INTRODUCTION — Uveal melanoma is a rare malignancy that arises from melanocytes within the uveal tract of the eye, which includes the iris, ciliary body, and choroid (figure 1). Uveal melanoma comprises approximately 85 percent of all ocular melanomas, with the remainder arising mostly from the conjunctiva (5 percent) or other sites (10 percent) [1,2].
The clinical presentation, diagnosis, and management of metastatic uveal melanoma are discussed here. The molecular biology of uveal melanoma and clinical presentation, diagnosis, and initial management of uveal and conjunctival melanomas are discussed separately.
Timing of metastases — Most patients develop metastatic uveal melanoma within five to seven years of treatment to the primary eye tumor, with a median time of approximately three years . Metastases can also appear after a decade or longer [4-6]. Despite effective treatment of the primary site, the risk of distant metastasis among patients with uveal melanoma is up to 50 percent (depending on the genetic subtype [4,7]). (See "Initial management of uveal and conjunctival melanomas", section on 'Posttreatment systemic surveillance'.)
Patients who present with a primary uveal melanoma and synchronous distant metastases are rare (less than four percent of all patients diagnosed with uveal melanoma) [8,9]. (See "Initial management of uveal and conjunctival melanomas", section on 'Staging of distant (extraocular) disease'.)
Sites of disease — The most common sites of metastases from uveal melanoma include :
●Liver (93 percent).
●Lung (24 percent).
●Bone (16 percent).
●Skin/subcutaneous tissue (11 percent).
●Lymph node and brain metastasis (5 to 6 percent) are rare .
Clinical symptoms — A majority of patients with metastatic uveal melanoma are asymptomatic at diagnosis since most cases are incidentally diagnosed during routine imaging surveillance. Patients with more indolent tumors, such as those harboring a SF3B1 mutation, may also present without symptoms. (See "Initial management of uveal and conjunctival melanomas", section on 'Posttreatment systemic surveillance'.)
Patients with significant disease burden typically develop symptomatic metastases. These patients may present with constitutional symptoms such as fatigue, weight loss, and anorexia. The presence of other symptoms can indicate disease location, such as abdominal pain, swelling, fullness, or back pain for those with liver metastases; chest pain or shortness of breath for those with lung metastases; and bone pain or pathologic fractures for those with bony metastases . Although central nervous system (CNS) metastases are generally rare, approximately six percent of patients with metastatic uveal melanoma develop neurologic symptoms, including headache, weakness, sensory loss, and confusion . (See "Staging work-up and surveillance of cutaneous melanoma", section on 'Symptoms of recurrence or metastatic disease'.)
Physical exam — Patients with limited tumor burden may have normal physical exam findings. Painless skin or subcutaneous nodules may be present. Unlike cutaneous melanoma, regional lymphadenopathy is rare. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Regional involvement'.)
Patients with high tumor burden and/or rapidly progressive disease involving the liver may demonstrate hepatomegaly, jaundice, or other stigmata of liver disease. (See "Overview of the evaluation of hepatomegaly in adults", section on 'Physical examination'.)
DIAGNOSTIC EVALUATION — The diagnosis of metastatic uveal melanoma should be suspected in patients with a known history of primary uveal melanoma and systemic metastases (such as predominant disease burden in the liver) diagnosed either on physical exam or imaging studies. Patients with indolent disease may be asymptomatic and are more likely to be diagnosed during routine posttreatment imaging surveillance. (See "Initial management of uveal and conjunctival melanomas", section on 'Posttreatment systemic surveillance'.)
Patients with de novo metastatic melanoma (especially those with hepatic metastases) and an unknown primary site should be referred to ophthalmology to assess for a primary lesion in the eye . The diagnosis of a primary uveal melanoma is discussed separately. (See "Initial management of uveal and conjunctival melanomas", section on 'Diagnosis of the primary tumor'.)
Laboratory testing — For patients with suspected metastatic uveal melanoma, we obtain a complete blood count with differential, complete metabolic panel (including liver function testing, alkaline phosphatase, and total bilirubin), and lactate dehydrogenase.
Imaging studies — For patients with suspected metastatic uveal melanoma, we obtain imaging studies as an initial diagnostic step to assess clinical symptoms, disease extent, and as a baseline to assess treatment response. Imaging studies are also necessary to determine a metastatic site for tissue sampling. (See 'Diagnostic biopsy' below.)
We obtain magnetic resonance imaging (MRI) of the liver with gadoxetate (Eovist) contrast to assess for hepatic metastases. We also obtain contrast-enhanced computed tomography (CT) of the chest to assess for extrahepatic sites of disease. Patients may be offered the option of an MRI of the brain with contrast to assess for CNS metastases. We do not routinely obtain fludeoxyglucose (FDG)-positron emission tomography (PET)-CT as part of initial diagnostic imaging. Uveal melanoma is not consistently FDG-avid on PET-CT It is also difficult to visualize hepatic metastases due to normal liver uptake of FDG. (See "Imaging studies in melanoma", section on 'Liver'.)
Diagnostic biopsy — The diagnosis of metastatic uveal melanoma is confirmed on biopsy and histopathologic evaluation of distant metastatic lesions, once metastatic lesions are detected on imaging studies. Further details on the histopathology of melanoma is discussed separately. (See "Pathologic characteristics of melanoma".)
Tissue can be obtained using fine needle aspiration (FNA) or core needle biopsy, depending upon the disease site. The metastatic tissue that is obtained for diagnosis (or archived tissue from the primary ocular tumor, if available) can also be assessed for molecular alterations, which can determine prognosis and guide management, including clinical trials. (See 'Molecular analyses' below and 'Treatment' below.)
Molecular analyses — The molecular pathogenesis of uveal melanoma is distinct from that of cutaneous melanoma and other melanoma subtypes, including conjunctival melanoma. Uveal melanomas usually harbor specific initiating mutations in GNAQ, GNA11, or other members of the G protein alpha subunit signaling pathway, as well as secondary driver mutations with prognostic significance in genes such as BAP1, SF3B1, and EIF1AX. Further details of the specific molecular alterations found in uveal melanoma are discussed separately. (See "The molecular biology of melanoma", section on 'Uveal melanomas'.)
Patients with metastatic uveal melanoma should have their tumors assessed using next generation sequencing (NGS) or gene expression profiling. While molecular alterations that are targetable for treatment are limited in uveal melanoma, some alterations may offer insights into prognosis as well as clinical trial options. A majority of patients with a known primary uveal melanoma may have already been assessed for these alterations, which are used to guide post-treatment surveillance. (See "Initial management of uveal and conjunctival melanomas", section on 'Posttreatment systemic surveillance'.)
In addition, we obtain a genotyping assay on whole blood for the presence of human leukocyte antigen (HLA)-A*02:01. Patients with this genotype are eligible for targeted therapy with tebentafusp. (See 'Genotype assessment' below and 'HLA-A*02:01 positive' below.)
STAGING — The American Joint Committee on Cancer AJCC and Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) staging system is used to stage patients with uveal melanoma. Staging is also based on the primary location of ocular disease, such as the iris (table 1) and choroidal and ciliary body (table 2).
TREATMENT — The optimal treatment approach for metastatic uveal melanoma is evolving. The choice of therapy is based upon clinical factors such as genotype assessment for HLA-A*02:01, tumor burden, rate of growth, and location, and the availability of clinical trials (algorithm 1).
Genotype assessment — Prior to initiating systemic therapy in all patients with metastatic uveal melanoma, we obtain a genotyping assay on whole blood for the presence of human leukocyte antigen (HLA)-A*02:01, which is seen in approximately 45 percent of individuals in the United States and Europe . Patients who are HLA-A*02:01 positive are candidates for targeted therapies such as tebentafusp, whereas those who are negative are offered locoregional and/or other systemic therapies (algorithm 1). A companion diagnostic HLA sequencing system with regulatory approval is available . (See 'HLA-A*02:01 positive' below.)
Tebentafusp — For patients with treatment-naïve metastatic uveal melanoma who are human leukocyte antigen (HLA)-A*02:01 positive, we suggest tebentafusp rather than other systemic agents, as this approach improved overall survival (OS) over chemotherapy and checkpoint inhibitor immunotherapy in a phase III trial .
Patients who are ineligible for tebentafusp (eg, due to systemic immunosuppression) or those with bulky or rapidly progressive disease may be treated using the same approach as those without the HLA-A*02:01 genotype. Although tebentafusp improves OS, including those whose best response was progressive disease, progression-free survival (PFS) and objective response rates are modest with this agent, and other therapies may offer more rapid disease control. (See 'HLA-A*02:01 negative' below.)
Tebentafusp is administered using a dose-escalation strategy of 20 mcg on day 1, 30 mcg on day 8, and 68 mcg on day 15 and weekly thereafter. Due to the risk of cytokine release syndrome (CRS), the first three doses of tebentafusp should be administered in a tertiary care inpatient setting with expertise in the management of CRS, where patients can be monitored during the infusion and for at least 16 hours after treatment completion. Patients who do not experience grade ≥2 hypotension that requires medical intervention during or after the third infusion can receive subsequent doses in an ambulatory infusion clinic, with monitoring for a minimum of 30 minutes following each infusion . (See "Cytokine release syndrome (CRS)".)
Tebentafusp (IMCgp100), a first-in-class immune mobilizing monoclonal T-cell receptor against cancer (ImmTAC), is comprised of a targeting end that constitutes a soluble affinity-enhanced HLA-A*02:01 restricted T cell receptor targeting glycoprotein 100, a uveal melanoma antigen, and an effector end targeting CD3 (figure 2) [11,14,15]. Once tebentafusp binds the peptide-HLA complexes expressed on the cancer cells, it activates polyclonal T cells through CD3 to release cytokines and cytolytic mediators against those cells. (See "Principles of cancer immunotherapy", section on 'Immune-mobilizing monoclonal TCRs against cancer'.)
Based on initial phase I and II trial data [16,17], a phase III trial was conducted in 378 patients with positive HLA-A*02:01 and systemic treatment-naïve advanced uveal melanoma, with no prior liver-directed therapy (except surgery) and any level of LDH . Other exclusion criteria included symptomatic central nervous system (CNS) metastases, autoimmune disease being treated with glucocorticoids, and active systemic immunosuppressive therapy. Patients were randomly assigned in a 2:1 ratio to tebentafusp or investigator's choice of pembrolizumab, ipilimumab, or dacarbazine.
At median follow-up of 14 months, compared with investigator's choice of therapy, tebentafusp improved both OS (one-year OS 73 versus 59 percent; median OS 22 versus 16 months, hazard ratio [HR] 0.51, 95% CI 0.37-0.71) and PFS (six-month PFS 31 versus 19 percent; median 3.3 versus 2.9 months, HR 0.73, 95% CI 0.58-0.94) . Tebentafusp also improved OS in patients whose best response was progressive disease (median 15 versus 7 months; HR 0.43, 95% CI 0.27-0.68). Objective responses were higher with tebentafusp (9 versus 5 percent), including one patient with a complete response. This disassociation between response rates and OS outcomes for tebentafusp is attributed to a different form to treatment response with this agent than has previously been seen with chemotherapy.
CRS occurred in 89 percent of patients receiving tebentafusp. However, most treatment-related toxicities decreased in frequency and severity after the first three to four doses. Grade ≥3 toxicities include rash (18 percent), pruritus (5 percent), pyrexia (4 percent), fatigue and hypotension (3 percent each). No tebentafusp-related deaths were reported.
Based on these data, the US Food and Drug Administration (FDA) approved tebentafusp for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma . Tebentafusp also is approved by the European Medicines Agency (EMA) for the treatment of metastatic uveal melanoma .
HLA-A*02:01 negative — For patients with treatment-naïve metastatic uveal melanoma who are not HLA-A*02:01-positive or those with bulky or rapidly progressive disease, we offer enrollment in formal clinical trials whenever possible.
For those who decline or are not eligible for clinical trials, our initial treatment approach is based on disease location, patient characteristics, and treatment preferences. The optimal treatment approach is not established as randomized studies are limited in this rare disease.
Treatment approach — For patients with liver-dominant disease, we suggest locoregional therapies rather than systemic therapy. However, initial systemic therapy is an appropriate alternative. Some patients may reasonably opt for this strategy, given the generally poor prognosis of metastatic uveal melanoma and limited randomized trials comparing locoregional and systemic therapies. (See 'Prognosis' below and 'Significant extrahepatic disease' below.)
After completion of locoregional therapy, patients with treated liver-dominant disease may be observed for disease progression with imaging studies every six to eight weeks. We reserve systemic therapy for patients with significant extra-hepatic disease or those who are ineligible for locoregional treatment. (See 'Significant extrahepatic disease' below.)
Most patients with both liver-dominant and limited extrahepatic disease may receive liver-directed therapy followed by systemic therapy. Systemic therapy can be initiated once liver-directed therapy has achieved some degree of hepatic disease control. Alternatively, select patients with low-volume, indolent metastases outside the liver (particularly within the lung) may be observed after completing liver-directed therapy.
Locoregional therapies — The liver is the most common site of disease in patients with metastatic uveal melanoma. In patients with hepatic metastases, data suggest that liver-directed therapy can improve objective response rates and is associated with longer progression-free survival (PFS) [19-21]. However, an OS benefit for liver-directed therapy has not been established. Liver-directed therapies are being compared with other locoregional and systemic treatments in randomized trials, but the optimal liver-directed therapy is not known. Selection of therapy is based on clinician and institutional expertise.
Locoregional therapies that are used to treat metastatic uveal melanoma include [22,23]:
●Hepatic arterial infusion of chemotherapy (HAI)
•Transarterial chemoembolization (TACE)
●Isolated hepatic therapy
•Percutaneous hepatic perfusion (PHP)
•Isolated hepatic perfusion (IHP)
●Ablative therapies (eg, radiofrequency ablation, cryoablation)
These techniques are described as follows:
●Hepatic arterial infusion of chemotherapy – HAI delivers chemotherapy directly to the liver metastases via a catheter connected to the hepatic artery. Catheters can be introduced surgically via the gastroduodenal artery or percutaneously via the femoral artery [22,23]. HAI treats liver metastases by taking advantage of the dual blood supply of the liver; recruited hepatic artery branches vascularize the melanoma metastases, whereas portal circulation provides blood to the normal liver tissue.
Fotemustine is the most common chemotherapy regimen used with HIA. Fotemustine is used in Europe, but this agent is not approved in the United States. Other regimens such as melphalan  and cisplatin  have also been used. In a randomized trial, intrahepatic artery infusion with fotemustine [26,27] improved progression-free survival (PFS) and response rates, but not OS compared with systemic chemotherapy.
•Fotemustine – In a phase III trial (EORTC 18021), 171 patients with uveal melanoma and metastases limited to the liver were randomly assigned to fotemustine given either intra-arterially or intravenously . At a median follow-up of 1.6 years, compared with intravenous fotemustine, intra-arterial fotemustine improved PFS (median 5 versus 4 months, hazard ratio [HR] 0.62, 95% CI 0.45-0.84), and response rates (11 versus 2 percent), but not OS (median 15 versus 14 months, HR 1.09, 95% CI 0.79-1.5). Grade ≥3 toxicities due to intra-arterial fotemustine included catheter complications (12 percent), liver toxicity (5 percent), and two treatment-related deaths.
●Embolization procedures – The hepatic artery supplies most of the blood to the hepatic metastases, rather than the portal vein. Various embolization procedures have been developed that target the hepatic artery to eliminate the tumor’s blood supply.
•Transarterial chemoembolization – Transarterial liver chemoembolization (TACE) combines hepatic artery embolization with intra-arterial infusion of chemotherapy. The embolization leads to ischemia of the metastatic liver lesions as well as targeted chemotherapy to the liver lesions, which reduces the risk of systemic toxicity. In observational and phase I/II studies of patients with metastatic uveal melanoma treated with TACE (using cisplatin [25,28-31], fotemustine [30,32], 1,3-bis(2-chloro-ethyl)-1-nitrosourea [BCNU] , or drug-eluting beads loaded with irinotecan [DEBIRI] [34-36]), objective response rates were variable (between 6 and 57 percent), and median OS ranged between 6 and 30 months . TACE is generally well-tolerated, although severe toxicities such as disseminated intravascular coagulation and cerebral infarctions have been reported .
The use of TACE in other liver malignancies, such as hepatocellular carcinoma, is discussed separately. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'Technique for TACE'.)
•Radioembolization – Radioembolization (ie, selective internal radiation therapy) uses intra-arterial injection of yttrium-90 (Y90)-labeled glass or resin microspheres to induce extensive tumor necrosis [38-41]. Radioembolization is frequently used to treat hepatic metastases from uveal melanoma.
A randomized phase II trial (SirTac) of 40 patients with liver-dominant metastatic uveal melanoma compared radioembolization to TACE . In preliminary results, at median follow-up of 14 months, best overall response rates (95 versus 85 percent) were similar for the two treatment arms. In an exploratory analysis, radioembolization improved hepatic (median 8 versus 2 months) and overall PFS (5 versus 2 months) compared with TACE.
•Other embolization procedures – Other embolization procedures include bland embolization and immunoembolization with granulocyte-macrophage colony-stimulating factor (GM-CSF) .
●Isolated hepatic therapy
•Isolated hepatic perfusion – IHP is a one-time opens surgical procedure where the vascular supply to the liver is isolated. This approach allows delivery of high doses of chemotherapy (typically melphalan) directly to the liver metastases. IHP is not widely used since the procedure takes many hours to complete, cannot be repeated, and is associated with significant toxicity and prolonged hospital stays .
In a randomized, controlled phase III trial (SCANDIUM) of 93 patients with metastatic uveal melanoma and isolated liver metastases, IHP improved hepatic PFS (9 versus 3 months), overall PFS (7 versus 3 months), and overall response rates (40 versus 5 percent) compared with investigators choice of best alternative care (chemotherapy, immunotherapy, or other locoregional therapies) . Follow-up of OS in this trial is still ongoing. In observational studies of patients with metastatic uveal melanoma treated with IHP, median OS was approximately 10 to 12 months [44-49].
•Percutaneous hepatic perfusion – PHP is a repeatable procedure where chemotherapy is administered via percutaneous catheters directly into the liver via the hepatic artery. The venous blood from the liver is then removed from a catheter in the inferior vena cava, filtered extracorporeally to remove the chemotherapy, and then returned into circulation [23,50-53]. Melphalan is the most commonly used chemotherapy in PHP.
-Melphalan – In a phase III trial, 93 patients with melanoma liver metastases were randomly assigned to either PHP of melphalan or best alternative care. A majority (approximately 89 percent) of patients had uveal melanoma . Melphalan infusion improved hepatic PFS (median 7 versus 2 months) and overall PFS (5 versus 2 months), but not OS (median 11 versus 10 months). Most treatment-related toxicities from melphalan were due to bone marrow suppression.
PHP improved efficacy and was well tolerated in a subsequent phase III trial (FOCUS) . In this study, 144 patients with ocular melanoma metastases were randomly assigned to either PHP with melphalan or best alternative care (transarterial chemoembolization, pembrolizumab, ipilimumab, or dacarbazine). In preliminary results, compared with best alternative care, PHP improved objective response rates (36 versus 13 percent) and overall PFS (median 9 versus 3 months, HR 0.38, 95% CI 0.23-0.63). OS was similar between the two treatment arms (median 19 versus 15 months, HR 0.70, 95% CI 0.43-1.13). Treatment-related toxicities for PHP included bone marrow suppression (22 percent), respiratory (6 percent), and cardiac disorders (5 percent). Of note, due to slow enrollment, the trial was amended to become a single-arm trial with all patients receiving PHP.
●Surgery, radiation therapy, and ablative procedures — In patients with oligometastatic disease, local therapies include surgery [23,55-57], stereotactic radiation therapy (RT) , or ablative procedures such as radiofrequency ablation (RFA) and cryotherapy. Some treatments can be performed with curative intent; however candidates for local therapies are rare (approximately 2 to 7 percent of all patients) and likely to have a better prognosis due to selection bias . There are no randomized trials that have compared metastasectomy or ablation with systemic therapy or best supportive care. (See "Metastatic melanoma: Surgical management".)
Significant extrahepatic disease
Nivolumab plus ipilimumab — For patients with significant extrahepatic disease who are eligible for systemic therapy, we suggest the combination of nivolumab plus ipilimumab (table 3) rather than single-agent immunotherapy, as indirect comparisons of some studies suggest better response rates and survival outcomes for this combination. Significant extrahepatic disease is defined as tumor burden outside the liver that is extensive enough to require treatment (eg, due to symptoms, tumor bulk, and/or rapidly progressive disease).
Observational and phase II studies suggest some limited activity for this combination as initial therapy in patients with uveal melanoma, with response rates of up to 18 percent, median PFS of up to six months, and median OS of up to 19 months [59-63]. This is in contrast to the dramatic efficacy of these agents in those with advanced or metastatic cutaneous melanoma, which is discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)
As an example, in a single-arm phase II study, 35 patients with metastatic uveal melanoma were treated with nivolumab plus ipilimumab for four cycles followed by maintenance nivolumab . At a median follow-up of 60 weeks, objective responses were seen in 6 of 33 patients (18 percent), including one complete and five partial responses; median PFS and OS were 6 and 19 months, respectively.
However, in another phase II study evaluating nivolumab plus ipilimumab in 52 patients with systemic therapy-naïve metastatic melanoma, median PFS and OS were 3 and 13 months, respectively , which is similar to the survival outcomes seen in separate studies of single-agent immunotherapy. (See 'Single-agent immunotherapy' below.)
Single-agent immunotherapy — Patients who decline or are ineligible for the combination of nivolumab plus ipilimumab (eg, due to potential toxicity) may alternatively be offered single-agent immunotherapy with a PD-1 inhibitor [59,65,66]. Our preferred agents include nivolumab (table 4) and pembrolizumab (table 5). However, efficacy for single-agent immunotherapy is limited in this disease.
Patients who are unable to tolerate systemic therapy may be offered best supportive care.
●Pembrolizumab – In a retrospective analysis, 56 patients with metastatic uveal melanoma refractory to prior therapies were treated with various PD-1 or programmed cell death ligand 1 (PD-L1) inhibitors, including approximately two-thirds with pembrolizumab . In the entire study population, objective responses were seen in two patients (4 percent); median PFS and OS were three and eight months.
●Nivolumab – In a single-arm, open-label phase II trial (CheckMate 172), the efficacy of nivolumab was evaluated in approximately 1000 patients with advanced melanoma refractory to ipilimumab . Among the subset of 103 patients with ocular melanoma, median OS was 13 months, and 18-month OS was 35 percent.
●CTLA-4 inhibitors – In patients with immunotherapy-naïve metastatic uveal melanoma, the use of single-agent cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors is less preferred than single agent PD-1 inhibitors. While clinical trials have not directly compared the efficacy of these agents in patients with uveal melanoma, ipilimumab is generally associated with a higher risk of immune-related adverse events. (See "Toxicities associated with immune checkpoint inhibitors" and "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab plus ipilimumab (preferred)'.)
Observational and early phase II studies have demonstrated only limited efficacy for these agents (eg, ipilimumab [67-70] and tremelimumab ), with objective response rates of up to 8 percent, median PFS of up to seven months, and OS of up to 10 months. Additionally, patients with uveal melanoma were excluded from the phase III trial that established a survival benefit of ipilimumab in those with metastatic cutaneous melanoma . (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Ipilimumab'.)
Brain metastases — The management of brain metastases in patients with melanoma is complex and may also involve other treatment strategies. This topic is discussed separately. (See "Management of brain metastases in melanoma".)
Options not typically used
Chemotherapy — We do not typically use chemotherapy in patients with metastatic uveal melanoma. No chemotherapeutic agent, alone or in combination, has been found to extend OS in patients with metastatic disease, with response rates generally under 10 percent. Agents studied have included dacarbazine, temozolomide, cisplatin, bendamustine, treosulfan, gemcitabine, fotemustine-based regimens, and others [26,43,73-79].
In an analysis of 64 patients treated for metastatic uveal melanoma with a variety of regimens that included cisplatin and dacarbazine, only one complete response and five partial responses were observed (9 percent) . Only two responses were seen in the 56 patients with hepatic metastases. Other studies have not resulted in consistently higher response rates [77,78]. (See "Cytotoxic chemotherapy for metastatic melanoma".)
Molecularly targeted agents — BRAF plus MEK inhibitors (dabrafenib plus trametinib) are approved for patients with any treatment-refractory solid tumor that has a BRAF V600E mutation. However, these agents are not used in metastatic uveal melanoma which rarely harbor BRAF mutations . The use of BRAF plus MEK inhibitors in other types of metastatic melanoma is discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Dabrafenib plus trametinib'.)
Additionally, we do not use MEK inhibitors to treat metastatic uveal melanoma, which has a different molecular pathogenesis than cutaneous melanoma. Data also suggest limited activity for MEK inhibitors, including several randomized trials of selumetinib as a single agent or in combination with chemotherapy [73,79,81,82]. (See "The molecular biology of melanoma", section on 'Uveal melanomas'.)
●Alrizomadlin – Alrizomadlin, a novel inhibitor of MDM2-p53, demonstrated objective response rates of 24 percent patients with metastatic melanoma who progressed on prior immunotherapy, in preliminary results from one phase II trial . Among the eight patients with uveal melanoma, the objective response and disease control rates were 14 and 72 percent, respectively.
●Autologous tumor-infiltrating lymphocytes – Preliminary evidence from a phase II study indicated that autologous tumor-infiltrating lymphocytes could mediate regression of metastatic uveal melanoma .
●Epigenetic therapies – Given that uveal melanoma is a genetically simple disease characterized by few somatic variants compared with cutaneous melanoma, other factors, such as epigenetic alterations, may be important in the pathogenesis of uveal melanoma. Preclinical data suggest efficacy for histone deacetylase (HDAC) inhibitors [85,86] and bromodomain and extra-terminal domain (BET) protein inhibitors . These treatments are in clinical development for uveal melanoma.
PROGNOSIS — A majority of patients diagnosed with uveal melanoma experience long-term survival, with an estimated thirty-year survival rate of 67 percent . However, the prognosis has historically been poor for those with metastatic disease. Further studies are necessary to determine if long-term survival will improve in the contemporary era of targeted therapy.
Prior to the approval of tebentafusp, the median overall survival (OS) for patients with metastatic disease was approximately six to twelve months [4,19,88-90]. In contrast, tebentafusp increased the median OS to approximately two years in a phase III trial . (See 'Tebentafusp' above.)
Prognostic factors associated with decreased survival included male sex, elevated lactate dehydrogenase (LDH), elevated alkaline phosphatase, and increased diameter of the largest liver metastasis (≥3 cm) . The extent of metastatic disease is incorporated into the AJCC Tumor, Node, Metastasis (TNM) staging system (table 2 and table 1), with increasing stage associated with lower OS (figure 3).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)
SUMMARY AND RECOMMENDATIONS
●Clinical presentation – Most patients with metastatic uveal melanoma develop recurrent disease after receiving treatment to the primary eye lesion. Patients who present with a primary uveal melanoma and synchronous metastases are rare. (See 'Timing of metastases' above.)
The most common sites include the liver, followed by the lung, bones, and skin/subcutaneous tissue. Lymph node and brain metastases are rare. (See 'Sites of disease' above.)
●Diagnostic evaluation – The diagnosis should be suspected in patients with a known history of primary uveal melanoma and systemic metastases (such as predominant disease burden in the liver). (See 'Diagnostic evaluation' above.)
•Unknown primary – Patients with de novo metastatic melanoma (especially those with hepatic metastases) and an unknown primary site should be referred to ophthalmology to assess for a primary eye lesion.
•Imaging studies – We obtain MRI of the liver with gadoxetate (Eovist) contrast to assess for hepatic metastases. We also obtain contrast-enhanced CT of the chest to assess for extrahepatic sites of disease. Patients may be offered the option of MRI of the brain with contrast to assess for CNS metastases. (See 'Imaging studies' above.)
•Biopsy – The diagnosis of metastatic uveal melanoma is confirmed on biopsy and histopathologic evaluation of distant metastatic lesions. (See 'Diagnostic biopsy' above.)
●Genotype assessment prior to systemic therapy – Prior to initiating systemic therapy in all patients with metastatic uveal melanoma, we obtain a genotyping assay for the presence of human leukocyte antigen (HLA)-A*02:01 (algorithm 1). (See 'Genotype assessment' above.)
●Patients with a positive HLA-A*02:01 genotype – For patients with treatment-naïve metastatic disease who are HLA-A*02:01 positive, we recommend tebentafusp (figure 2) rather than other systemic agents (Grade 1B), as this approach improved overall survival (OS) in a phase III trial. (See 'HLA-A*02:01 positive' above.)
●Patients with a negative HLA-A*02:01 genotype – For patients with treatment-naïve metastatic disease who are not HLA-A*02:01-positive or those with bulky or rapidly progressive disease, we offer enrollment in formal clinical trials whenever possible (see 'HLA-A*02:01 negative' above and 'Experimental agents' above):
For patients who are ineligible for or decline clinical trials, our initial treatment approach is based upon the predominant location of metastatic disease (algorithm 1):
•Liver-dominant disease – For patients with liver-dominant disease, we suggest locoregional therapies rather than systemic therapy (Grade 2C). However, initial systemic therapy is an appropriate alternative, given the poor prognosis of this disease and limited randomized trials comparing locoregional and systemic therapies. (See 'Liver-dominant disease' above.)
Examples of locoregional treatments include liver-directed therapy for hepatic metastases (hepatic arterial infusion of chemotherapy; embolization procedures; isolated hepatic therapy), surgery, radiation therapy (RT), and ablative therapies. (See 'Locoregional therapies' above.)
•Significant extrahepatic disease – For patients with significant extrahepatic disease who are eligible for systemic therapy, we suggest initial treatment with the combination of nivolumab plus ipilimumab (table 3) rather than single-agent immunotherapy (Grade 2C). Significant extrahepatic disease is defined as tumor burden outside the liver that is extensive enough to require treatment (eg, due to symptoms, tumor bulk, and/or rapidly progressive disease). (See 'Significant extrahepatic disease' above and 'Nivolumab plus ipilimumab' above.)
Patients who decline or are ineligible for combination immunotherapy (eg, due to potential toxicity) may alternatively be offered single-agent immunotherapy with PD-1 inhibitors (eg, nivolumab (table 4), pembrolizumab (table 5)). (See 'Single-agent immunotherapy' above.)
●Prognosis – The prognosis has historically been poor for patients with metastatic uveal melanoma. Further studies are necessary to determine if long-term survival will improve in the contemporary era of targeted therapy. (See 'Prognosis' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟