us what are their future risk of developing metastatic disease. Um, we know that about 50% of the patients will go on to develop metastatic disease, and it can be or has been in the past quite challenging to manage these patients. So some of the prognostic or predictive prognostic marker that we use are the tumor size itself, uh, basal diameter and height. And additionally, we've been using uh gene expression profiling in ubial melanoma that's very well studied where the tumors are actually uh sequenced and split into either class 1 or class 2 and based on that, we know that their, their long-term outcomes can be predicted fairly uh with good confidence. Um, as you can see that, you know, if you're a class one subgroup, uh, you're likely to do fairly well, um, and that they tend to be very different in terms of their, um, recurrence risks and how far they recur. Um, they tend to recur later in time rather than early on where class 2 are the sort of early recurrence patients, um. And then some of the additional information that we've seen is the an antigen, uh, which we'll talk about a little bit later as a target, but it also a prognostic marker, um, individuals who have ocular melanoma that not only, uh, class one or class 2 were also differentiated based on their brain, um, um, as in, um, it having brain marker on the uylas will actually, uh, portends a poor prognosis and decrease overall survival. So going back to looking at here, is tumor size good enough as as a prognostic marker? Well, not exactly the case. we still tend to use that, but most often the gene expression profiling, uh, and Pra and monosomy 3 are some of these, uh, markers that we will, um, use to define a ubi meloon being a high risk or not. And why is that important? Because that allows us to at least look at these patients and try to offer them therapeutic options either in center of care or in clinical trial settings to reduce their risk of recurrences in the future. Um, in the past, this task has been very challenging as you know, the uveal melanoma is not the most common disease, so doing large trials that are required for adjuvant therapies aren't all that. You know, easily done, but, um, that is changing because, you know, the, the, the road's been up for us with number of clinical trials with number of different target therapies or immune therapies or um. Um, sort of, um, intralesional therapies to see if we reduce the risk of cancer. Most of these trials have led to sort of make results. Um, occasionally I'll see patients who received slinib, a multi styrosine kinase inhibitor in adjuvant setting because it's known to improve overall survival in patients who are under 60 years of age, uh, but rest of them are a bit of a mixed bag, um, until, um, Last year at ASCA when uh one of our colleagues, uh, Doctor Apisan from uh I believe he's at Georgetown, uh, he presented the data on iilumab and evolumab that was um used in treating patients who had high risk, uh, uveal melanoma and what high risk meant was their class 2 or their uh tumor's basal diameter was greater than or equal to 12 millimeter. And these patients were treated with nivolumab 240 mg every 2 weeks and bilimumab 1 mg per kilogram every 6 weeks up to 48 weeks with a primary endpoint of 3 year, uh, distant metastatic free survival and also had a couple of uh secondary endpoints and they compared it to a a standardized control group uh from the cooperative ocular oncology group and when they did this sort of synthetic. Arm comparison, the individuals who um that received ibiliumab and Nevalliab actually showed improvement in their DMFs, um, outcomes. It was 70% versus 43% with the propensity score matching method. And then median DMFS wasn't reached in these patients. So as you can see that this is a reasonable option for some of these patients, but this is a small study, um, you know, we know that epillo maloma could could be quite toxic for some of these individuals, so we do need bigger numbers to sort of make this as a standard care for our patients. So since the roadmap's already there, now we're looking at some of the other therapeutic options that could play a part in the adjuvant um sort of therapeutic uh space and We're gonna talk a little bit later about Tabeifu or Kimtrac, which is FDA approved therapy for HLAA 0201 positive patients with metastatic uvulal myeloma who haven't seen any treatment or it's shown overall survival benefit, meaning it's already proven to work. In advanced stage, can we bring that therapy in early setting in adjuvant setting to see if we prevent some of these recurrences. So this atom trial, which will be open at our site soon and is actually planning to be open uh at multiple sites in the United States, um. Looking at um high risk patients who had uh TNM stage 3 or gene expression profiling class 2 or have monosom 3 in their yoga melanoma, they have to be HLAA0201 positive and the treatment is with tabanhaus up to 6 months and then end points of primary uh at the relapse free survival and secondary endpoints being overall survival, uh, toxicity of the therapy and quality of flight. The flip side of that is, you know, what if you don't have a uh E0201 allele, you know, then what is your adjuvant option? Uh, can you have you, you know, we can't leave you alone in a sense, because if you have high risk melanoma, for example, GAP class 2, you know, what are your some of your options? Well, There there's been sort of a pre-clinical work looking at uh bat one mutation and what its role is in metastasis driving genes, and we know that they're up regulated and quiznestat is a drug which inhibits. Histone Dylase 4 enzyme and it sort of decreases these metastatic uh driving genes and, and hope to reduce the risk of recurrences. So that's a pre-clinical work. So based on that, uh, University of Miami. A team has put for this trial that'll be opening up, um, and it's looking at, uh, uz that treatment 12 mg via capsule taken orally 3 times per week, uh, for a 21 day cycle and total of. 17 cycles. So about roughly about a year of treatment and with the primary endpoint again of distant metastatic free survival with the secondary endpoint being uh progression free survival, overall survival, uh, first sight of occurrences and adversity. So we're actually very excited to look at these options, multiple options and adjuvant setting with a really good scientific background or already clinically established benefit. Few years ago, we had only one therapy option in metastatic setting, and now we have more than few and we're talking adjuvant therapy in uveal melanoma. And on top of that, we're talking about neoadjuvant therapies uval melanoma. What is neoadjuvant therapy before the primary eye tumor. Is treated by radiation, the typical plaque therapy or for some of the um individuals that need their Inucleated. Can we give them treatment to reduce the amount of radiation or the plaque size or can we um sort of reduce their risk of e-nucleation? Um, and with that's the new adjuvan approach and it's proven to be, uh, amazing and cutaneous melanoma and we apply that sort of, um, Principle in in uil melanoma as well, there's been a a signal that's been seen uh using Dro assertive, the IDE 196 drug from IDEA that's already in first line uh phase three study in metastatic ual melanoma and seeing if that can be applied. Neoadjuvant setting before the metastatic disease is developed and to uh reduce the size of the tumor, reduce the chances of nucleation um and uh so they've seen some responses, uh, median reduction of about 47% in the tumor, um, most of the patients benefited. So based on that, the new graduate study is ongoing and hopefully we have more data for us. Additionally, the neoadjuvant study by Aurora Bioscience, they're looking at a uh A virus-like particle packaged that's injected close to the tumor in the eye, and that leads to a destruction on the cell membrane of the tumor and releases these signals that the immune system can pick up and hopefully learn to control the the the the. Ual melanoma cells, uh, whenever, you know, that they, they move somewhere else or. Uh, so again, this trial is ongoing and uh hopefully we'll have some uh data to present on it in the future. So as we um already talked about that, a lot of the patients or 50% of the patients will develop metastatic disease, um, you know, if they are high risk, and Many times this metastatic disease tends to be in the liver up to about 80% of the patients will have disease in the liver, so, Are there mechanisms to treat the liver only rather than uh treating the whole person, which usually leads to increased side effects? Well, yes, uh there are a number of liver directed therapies that are available and a lot of them shown limited benefit, not overall survival advantage, but some progression free survival benefit and there are a number of different ways, immuno embolization, chemo embolizations, radio embolization. Um, perfusion of the liver itself with chemotherapy and one such thing, um, or, or therapeutic option is, uh, uh, percutaneous hepatic perfusion PHP, um, which actually is already FDA approved over the last couple of years and is in application. Um, and here we use, um, to isolate the liver supply of the, uh sorry, blood supply of the liver and infuse it with melphalan high dose, um, and that's shown to, um, To decrease the liver burden, and most of the time the toxicity tends to be limited and it's uh mostly the cell counts that decrease in nature, some nausea, vomiting, increase in liver enzymes also been seen, but this is actually FDA approved therapy um that is uh available at selected centers. OK, um, we talked about Doctor Moyer spent a good bit of time on target therapy. Are there opportunities for targeted therapy in uval melanoma? Well, we know that a lot, lots of the uval melanoma have uh GNAQ GNA 11 mutations that seem to drive the cancer and their downstream signal can we Interrupt that, and that's the basis of uh Grobe assertive with the crizotinib um to see if that could be uh um uh sort of applicable uh interruption of the signal transduction to improve patient outcomes. In the past, other uh pro uh protein pathways been looked at with serafenib, slamitinib, trumitinib, and most of them have had Very limited overall responses, not durable, toxicity issues, so they haven't been really um widely used in this. So this is the idea of 196 um uh compound or also known as dro assertive that showed benefit in an early phase study uh with the 50% overall response rate, uh, in the first line, metastatic uveal melanoma, 30% overall response rate in Asia super C therapy. So based on this data, the phase three studies is ongoing and we'll have some data available to report in the future. We also know that immune system is quite important in uh cancer control, especially in melanoma. However, uveal melanoma is what's thought to be a cold tumor. There are not a lot of immune cells present within the tumor, but there is a small group of patients who still benefit from immunotherapy that's been demonstrated in two separate trials, one, By MD Anderson, uh, another one, in, uh, in, uh, Spain. Both of these studies used, uh, epilimumab nivolumab in metastatic uveal melanoma that hadn't received prior therapies and showed about 18% response rate. Some of these responses are quite durable, um, and, uh, we didn't see any newer toxicity in uveal melanoma because of, uh, epinevo, so it's an option for some of some of our. Yeah So, one of the most interesting sort of upcoming studies I think is for patients who are HLA0201 negative or uh potentially, you know, uh. Not candidate for whatever reason for ID study, um, I think Chopin trial looks very promising even though it's only a 7 patient data that looked at combination of ipilimumab and nivolumab and liver perfusion with chemotherapy and uh this is shown about 80% uh overall response rate with one complete response, 5 partials and one stable disease, um, I think. It it's a story that's developing and uh we look for more data in this, um, and, and expand on this experience. Next, to talk in in space of um meta uveal melanoma is Again, continuing with immune, uh, sort of control of cancer, and we know that uh T cell cytotoxy T cells are very important, but there's, we need to get them to the right place. Um, so to do that, it's these impact class molecules that bring in T cells from the periphery into the tumor to control, um. Yo metavio marama and this is established by um demonstration of overall survival benefit with banta was in me Maor published in New England Journal of Medicine in one and it showed uh that. You know, in HLA 0201 restricted patients, um, When Debentius was given and compared to either Pembro or II or chemotherapy, the, the overall survival was increased uh for patients treated with, uh, with Dementifus, and now we have 3 year data, follow-up data, and that still shows the ongoing benefit. Um, the median overall survival for Dementhauss was 21.7 months and for the control group, it's 16 months, so obviously showing benefit with the um. The risk of, of death at um with 0.5% or 50% of reduction in risk of death. So most of the um adverse events that tend to happen with Kimtrac or tent, they, they are focused in the first three doses and that's mostly cytokine release syndrome, uh, fever, chills, um, and most of these uh low blood pressures. Most of these are low grade and, and they tend to improve with typically with hydration, acetaminophen, and things like that. Um, in a small, very tiny fraction of patients, uh, they may need, uh, steroids or other ways to improve their blood pressures. And skin rash is quite common in these patients, but typically uh improves with topical steroids uh at rarely um oral steroids as well. Other ways to bring these T cells, um, as we talked before that frame is an antigen, um, quite widely expressed on uveal melanoma cells in addition to some of the other tumors as well. And Dr. Hamiz presented this data at amo a couple of years back showing that, you know, this is an approach that potentially is meaningful for uveal melanoma patients, and there were a handful of ual melanoma patients, but they had ongoing benefit uh durable benefit, um, and, uh. So we'll look to develop this story further in the future. Doctor uh Moyris talked to you guys about RP1, uh, the modified virus injection into metastatic site and uh showing benefit in the uninjected, uh, lesions as well. So RP2 is the counterpart here to RP1 in combination with nivolumab to show you benefit um in a metastatic uveal melanoma. This trial is ongoing, but the phase one study uh showed that um. There is a potential benefit uh when you're looking at RP2 um in the uveal melanoma. So these are the 17 patients that were treated um with RP2 and nivolumab together in a single arm study objective response of 29.4% and a disease control rate of 58.8%. safety, most of the toxicity are in the injected lesions or injection site reactions, um, and, uh. Significant number of these patients underwent intrahepatic injunctions without any sickness. These are some of the characteristics of these patients that were needed, um. There's an ongoing trial. Uh, Doctor Moyers also talked to you about the till. Um, there is a signal of till, uh, in metastatic uveal melanoma, but the number of patients treated is small, so this is not a complete story, but we look to see its development. happily ask any question, answer any. Created by Related Presenters Inderjit Mehmi, MD Medical Oncology View full profile
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