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Cancer Aug 2016Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United... (Review)
Review
Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society.
Topics: Chromosome Aberrations; Combined Modality Therapy; Early Detection of Cancer; Genetic Predisposition to Disease; Genetic Testing; Humans; Melanoma; Mutation; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Research; Treatment Outcome; Uveal Neoplasms
PubMed: 26991400
DOI: 10.1002/cncr.29727 -
The British Journal of Ophthalmology Jan 2017Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and,... (Review)
Review
Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis. There is currently little published evidence for the optimal management and treatment of metastatic uveal melanoma and the lack of effective therapies in this setting has led to the widespread use of systemic treatments for patients with cutaneous melanoma. Uveal and cutaneous melanomas are intrinsically different diseases and so dedicated management strategies and therapies for uveal melanoma are much needed. This review explores the biology of uveal melanoma and how this relates to ongoing trials of targeted therapies in the metastatic disease setting. In addition, we consider the options to optimise patient management and care.
Topics: Humans; Incidence; Liver Neoplasms; Melanoma; Molecular Biology; Molecular Targeted Therapy; Neoplasm Metastasis; Prognosis; Uveal Neoplasms
PubMed: 27574175
DOI: 10.1136/bjophthalmol-2016-309034 -
Progress in Retinal and Eye Research Sep 2022Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are... (Review)
Review
Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10-13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95-100% and 83-100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.
Topics: Clinical Trials, Phase III as Topic; Humans; Liver Neoplasms; Melanoma; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Retrospective Studies; Uveal Neoplasms
PubMed: 34999237
DOI: 10.1016/j.preteyeres.2022.101041 -
The Israel Medical Association Journal... Jul 2019Uveitis is an inflammatory disorder of the uveal tract of the eye that can affect both adults and children. Non-infectious uveitis can be an expression of a systemic... (Review)
Review
Uveitis is an inflammatory disorder of the uveal tract of the eye that can affect both adults and children. Non-infectious uveitis can be an expression of a systemic autoimmune condition, or it can be idiopathic. It is a serious disease, associated with possible severe complications leading to visual impairment and blindness. For this reason, a prompt diagnosis and assessment of an appropriate treatment, with the collaboration of specialists such as ophthalmologists and rheumatologists, are extremely important. Many treatment options may be associated to side effects; therefore, clinicians should follow a stepladder approach starting with the least aggressive treatments to induce remission of inflammation. In this review, we reported the current evidence-based treatments for non-infectious uveitis in pediatric and adult patients with particular attention to the biologic response modifier treatment options. Important multicenter studies have demonstrated the efficacy of adalimumab, both in adults (VISUAL I, VISUAL II, VISUAL III) and in children (SYCAMORE, ADJUVITE), while for other agents data are still scarce.
Topics: Adalimumab; Adult; Child; Cooperative Behavior; Evidence-Based Medicine; Humans; Immunologic Factors; Inflammation; Uveitis
PubMed: 31507124
DOI: No ID Found -
The New England Journal of Medicine Sep 2021Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells.
METHODS
In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival.
RESULTS
A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported.
CONCLUSIONS
Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cytokine Release Syndrome; Dacarbazine; Exanthema; Female; Humans; Ipilimumab; Male; Melanoma; Middle Aged; Recombinant Fusion Proteins; Survival Analysis; Uveal Neoplasms
PubMed: 34551229
DOI: 10.1056/NEJMoa2103485 -
Archives of Pathology & Laboratory... Apr 2020There have been major advances in the understanding of melanoma since the last revision of the World Health Organization (WHO) classification in 2006. (Review)
Review
The 2018 World Health Organization Classification of Cutaneous, Mucosal, and Uveal Melanoma: Detailed Analysis of 9 Distinct Subtypes Defined by Their Evolutionary Pathway.
CONTEXT.—
There have been major advances in the understanding of melanoma since the last revision of the World Health Organization (WHO) classification in 2006.
OBJECTIVE.—
To discuss development of the 9 distinct types of melanoma and distinguishing them by their epidemiology, clinical and histologic morphology, and genomic characteristics. Each melanoma subtype is placed at the end of an evolutionary pathway that is rooted in its respective precursor, wherever appropriate and feasible, based on currently known data. Each precursor has a variable risk of progression culminating in its fully evolved, invasive melanoma.
DATA SOURCES.—
This review is based on the "Melanocytic Tumours" section of the 4th edition of the , published in 2018.
CONCLUSIONS.—
Melanomas were divided into those etiologically related to sun exposure and those that are not, as determined by their mutational signatures, anatomic site, and epidemiology. Melanomas on the sun-exposed skin were further divided by the histopathologic degree of cumulative solar damage (CSD) of the surrounding skin, into low and high CSD, on the basis of degree of associated solar elastosis. Low-CSD melanomas include superficial spreading melanomas and high-CSD melanomas incorporate lentigo maligna and desmoplastic melanomas. The "nonsolar" category includes acral melanomas, some melanomas in congenital nevi, melanomas in blue nevi, Spitz melanomas, mucosal melanomas, and uveal melanomas. The general term is proposed to encompass "intermediate" tumors that have an increased (though still low) probability of disease progression to melanoma.
Topics: Humans; Melanoma; Mucous Membrane; Skin Neoplasms; Uveal Neoplasms; World Health Organization; Melanoma, Cutaneous Malignant
PubMed: 32057276
DOI: 10.5858/arpa.2019-0561-RA -
Eye (London, England) Feb 2017Although it is a relatively rare disease, primarily found in the Caucasian population, uveal melanoma is the most common primary intraocular tumor in adults with a mean... (Review)
Review
Although it is a relatively rare disease, primarily found in the Caucasian population, uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in iris (4%), ciliary body (6%), or choroid (90%). The host susceptibility factors for uveal melanoma include fair skin, light eye color, inability to tan, ocular or oculodermal melanocytosis, cutaneous or iris or choroidal nevus, and BRCA1-associated protein 1 mutation. Currently, the most widely used first-line treatment options for this malignancy are resection, radiation therapy, and enucleation. There are two main types of radiation therapy: plaque brachytherapy (iodine-125, ruthenium-106, or palladium-103, or cobalt-60) and teletherapy (proton beam, helium ion, or stereotactic radiosurgery using cyber knife, gamma knife, or linear accelerator). The alternative to radiation is enucleation. Although these therapies achieve satisfactory local disease control, long-term survival rate for patients with uveal melanoma remains guarded, with risk for liver metastasis. There have been advances in early diagnosis over the past few years, and with the hope survival rates could improve as smaller tumors are treated. As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma. These observations call attention to an unmet medical need for the early treatment of small melanocytic lesions or small melanomas in the eye to achieve local disease control and vision preservation with the possibility to prevent metastases and improve overall patient survival.
Topics: Age Distribution; Combined Modality Therapy; Humans; Incidence; Iridectomy; Melanoma; Radiosurgery; Radiotherapy; Risk Factors; Sex Distribution; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Ultraviolet Rays; Uveal Neoplasms
PubMed: 27911450
DOI: 10.1038/eye.2016.275 -
Expert Review of Anticancer Therapy Oct 2022Metastatic uveal melanoma is associated with poor prognosis and few treatment options. Tebentafusp recently became the first FDA-approved agent for metastatic uveal... (Review)
Review
INTRODUCTION
Metastatic uveal melanoma is associated with poor prognosis and few treatment options. Tebentafusp recently became the first FDA-approved agent for metastatic uveal melanoma.
AREAS COVERED
In 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 OPINION
Tebentafusp 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.
Topics: Adult; Cytokines; HLA-A Antigens; Humans; Immunoconjugates; Melanoma; Recombinant Fusion Proteins; Uveal Neoplasms
PubMed: 36102132
DOI: 10.1080/14737140.2022.2124971 -
Current Opinion in Ophthalmology May 2022This article reviews the latest proteomic research on uveal melanoma. (Review)
Review
PURPOSE OF REVIEW
This article reviews the latest proteomic research on uveal melanoma.
RECENT FINDINGS
Proteomic analysis of uveal melanoma cell lines and tissue specimens has improved our understanding of the pathophysiology of uveal melanoma and helped identify potential prognostic biomarkers. Circulating proteins in patient serum may aid in the surveillance of metastatic disease. The proteomes of aqueous and vitreous biopsy specimens may provide safer biomarkers for metastatic risk and candidate therapeutic targets in uveal melanoma. Proteomic analysis has the potential to benefit patient outcomes by improving diagnosis, prognostication, surveillance, and treatment of uveal melanoma.
SUMMARY
These recent findings demonstrate that proteomic analysis is an important area of research to better understand the pathophysiology of uveal melanoma and improve the personalized management of our patients.
Topics: Biopsy; Humans; Melanoma; Proteomics; Uveal Neoplasms
PubMed: 35102096
DOI: 10.1097/ICU.0000000000000835 -
Nature Medicine Nov 2022In 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...
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.
Topics: Humans; Uveal Neoplasms; Melanoma; Progression-Free Survival
PubMed: 36229663
DOI: 10.1038/s41591-022-02015-7