First FDA-Approved Treatment for Uveal (Eye) Melanoma: Tebentafusp-tebn

HLA-A*02:01-positive adults with unresectable or metastatic uveal (eye) melanoma can be treated with a T-cell enhancer protein molecule, tebentafusp-tebn (Kimmtrak, Immunocore Limited), which received FDA (US Food and Drug Administration) approval on 25 January 2022.

What Is Eye Melanoma?

Uveal (eye) melanoma is a rare subtype of the aggressive cancer responsible for around 5% of skin cancers, malignant melanoma. Uveal melanoma begins in the eye's pigment cells (see the figure below).

Most melanomas originate on the skin's surface, and immunotherapies such as pembrolizumab work in many patients with these types. However, these immunotherapies have limited effects in intraocular (inside the eye) melanomas. Approximately 50% of uveal melanoma patients are at the metastatic (stage 4) stage at diagnosis, most often with liver metastases; this is associated with a poor prognosis (disease course).

How Does Kimmtrak Work?

Kimmtrak, whose active ingredient is tebentafusp (code name IMCgp100), contains a soluble receptor that binds strongly to HLA-A*02:01 glycoprotein 100 (gp100) presented on uveal melanoma cells: a T-cell receptor and anti-CD3 antibody form its components.

The gp100 protein is expressed at high levels by melanoma cells and at low levels by normal melanocytes and other tissues, and is a tumor-associated antigen (TAA).

The IMCgp100-202 Study Leading to FDA Approval

Tebentafusp's efficacy was evaluated in IMCgp100-202, a randomized, open-label, multicenter study involving 378 patients with metastatic uveal melanoma. Patients had to test positive for the HLA-A*02:01 genotype. Patients who had received any previous treatment (systemic treatment or localized liver-directed treatment) were excluded. Previous surgical resection of oligometastatic disease was permitted. Patients with clinically significant heart disease or symptomatic, untreated brain metastases were excluded.

Patients were randomized 2:1: 252 to tebentafusp-tebn and 126 to the investigator's choice of pembrolizumab, ipilimumab or dacarbazine. Tebentafusp-tebn was administered by intravenous infusion weekly, at 20 mcg on day 1, 30 mcg on day 8, 68 mcg on day 15 and in subsequent weeks, until disease progression or unacceptable toxicity. The main efficacy outcome was overall survival. An additional efficacy outcome, assessed by the investigator according to RECIST 1.1, was progression-free survival (PFS).

The study's 3-year survival data were published on 14 December 2023 in NEJM as a journal publication.

Results

• Median overall survival was 21.6 months (95% CI: 18.6, 28.6) for patients treated with tebentafusp and 16.9 months (95% CI: 9.7, 18.4) in the investigator's-choice arm (HR=0.51, 95% CI: 0.37, 0.71, p<0.0001).
• Median progression-free survival was 3.3 months (95% CI: 3-5) for those receiving tebentafusp and 2.9 months (95% CI: 2.8-3) in the investigator's-choice arm (HR=0.73, 95% CI: 0.58, 0.94, p=0.0139).
• At year 3, survival was 27% in the tebentafusb arm and 18% in the control arm.

Side Effects

The most common adverse reactions (≥30%) were cytokine release syndrome, rash, fever, itching, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache and vomiting. The most common laboratory abnormalities (≥50%) were decreased lymphocyte count, increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin and decreased phosphate.

Although cytokine release syndrome was common with tebentafusp (89%), the rate of grade 3–4 cytokine release syndrome was very low (1%).

Dose

The recommended intravenous dose of tebentafusp-tebn is:

• 20 mcg on day 1,
• 30 mcg on day 8,
• 68 mcg on day 15, and
• then 68 mcg once a week.

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Immunocore is a global clinical-stage biotechnology company based in Oxfordshire, United Kingdom, operating since 2008 and researching and developing biologic medicines using soluble T-cell receptor technology.

The video below was prepared by the company to explain how tebentafusp-tebn works.