FDA Follow-Up: Utilizing Tebentafusp in Clinical Practice for Metastatic Uveal Melanoma

Paul Nathan, PhD

The FDA recently approved tebentafusp-tebn (Kimmtrak) as a treatment option for adult patients with unresectable or metastatic uveal melanoma whose disease harbors HLA-A*02:01.¹

This approval was particularly significant, Paul Nathan, PhD, explained, because it represents both the first FDA-approved therapy to treat unresectable or metastatic uveal melanoma, as well as the first FDA-approved T-cell receptor therapeutic.

Moreover, the approval was supported by data from the phase 3 IMCgp100-202 trial (NCT03070392), which revealed that patients who received tebentafusp experienced a clinically meaningful improvement in overall survival compared with investigators choice of therapy (HR, 0.51; 95% CI, 0.37-0.71; P <.0001).²

Nathan, a medical oncologist at Mount Vernon Cancer Centre, and lead investigator in the IMCgp100-202 trial, recently met with Oncology Nursing News® to discuss the significance of the trial findings. Nathan underscored the rationale behind the study, key takeaways, and important administration and safety details related to tebentafusp.

Oncology Nursing News®: What was the rationale behind the study?

Nathan: Eye (uveal) melanoma is a very rare disease. It's the most common malignancy of the eye, but it's unusual to have cancers in the eye. It’s much rarer than other forms of melanoma and it's very different.

Although we have made huge advances for the treatment of [patients with] skin melanoma—when it unfortunately metastasizes, with treatments that are either targeting genetic abnormalities or stimulating the immune system to fight the disease—those types of treatments are relatively useless in uveal melanoma, and that's because [this disease] does not have the same genetic changes in it as skin melanoma.

Unfortunately, it's a disease [where] currently available treatments have not helped most patients. Although it's rare, it's an area of great unmet clinical need: When the disease does metastasize, it's associated with a very poor prognosis.

This was the first phase 3 study to show a survival benefit in uveal melanoma. It really is a breakthrough moment for this disease. Tebentafusp is an immune therapy, but it's an entirely different class of immune therapy. Tebentafusp is a T-cell receptor that's been engineered to identify a particular peptide presented on the surface of the cancer cells.

At the other end of the molecule, it's got a bit that activates T cells in the environment. I describe it to my patients as if it's a “molecular bridge between the cancer cell and between any T lymphocytes that are nearby.” The T cells don't have to be specific for the cancer, because the treatment introduces them to the cancer. It takes advantage of any T cells that happen to be in the environment.

Because of the way the drug works, because it's a T-cell receptor, it needs to see a peptide presented to it in the right way with an HLA-A*02:01 molecule. The drug only works in people who have the right HLA grouping, which is an HLA molecule called HLA-A*02:01, which is present in about 50% of the population. For patients who have an opportunity to be treated with this drug, obviously they have to have advanced uveal melanoma, but also their immune system needs to be of the right HLA type [for it to be effective].

Could you provide an overview of the study and its key findings?

The study that was reported in the New England Journal of Medicine in September was the results of a phase 3 trial with tebentafusp. There were 378 patients who were randomized into this international clinical trial, and 2 out of 3 received tebentafusp while 1 out of 3 patients received the investigator’s choice of treatment. Because there isn't an agreed standard of care for these patients, we therefore designed the trial to give investigators the option to use whatever they felt was most comfortable with.

The reality was that the vast majority of those patients had received a checkpoint inhibitor; a small fraction were also were given chemotherapy. Eighty-two percent of patients [received] pembrolizumab [Keytruda], which is a very commonly used immunotherapy drug.

The bottom line for the study is [that] we found a major survival benefit for the first time. The hazard ratio for overall survival was 0.51. In other words, patients who received tebentafusp had a 49% reduction in the likelihood of dying during the period that they were on the study compared with those on standard therapy. That was a very heartening effect.

Could you comment on tebentafusp’s safety profile and toxicity management considerations that nurses might want to be aware of?

The drug has an interesting side effect profile. We didn't have anybody who had to stop treatment because of toxicity. It does require active management initially, but it's entirely doable.

The drug is given intravenously once a week, and because it activates the T lymphocytes in the local environment, it can cause mild cytokine release syndrome. Because you're getting cellular activation of immune cells, they release cytokines that have a whole-body effect, predominantly on blood pressure; [it] can make your blood pressure drop. It can also cause a lot of skin, itching, rash, and fever.

Those are the kind of things that are mainly associated with the drug. For the first 3 infusions, we mandate that patients stay overnight on the day of their infusion, so that they have their observations monitored and have fluid support if they need it. If they don't respond adequately to fluid support, they can have steroid hydrocortisone steroid treatments to reverse cytokine release syndrome—that wasn't required very often.

Interestingly, with this drug, after 3 to 4 weeks of treatment, the side effect profile entirely changes. It’s like using 2 different drugs. Once patients get through the first 3 to 4 weeks, they no longer have to stay overnight. They come in, [receive their] infusion, and then go home.

In terms of the nursing experience on the ward, [the biggest consideration is] cytokine release syndrome. For an oncology-trained nurse, it's not a difficult drug to use; you need to have accurate monitoring of patients and most centers will have protocols of how to deal with the changes that the drug can induce in the first 3 to 4 infusions.

Is there anything we else we did not discuss that you would like to highlight?

The key take home is [that] it's the first drug that's been proven to improve overall survival for uveal melanoma, which is a distinct disease. It's also the first drug of its class—a soluble T-cell receptor—that has been shown to have an overall survival benefit in a solid cancer.

Reference

1. Immunocore announces FDA approval of Kimmtrak (tebentafusp-tebn) for the treatment of unresectable or metastatic uveal melanoma. News release. Immunocore Holdings Limited; January 26, 2022. Accessed January 26, 2022. https://yhoo.it/3r1C3fk

2. Nathan P, Hassel JC, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385(13):1196-1206. doi:10.1056/NEJMoa2103485