Uveal melanoma, which is also called ocular melanoma, is the most common primary intraocular cancer in adults. Up to 50% of patients diagnosed with uveal melanoma will develop metastases. In most cases, these patients will have a poor outcome. The clinical course of patients with metastatic uveal melanoma is generally determined by the progression of the disease in the liver. Chemotherapies or liver-directed treatments do not necessarily result in long-term tumor control.[1]

Historically, the median survival of patients with metastatic uveal melanoma to the liver has been up to 5 months. Today, there are currently no effective systemic chemotherapy regimens for the treatment of liver metastases from this type of rare cancer. This is, in part, due to the fact that only a few clinical trials have been conducted for metastasized uveal melanoma.

However, researchers have observed remarkably increased one-year overall survival rate, and similarly increased disease control rates in early phase studies for some very recently investigated agents including the bispecific tebentafusp (IMCgp100).[1]

Tebentafusp, a novel bispecific fusion protein that redirects T-cells, showed clinical benefit, including target lesion reduction, in patients with metastatic uveal melanoma. Compared with available standard therapies, including immune checkpoint inhibitors, treatment with tebentafusp nearly halved the risk of death among patients with metastatic uveal melanoma (mUM), according to results of a phase III clinical study presented during Week 1 of the virtual AACR Annual Meeting 2021, held April 10-15, 2021.[2]

This study was sponsored by Immunocore.

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“Even though uveal melanoma is rare overall, it is the most common eye cancer in adults, and represents approximately 3-5% of all melanomas,” said Jessica Hassel, MD, associate professor and section head of DermatoOncology in the Department of Dermatology and the National Center for Tumor Diseases at the University Hospital Heidelberg in Heidelberg, Germany.

“Prognosis for uveal melanoma is very poor with a median survival after metastasis of less than one year, and there are currently no standard-of-care treatments for this aggressive cancer,” she noted

Bispecific fusion protein
Tebentafusp is a bispecific fusion protein that recognizes two targets, with one target present on melanoma cells, and the second target present on T cells.

“Tebentafusp builds a bridge between the tumor and the immune cells, enabling the immune cells to attack the tumor,” Hassel explained.

One end of tebentafusp recognizes a part of the gp100 protein expressed in melanoma cells. This recognition occurs through a high-affinity T-cell receptor (TCR) binding domain that targets the gp100 antigen, which is presented by the tumor cells using a specific HLA (for human leukocyte antigen) type, known as HLA-A*02:01. The other end of tebentafusp binds, activates, and redirects T cells to attack the gp100-expressing melanoma cells, explained Hassel.

Because the TCR binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type, Hassel said. However, this HLA type is frequently observed in Caucasians, the population most affected by uveal melanoma, with roughly 50% of Caucasians expressing this HLA type, she added.

Hassel and colleagues compared tebentafusp with investigator’s choice as first-line therapy in 378 previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma. Patients were randomly assigned 2:1 to receive tebentafusp (252 patients) or investigator’s choice, which included the checkpoint inhibitors pembrolizumab (Keytruda®; Merck & Co., Inc; 103 patients) and ipilimumab (Yervoy®; Bristol Meyers Squibb; 16 patients) or the chemotherapeutic dacarbazine (seven patients). A primary endpoint of the trial was overall survival (OS) between the randomized arms.

After a median follow-up of 14.1 months, compared with patients randomly assigned to investigator’s choice, patients randomized to tebentafusp had almost half the risk of death. Further, the estimated one-year OS rate was 73.2% among patients in the tebentafusp arm, compared with 58.5% in the investigator’s choice arm. The difference in progression-free survival (HR 0.73) was statistically significant between the two treatment arms, but much less compared to overall survival.

Jessica Hassel, MD, is an associate professor and section head of DermatoOncology in the Department of Dermatology and the National Center for Tumor Diseases at the University Hospital Heidelberg in Heidelberg, Germany.

Response rates according to RECIST were 9% with tebentafusp (one complete response, 22 partial responses) and 5% with investigator’s choice. The disease control rate including patients with stable disease at 12 weeks was 46% and 27%, respectively.

Patients who do not have either a partial response or stable disease but experience disease progression, called best response of progressive disease, are generally not considered to be benefiting from a therapy.

“However, surprisingly, in a landmark Day 100 analysis limited to patients who had a best response of progressive disease, tebentafusp still conferred a better overall survival compared to the investigator’s choice,” Hassel explained.

Immune checkpoint inhibitors
While immune checkpoint inhibitors are commonly used treatments for metastatic uveal melanoma, the benefit is very limited, in contrast to cutaneous melanoma. This difference may, in part, be explained by the fact that uveal melanoma belongs to the cancers with a low mutational burden, which can lead to impaired T-cell recognition, Hassel explained.

“Tebentafusp redirects any T cell to target cells expressing gp100 and thereby has the chance to activate the immune response against the gp100-expressing uveal melanoma,” she added.

Tebentafusp demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) as a first-line treatment in mUM. The OS Hazard Ratio (HR) in the intent-to-treat population favored tebentafusp, HR=0.51 (95% CI: 0.37, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 12% ipilimumab; 6% dacarbazine).

Practice-changing
“As there are currently no standard treatments for patients with metastatic uveal melanoma, tebentafusp has the potential to become a practice-changing therapy for patients with this disease,” Hassel said.

The major limitation of tebentafusp is that it can only be used in patients who have a specific HLA type, Hassel said.

“There still remains an unmet need for patients who do not have this particular surface protein,” she noted.

Commenting on the results, Antoni Ribas, MD, Ph.D., professor of medicine, surgery, and molecular and medical pharmacology at the University of California in Los Angeles and the the 2020 – 2021 president of the American Association for Cancer Research or AACR, said: “In over 50 or 60 years of research, there had never been a treatment that had shown improvement in overall survival is one being the first one.”

“This study has several firsts.  It’s the clinical trial which demomstrated an improved overall survival in patients with uveal melanoma. It is also the first TCR therapeutic that has been successfully developed. And it’s the first, therapeutic that’s has shown an improvement in a randomized trial. So I think it’s a practice changing study to be able to use this in the clinic,” Ribas added

Adverse events
Treatment-related adverse events were manageable and consistent with the proposed mechanism.Adverse events associated with tebentafusp treatment were predictable and manageable, Hassel noted, and the rate of treatment discontinuation was lower in the tebentafusp arm compared with the investigator’s choice arm (2% versus 4.5%, respectively).

In a separate oral presentation during the virtual annual meeting of the AACR, Marcus O. Butler shared an analysis of previously treated uveal melanoma patients who had prolonged survival.

Furthermore, two posters from the phase II IMCgp100-102 study include analyses that investigated the proposed mechanism of action (MoA), including inducing an increase in cytokines and T cell trafficking into the tumor.

Regulatory development
Tebentafusp has been granted Breakthrough Therapy Designation, Fast Track designation, and orphan drug designation by the U.S. Food and Drug Administration (FDA) and Promising Innovative Medicine (PIM) designation under the UK Early Access to Medicines Scheme for metastatic uveal melanoma. Immunocore will be working with the FDA to complete the submission of a BLA for tebentafusp in the third quarter of 2021.

Clinical trials
Safety and Efficacy of IMCgp100 Versus Investigator Choice in Advanced Uveal Melanoma – NCT03070392
A Study of the Intra-Patient Escalation Dosing Regimen With IMCgp100 in Patients With Advanced Uveal Melanoma (IMCgp100-102) – NCT02570308

Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co., Inc) [Prescribing Information]
Ipilimumab (Yervoy®; Bristol Meyers Squibb)[Prescribing Information]
Dacarbazine [Prescribing information]

Reference
[1] Schank TE, Hassel JC. Immunotherapies for the Treatment of Uveal Melanoma-History and Future. Cancers (Basel). 2019 Jul 24;11(8):1048. doi: 10.3390/cancers11081048. PMID: 31344957; PMCID: PMC6721437.
[2] Piperno-Neumann S, Hassel JC, Rutkowski P, Baurain J, Butler MO, Schlaak M, Sullivan RJ, Ochsenreither S, Dummer R,et al. Phase 3 randomized trial comparing tebentafusp with investigator’s choice in first line metastatic uveal melanoma. Presented at: AACR Annual Meeting 2021; April 9-14; Virtual. Abstract: #5342

Featured image: The eye. Photo courtesy: © 2012 Julizs. This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported

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