Novel Immunotherapy Agent Tebentafusp for Treatment of Metastatic Uveal Melanoma


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.

Ryan Sullivan, MD: 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.

Omid Hamid, MD: 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.

Ryan Sullivan, MD: 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?

Omid Hamid, MD: 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.

Transcript edited for clarity.

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