Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tebentafusp: a first-in-class treatment for metastatic uveal melanoma.

ABSTRACT: Tebentafusp is a first-in-class immunotherapy agent that comprises an engineered T-cell receptor targeting a gp100 epitope presented by human leukocyte antigen-A*02:01 cells, fused to an anti-CD3 single-chain variable fragment. Tebentafusp is both the first bispecific T-cell engager to show efficacy in the treatment of advanced solid cancer and the first anti-cancer treatment to demonstrate an overall survival benefit in patients with uveal melanoma (UM). This review article will focus on the clinical development of tebentafusp, the mechanism of action and resultant evolution of the management of advanced UM.

SUBMITTER: Howlett S

PROVIDER: S-EPMC10031621 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Tebentafusp: a first-in-class treatment for metastatic uveal melanoma.

Howlett Sarah S Carter Thomas J TJ Shaw Heather M HM Nathan Paul D PD

Therapeutic advances in medical oncology 20230321

Tebentafusp is a first-in-class immunotherapy agent that comprises an engineered T-cell receptor targeting a gp100 epitope presented by human leukocyte antigen-A*02:01 cells, fused to an anti-CD3 single-chain variable fragment. Tebentafusp is both the first bispecific T-cell engager to show efficacy in the treatment of advanced solid cancer and the first anti-cancer treatment to demonstrate an overall survival benefit in patients with uveal melanoma (UM). This review article will focus on the cl ...[more]

PMID: 36970111

Similar Datasets

Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma.

Project description:Metastatic disease from uveal melanoma occurs in almost 50% of patients suffering from this ocular tumour, with median survival from development of symptoms being around 1 year. In contrast to cutaneous melanoma, kinase inhibitors and immune checkpoint inhibitors are usually ineffective in patients with metastatic uveal melanoma. Tebentafusp is a novel form of immunotherapy based on the immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) platform, which comprises a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment. The T cell receptor domain of tebentafusp targets cells present a human leukocyte antigen-A*02:01 complexed with a peptide derived from the melanoma-associated antigen gp100, which is expressed strongly by melanoma cells, weakly by normal melanocytes and minimally by other tissues. The anti-CD3 domain recruits CD3+ T cells (and, indirectly, other immune cells), redirecting these to the melanoma cells. The most common adverse events with tebentafusp are manageable and usually transient. Early survival data in patients with metastatic uveal melanoma are promising when considered alongside historical data. Based on these encouraging results, a randomised study comparing tebentafusp to investigator's choice of therapy in metastatic uveal melanoma is ongoing.

| S-EPMC6679206 | biostudies-literature

Tebentafusp in the Treatment of Metastatic Uveal Melanoma: Patient Selection and Special Considerations.

Project description:Uveal melanoma (UM) is a rare type of melanoma with distinct features from cutaneous melanoma, low response rates to immune checkpoint inhibition, and poor survival rates. Tebentafusp, a bispecific antibody engaging T cells with gp 100 on HLA-A*02:01, was recently approved by the FDA as the first drug of its class and the first treatment approved by the FDA to treat UM. In this review, we summarize the preclinical and clinical data on tebentafusp for UM. We additionally discuss patient selection and the relevant challenges. For the literature search, PubMed search and relevant articles presented at international conferences were used.

| S-EPMC9921510 | biostudies-literature

Patterns of radiological response to tebentafusp in patients with metastatic uveal melanoma.

Project description:Metastatic uveal melanoma (mUM) is a rare type of melanoma with poor outcomes. The first systemic treatment to significantly prolong overall survival (OS) in patients with mUM was tebentafusp, a bispecific protein that can redirect T-cells to gp-100 positive cells. However, the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the clinical impact of tebentafusp. As metabolic response assessed by PET Response Criteria in Solid Tumors (PERCIST) has been reported to better correlate with clinical outcome, we here compared the patterns of radiological and morphological responses in HLA-A*02:01-positive patients with mUM treated with tebentafusp. In the 19 enrolled patients, RECIST showed an overall response rate (ORR) of 10%, median progression-free survival of 2.8 months (95% CI 2.5-8.4), and median OS (mOS) of 18.8 months. In 10 patients, where both RECIST and PERCIST evaluation was available, the ORR was 10% for both; however, the PFS was longer for PERCIST compared to RECIST, 3.1 and 2.4 months, respectively. A poor agreement between the criteria was observed at all assessments (Cohen's kappa ≤0), yet they differed significantly only at the first on-treatment imaging ( P = 0.037). Elevated baseline LDH and age were associated with an increased risk for RECIST progression, while lymphocyte decrease after the first infusions correlated to reduced risk of RECIST progression. Detectable ctDNA at baseline did not correlate with progression. Early response to tebentafusp may be incompletely captured by conventional imaging, leading to a need to consider both tumor morphology and metabolism.

| S-EPMC10906186 | biostudies-literature

Tebentafusp for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

Project description:IntroductionMetastatic uveal melanoma is associated with poor prognosis and few treatment options. Tebentafusp recently became the first FDA-approved agent for metastatic uveal melanoma.Areas coveredIn this review, we describe the mechanism of action of tebentafusp as well as preclinical data showing high tumor specificity of the drug. We also review promising early-phase trials in which tebentafusp demonstrated activity in metastatic uveal melanoma patients with an acceptable toxicity profile that included cytokine-mediated, dermatologic-related, and liver-related adverse events. Finally, we summarize findings from a pivotal phase III randomized trial in which tebentafusp demonstrated significant improvement in overall survival in comparison with investigator choice therapy.Expert opinionTebentafusp has transformed the treatment paradigm for metastatic uveal melanoma and should be the preferred frontline agent for most HLA-A*0201 positive patients. However, patients with rapidly progressing disease or high tumor benefit may not derive the same benefit. Areas of future study should focus on its role in the adjuvant setting as well as strategies to improve the efficacy of tebentafusp in the metastatic setting.

| S-EPMC10184536 | biostudies-literature

Immuno-oncology approaches in uveal melanoma: tebentafusp and beyond.

Project description:Uveal melanoma (UM) is the most common ocular malignancy in adults, associated with the poorest prognosis, with metastatic disease occurring in up to 50% of patients. In contrast to metastatic cutaneous melanoma, the use of immune checkpoint inhibitors is associated with poor outcomes in metastatic uveal melanoma (mUM). Tebentafusp, a bispecific molecule, has recently become the first treatment in decades to improve overall survival for mUM. This review summarises the existing and emerging immuno-oncology approaches for the treatment of mUM, and biomarkers of response and resistance to the same. Finally, we propose future research directions that could maximise treatment benefit to a wider pool of patients with UM.

| S-EPMC10362360 | biostudies-literature

Efficacy and safety of tebentafusp in patients with metastatic uveal melanoma: A systematic review and meta-analysis.

Project description:Patients with metastatic uveal melanoma (mUM) have a poor prognosis, and few appropriate medications are available. Tebentafusp is approved by the Food and Drug Administration for mUM recently. However, the real efficacy and safety of tebentafusp are still unclear. We searched PubMed, Embase, and Cochrane Library from inception to March 20, 2024. The research was reported based on the preferred reporting items for systematic reviews and meta-analysis guidelines. We used random effects models to aggregate data on the response rates and adverse events of tebentafusp therapy. Six studies met the inclusion criteria with a total sample of 589 participants. The pooled objective response rate was 0.08 (95% CI: 0.05-0.12), and pooled disease control rate was 0.51 (95% CI: 0.44-0.57). The overall incidence was 0.99 (95% CI: 0.95-1.00) for any grade adverse events, 0.50 (95% CI: 0.41-0.59) for grade 3-4 adverse events, and 0.01 (95% CI: 0-0.03) for discontinuation due to adverse events. Tebentafusp exhibits promising treatment outcomes for mUM patients. Although accompanied with a common occurrence of adverse events, which can typically be managed and controlled. Future research is necessary for substantiating these findings and refining guidelines for management of mUM.

| S-EPMC11249029 | biostudies-literature

Treatment of Metastatic Uveal Melanoma: Systematic Review.

Project description:INTRODUCTION:More than 50% of patients with uveal melanoma end up developing metastases. Currently, there is no standard first-line treatment that facilitates proper management of the metastatic disease. METHODS:A systematic review of the last 40 years in PubMed with an exhaustive and strict selection of studies was conducted, in which the unit of measurement was overall survival (OS) expressed in Kaplan-Meier curves or numerically. RESULTS:After the selection process, 110 articles were included. Regional therapies, such as intra-arterial liver chemotherapy (OS: 2, 9-22 months), isolated liver perfusion (OS: 9, 6-27, 4 months), or selective internal radiation therapy (OS: 18 months in monotherapy and 26 months in combination with other therapies) showed some superiority when compared to systemic therapies, such as chemotherapy (OS: 4, 6-17 months), immunotherapy (OS: 5-19, 1 month), immunosuppression (OS: 11 months), or targeted therapy (OS: 6-12 months), without being significant. CONCLUSIONS:The results of this review suggest that there are no important differences in OS when comparing the different current treatment modalities. Most of the differences found seem to be explained by the heterogenicity of the different studies and the presence of biases in their design, rather than actual extensions of patient survival.

| S-EPMC7565536 | biostudies-literature

Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial.

Project description:In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2-10%), the 1 year overall survival rate was 62% (95% CI: 53-70%) with a median overall survival of 16.8 months (95% CI: 12.9-21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.

| S-EPMC9671803 | biostudies-literature

Darovasertib, a novel treatment for metastatic uveal melanoma.

Project description:The FDA granted orphan drug designation to darovasertib, a first-in-class oral, small molecular inhibitor of protein kinase C (PKC), for the treatment of uveal melanoma, on 2 May 2022. Primary uveal melanoma has a high risk of progressing to metastatic uveal melanoma, with a poor prognosis. The activation of the PKC and mitogen-activated protein kinase pathways play an essential role in the pathogenesis of uveal melanoma, and mutations in the G protein subunit alpha q (GNAQ), and G protein subunit alpha11 (GNA11) genes are considered early events in the development of uveal melanoma. Compared to other PKC inhibitors, such as sotrastaurin and enzastaurin, darovasertib is significantly more potent in inhibiting conventional (α, β) and novel (δ, ϵ, η, θ) PKC proteins and has a better tolerability and safety profile. Current Phase I/II clinical trials indicated that darovasertib, combined with the Mitogen-activated protein kinase/Extracellular (MEK) inhibitors, binimetinib or crizotinib, produced a synergistic effect of uveal melanoma. In this article, we summarize the development of drugs for treating uveal melanomas and discuss problems associated with current treatments. We also discuss the mechanism of action, pharmacokinetic profile, adverse effects, and clinical trial for darovasertib, and future research directions for treating uveal melanoma.

| S-EPMC10419210 | biostudies-literature

Metastatic Uveal Melanoma: Treatment Strategies and Survival-Results from the Dutch Melanoma Treatment Registry.

Project description:Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Up to 50% of UM patients will develop metastases. We present data of 175 metastatic UM patients diagnosed in the Netherlands between July 2012 and March 2018. In our cohort, elevated lactate dehydrogenase level (LDH) is an important factor associated with poorer survival (Hazard Ratio (HR) 9.0, 95% Confidence Interval (CI) 5.63-14.35), and the presence of liver metastases is negatively associated with survival (HR 2.09, 95%CI 1.07-4.08). We used data from the nation-wide Dutch Melanoma Treatment Registry (DMTR) providing a complete overview of the location of metastases at time of stage IV disease. In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases. In 63 (36%) patients, mutation analysis was performed, showing a GNA11 mutation in 28.6% and a GNAQ mutation in 49.2% of the analyzed patients. In the absence of standard care of treatment options, metastatic UM patients are often directed to clinical trials. Patients participating in clinical trials are often subject to selection and usually do not represent the entire metastatic UM population. By using our nation-wide cohort, we are able to describe real-life treatment choices made in metastatic UM patients and 1-year survival rates in selected groups of patients.

| S-EPMC6678641 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data