Videos

Omid Hamid, MD, and Ryan Sullivan, MD, discuss what they look forward to in the future of metastatic uveal melanoma treatment.

Future Directions in Metastatic Uveal Melanoma Treatment

 From a toxicity standpoint, it’s an interesting molecule because almost all of the toxicity is early on. To your point earlier about cytokine release syndrome, we hospitalize patients, or at least we observe patients, for 16 hours. We do the same as you do, Dr Hamid. We hospitalize patients for observation and then send them out the next morning. But we do that only for the first 3 visits because cytokine release syndrome doesn’t seem to be a big deal after that. In fact, once patients are on this for weeks at a time—5, 8, 10, 15 weeks—it’s like the easiest drug to give. Patients come in and get treated. I don’t know if you have the same impression.

 I agree with that, and clinical trials bear this. There were very few patients who discontinued the study therapy because of an adverse effect. It’s important to understand cytokine release syndrome because this is new to most of our colleagues. It shows up with fever, fatigue, vomiting, chills, hypotension, hypoxemia, headache, dizziness. The grades range from very low, if you have a mild fever and mild shortness of breath, to very high, where you have someone in an immune type of flare condition where you need to use something like tocilizumab, but that has been very rare for us. We’ve seen some of that in patients who are adrenally insufficient because they can’t mount that, and you can support them with hydrocortisone or others.

Once you’re aware of this and you can manage this adverse effect, the rest of the adverse effects, such as the rash, fevers, or periorbital swelling, are very manageable. You can see abnormal liver function tests, itching, and some nausea, but other than that, it’s very easy to manage and very easy to manage prophylactically. In some trials, they’re even giving an early steroid before the infusions. I agree with you, the rash and some of those [adverse effects] are seen only initially, and then they resolve. We monitor their blood pressure, pulse, and oxygenation, similar to anyone who’d have an infusion reaction. We’ve seen that 1-time doses of corticosteroids to treat adverse events don’t impact the overall survival. That was presented at ASCO [the American Society of Clinical Oncology Annual Meeting]. Just like with checkpoint inhibitors, they don’t affect outcome when you’re giving them for an adverse effect, so it makes a lot of sense.

Is there a patient population for which you wouldn’t consider tebentafusp? I’d say someone who would have a life-threatening event if they had a cytokine release syndrome, whether it’s cardiac insufficiency or pulmonary insufficiency, but I’ve rarely run into that type of person. It might be someone who has a poor performance status who can’t handle a setback of a toxicity, or someone who has autoimmune disease. But those are rare findings in this population.

 I have a quick note about toxicity. I agree with everything about cytokine release syndrome. The other thing you mentioned early on is that rash is the other toxicity we see. It’s a weird rash. It’s total body. You think that the person needs to be in a burn unit, because they become very red very quickly and it’s terrifying. They also get swollen. You think that this person¼is going to die of this rash, but that isn’t the case. It gets better. You can use topical therapies. We use a ton of antihistamines. Fexofenadine is probably our go-to to help prevent the rash and the itchiness that’s associated with it. But mostly it’s just teaching people, including patients, that you’re going to turn red and it’s OK. Then you’re going to go back to your normal hue after 24 or 48 hours of initial treatment.

 That’s the point to make, that the rash and erythema are usually short-lived. The only issue is that it’s itchy, but it resolves. Sometimes we see [the rash] overnight and in the morning when I see the patient, and by the time I see them in the clinic the afternoon or the next day, it’s already gone. We utilize some preventative [medications], maybe some H2 inhibitors or Benadryl, and it’s manageable.

 It is. But the first time you see it, it’s terrifying, because there’s this paradigm of rapid-onset total body erythematous itchy rash. This doesn’t sound good. But it’s important to note that the reason we give this drug weekly is because it doesn’t stick around very long. Those toxicities dissipate quite quickly.

Experts highlight strategies for managing the adverse events of tebentafusp, especially cytokine release syndrome.

Managing Tebentafusp Toxicities in Metastatic Uveal Melanoma

 Now is a good time to talk a little about the clinical trial data, and then we can have a discussion about the toxicities and the management of the toxicities. One of the toxicities, as you mentioned, is cytokine release syndrome, which requires hospitalization. It’s important to note that the clinical trial that led to the approval of this agent was built on phase 1 and 2 testing.

The initial trial of this agent was in cutaneous melanoma in patients who had surgical resection. It was presented by one of our colleagues, Mark Middleton, at an AACR [American Association for Cancer Research] meeting about 6 years ago. I remember watching him give this talk and thinking, “This is a really neat thing, but that’s a weird population to start looking at a drug like this.” It fit in with the field of melanoma, where there were a lot of adjuvant studies of vaccines, and this was maybe a weird kind of vaccine. Obviously, it isn’t that. It’s a very different type of molecule. But soon after, it transitioned to being looked at in both cutaneous and uveal melanoma.

To your point, the gp100 peptide is much more consistently expressed in uveal melanoma than in cutaneous melanoma for reasons that probably are immunologic. Cutaneous melanoma is typically so genetically altered by UV or radiation that it has to come up with all kinds of mechanisms to get around the immune system, whereas uveal melanoma is much less genetically disturbed. It’s probably better able to remain differentiated as opposed to the dedifferentiated subtypes that we see in cutaneous melanoma. With that expression of the protein, it seemed like patients with uveal melanoma are doing better. But interestingly, doing better doesn’t mean high response rates.

We’ve collectively treated a number of these patients, Dr Hamid [Omid Hamid, MD]. I have a few responders and you probably have a few responders. But we have a lot of patients who have been treated for a while on this drug who didn’t respond but survived longer than we might have predicted. In fact, that was seen in those early studies. Patients seemed to live longer than we thought they would, based on their disease. Based on that, the design of the study wasn’t looking at response rate or progression-free survival, which are typical metrics for primary end points on definitive trials. The primary end point was overall survival, and it met its overall survival comparison of the Kaplan-Meier curves. In fact, the hazard ratio for overall survival was 0.51, which is about as good as you’re going to find in a clinical trial of a drug.

The trial design was 2:1 randomization. Patients were randomized to either tebentafusp or an investigator choice. We had 3 options in the investigator choice [arm]: single-agent pembrolizumab, single-agent ipilimumab, or dacarbazine. Most people recommended pembrolizumab as the investigator choice. Second to that was ipilimumab, and third to that was dacarbazine. Ultimately, this was a positive trial that led to the FDA approval of this agent.

Dr Ryan Sullivan details clinical trial data presented at ASCO 2022 on the use of tebentafusp for mUM.

Recent Trial Data on Tebentafusp in Metastatic Uveal Melanoma

 I’ll ask you specifically: can you describe what tebentafusp is, why it might work, how it works, and then go into some of the data? Then maybe we can go back and forth in terms of our experience using this drug.

 Thank you. It’s unbelievable to say that we have an FDA-approved immunotherapy for metastatic uveal melanoma. As you said, historically, this has been an immune desert because nothing works. The idea of checkpoint inhibition, although it had low response rates, was the beginning of understanding that we needed to bring T cells into the tumor environment.

Tebentafusp, which is now called Kimmtrak, is a bispecific gp100 peptide-HLA-directed CD3 T-cell engager. That’s a lot, and it’s indicated for HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. It goes by different names, but we call it an ImmTAC, or an immune-mobilizing monoclonal T-cell receptor against cancer. It’s a T-cell receptor. I like to think of it as a double-sided antibody bringing 2 things together, like a matchmaker. On 1 side, it’s a binder of a T cell with an anti-CD3 cluster of differentiation end that would be attracted only to the T cell. On the other end, it binds the antigen gp100, which is bound on the surface of the tumor.

This dual antibody forces the T cell to get into the area and engage with the cancer, and just like a matchmaker that makes a good match, this makes a bad match for the cancer. This allows the T cell to become activated and attack the cancer. Because of the immune system itself not being able to acknowledge uveal melanoma, this drags the immune system to the cancer and forces them to engage. That’s the simplest way to say this.

As a target, gp100 is uniformly expressed on uveal melanoma. But the other place we see it most commonly is in the skin, which leads to some of the adverse effects of the rash. This is in HLA-A*02:01-positive patients. That’s about 50% of White patients and 25% of non-White, so you need this recognition of gp100 in the context of HLA-A*02:01.

It’s important for our audience to know what HLA—human leukocyte antigen—status is. This is the identification of your immune system and what we use to find the perfect match for transplant. This drug was designed to identify the fragment in the context of HLA-A*02:01, so only patients who express that HLA type are candidates for this therapy. How do you test that? The most common way is a simple blood test. In our initial clinical trials, we consented patients to have a bit of blood drawn and sent. The Red Cross and multiple laboratories do this. There are other ways to test it by looking at tumor tissue, but this is the easiest way and the way that it was FDA approved.

We administer tebentafusp intravenously weekly in a dose-escalating fashion, which is an initial dose of 20 μg, then 30 μg, and then the full-dose 68 μg to allow the patients to avoid the major adverse effects we’ve seen with this: cytokine release syndrome, which we’ll talk a little about. For the first 3 weeks of treatment, patients need to be evaluated for 16 hours to see that they don’t have a cytokine release syndrome. That’s the logistical burden that we’re learning to do more about.

This is T-cell therapy, which is new. This is a bispecific, which is new. This has shown benefit for the patients, but you have to administer it in different ways and monitor. If you have issues as a physician or want to know more about it, there’s a lot of support through Kimmtrak Connect. Case managers help you one-on-one with financial assistance and site coordination and how to coordinate care and access this. I find it amazing that this is a T-cell therapy that has been tested in clinical trials, approved, and come into our clinics in a very rapid fashion through this mechanism.

 Dr Hamid, how do you guys handle the 16-hour observation? Because you might imagine a few different scenarios. One scenario probably isn’t treating somebody at 2 AM and then watching them until 8 PM. How do you handle that at the Angeles Clinic?

 We arrange for them to be evaluated overnight in a local hospital for fewer than 24 hours. For the clinical trials of these types of therapies—there’s more coming out now—we infuse them in the clinic, watch them for 8 hours, and then as the clinic is beginning to close, they’re transported to the hospital. There are orders and they’re monitored, and then we see them in the morning before discharging them home. That’s a lot to do initially if you aren’t familiar with it. But as we say, “See one, do one, teach one.” It becomes very easy. We have multiple patients during the week going through this cycle.

Dr Omid Hamid explains the mechanism of action of recently approved tebentafusp for mUM, and why HLA testing is necessary for patients being considered for the treatment.

Novel Immunotherapy Agent Tebentafusp for Treatment of Metastatic Uveal Melanoma

 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.

 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.

 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, 

 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.

Ryan Sullivan, MD, provides an overview of metastatic uveal melanoma, currently available treatment options, and unmet needs in the field.

Overview of Metastatic Uveal Melanoma

Ryan J. Sullivan, MD, associate professor of Medicine, Harvard Medical School, associate professor, Hematology/Oncology, Massachusetts General Hospital, discusses the examination of tebentafusp-tebn (Kimmtrak) in uveal melanoma.

The phase 3 IMCgp100-202 trial (NCT03070392) examined efficacy of tebentafusp vs investigator’s choice of dacarbazine (Bayer), ipilimumab (Yervoy), or pembrolizumab (Keytruda) in patients with untreated, advanced, uveal melanoma. In January 2022, 

the FDA approved tebentafusp for the treatment of HLA-A*02:01–positive adult patients with unresectable or metastatic uveal melanoma

The new treatment option for uveal melanoma is a step forward in a disease that has been difficult to treat and has been associated with poor outcomes, Sullivan explains. As tebentafusp is incorporated into standard practice, it will be important to be selective about which patients continue beyond progression, Sullivan adds.

Conversations with a patient can help inform future treatment plans to see if they can continue to benefit from tebentafusp, Sullivan continues. The discovery of additional variables, such as other biomarkers, could help further identify which patients should continue treatment with tebentafusp, Sullivan concludes.

Ryan J. Sullivan, MD, discusses the examination of tebentafusp-tebn in uveal melanoma.


Dr. Sullivan on the Examination of Tebentafusp in Uveal Melanoma

Ryan Sullivan, MD, a medical oncologist and attending physician in the Division of Hematology/Oncology at Massachusetts General Hospital, discusses the future of triplet therapies for patients with melanoma.

One regimen that received regulatory approval from the FDA in July 2020 is the combination of atezolizumab (Tecentriq), vemurafenib (Zelboraf), and cobimetinib (Cotellic), which was indicated for patients with 

 V600 mutation–positive, advanced melanoma. However, the field isn't entirely sure of how to optimally use this regimen, according to Sullivan.

Based on findings from phase 1/2 clinical trials and randomized data from a small phase 2 study, investigators theorize that triplet therapies, namely a combination of BRAF, MEK, and PD-1 or PD-L1 inhibitors, have the potential to replace BRAF-targeted therapy as a new standard regimen in this patient population, Sullivan concludes.

Ryan Sullivan, MD, discusses the future of triplet therapies for patients with melanoma.

Dr. Sullivan on Future of Triplet Therapies in Melanoma

Ryan Sullivan, MD, medical oncologist, attending physician, Division of Hematology/Oncology, Massachusetts General Hospital, discusses treatment sequencing with targeted therapy and immunotherapy in melanoma. 

Typically, patients with advanced melanoma receive immunotherapy in the frontline setting, Sullivan explains. However, with the emergence of BRAF/MEK targeted therapies, the question remains whether targeted therapy or immunotherapy is the optimal frontline regimen, says Sullivan. Whether targeted therapy can replace single-agent PD-1 inhibitors or combination regimens with PD-1 and CTLA-4 inhibitors in this setting is unknown.

As such, treatment decisions should be made on an individualized basis in melanoma, Sullivan explains. Additionally, ongoing efforts are exploring how to optimize second-line treatment for patients who progress in the frontline setting. Few patients will retain long-term disease control with targeted therapy, single-agent immunotherapy, or combination immunotherapy, so additional advances are needed in this space, concludes Sullivan. 

Ryan Sullivan, MD, discusses treatment sequencing with targeted therapy and immunotherapy in melanoma.  



Dr. Sullivan on Sequencing Targeted Therapy and Immunotherapy in Melanoma 

Ryan Sullivan, MD, medical oncologist, attending physician, Division of Hematology/Oncology, Massachusetts General Hospital, discusses treatment options in 

 mutation are eligible to receive combination BRAF/MEK inhibitor therapy, ipilimumab (Yervoy) in combination with nivolumab (Opdivo), or single-agent checkpoint inhibitor therapy with nivolumab or pembrolizumab (Keytruda) in the frontline setting, says Sullivan. However, BRAF-targeted therapy is not appropriate for patients without 

Single-agent nivolumab and pembrolizumab, as well as the BRAF/MEK inhibitor combination of dabrafenib (Tafinlar) and trametinib (Mekinist) are approved for use in the adjuvant setting for patients with 

-mutant disease, Sullivan explains. Although the tendency is to offer immunotherapy up front to patients with metastatic melanoma, it may be preferable to offer patients with 

 mutations BRAF-targeted therapy rather than checkpoint inhibitors in the adjuvant space, concludes Sullivan.

Ryan Sullivan, MD, discusses treatment options in BRAF-mutant melanoma.   



Dr. Sullivan on Treatment Options in BRAF-Mutant Melanoma 

Ryan Sullivan, MD, assistant in medicine, Massachusetts General Hospital, assistant professor, Harvard Medical School, discusses the need for the development of biomarkers to predict an optimal therapy for patients with 

Since 2011, a host of new therapies have gained approval for the treatment of 

-mutant melanoma, including the combination of the BRAF inhibitor dabrafenib and MEK inhibitor trametinib and the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab. In addition to these therapies, other BRAF and MEK combinations have also gained approval along with other immunotherapies.

Given the large amount of available therapies, it is important for researchers and doctors to identify which patients will benefit from which drugs, and how best to sequence these agents. Until markers are identified to show which patients should receive immunotherapy versus combination BRAF and MEK inhibition, it is left up to the treating physician and the patient to decide which option is best. The ability to make data-driven decisions, Sullivan says, will lead to better care and outcomes.

View more from the 2016 SMR Annual Meeting

Ryan Sullivan, MD, Massachusetts General Hospital, discusses how best to treat patients with melanoma who have the BRAF mutation. 

Ryan Sullivan, MD

Articles