Treatment of Metastatic Choroidal Melanoma
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and is derived most frequently from choroidal melanocytes. It has a strong tendency to metastasize to the liver and other organs including the lung, bones, skin, lymph nodes, and brain. Metastasis is rapidly progressive and fatal. Typically, UM is initially asymptomatic, which is an important barrier to early treatment.
Despite technological advances and newer targeted therapies, no established, effective treatments are known in advanced stages. Current management strategies depend on the location and size of the tumor, degree of metastasis, and the patient’s goals. This article summarizes the treatment strategies in metastatic UM.
Goals of Treatment of Uveal Melanoma
The treatment of UM is to achieve the following goals:
- Prevention of metastasis
- Prevention of removing the eye
- Preservation of useful vision in the affected eye
General Biology of Uveal Melanoma
Disruptions in various molecular pathways have been reported in UM, including the MAPK, PI3K/Akt, and YAP1 pathways.
Mutations in G alpha (Gα) protein subunits, such as Gαq (GNAQ) and Gα11 (GNA11) are common and believed to be early events in the pathogenesis of UM. Under normal circumstances, these Gα protein subunits are activated when an external signal stimulates its associated G-protein coupled receptor (GPCR). The external stimulus is transduced through the GPCR and Gα protein subunits to intracellular signaling pathways. Various pathways are regulated by GNAQ and GNA11 as discussed below.
Growth factors excite receptor tyrosine kinases (RTKs) that activate Gα proteins, such as GNAQ. GNAQ stimulates phospholipase C-β (PLCβ), which upregulates production of second messengers diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 then increases intracellular calcium, stimulating various calcium-driven pathways and protein kinase C (PKC). PKC subsequently activates the mitogen-activated protein kinase (MAPK) signal transduction pathway that ultimately stimulates cellular growth and proliferation through activating various serine/threonine-specific protein kinases including RAS, RAF, MEK, and ERK.
In UM, mutations in GNAQ and GNA11 result in the constitutive activation of the MAPK signal transduction pathway. The constitutively active GNAQ and GNA11 results in increased MEK activity and cellular proliferation. In contrast to UM, BRAF mutations are common in cutaneous melanoma but are rare in UM.
RTKs also stimulate Gα proteins that activate the phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) signaling pathways. PI3K phosphorylates phosphatidyl inositol-4,5-bisphosphate (PIP2), generating phosphatidyl inositol-3,4,5-triphosphate (PIP3) that activates Akt, stimulating the mammalian target of rapamycin (mTOR) to stimulate cellular growth and proliferation. The activity of PI3K is opposed by PTEN, a major tumor suppressor that dephosphorylates PIP3. In UM, overactivation of PI3K/Akt has been observed due to hemizygous deletions of PTEN and activating mutations to RTKs, such as c-kit, that are implicated in activating the MAPK and PI3K/Akt pathways.
Stimulation of GNAQ and GNA11 are also involved with the activation of transcriptional co-activator Yes-associated protein 1 (YAP1), an important component of the Hippo signaling pathway through the Trio-Rho/Rac signaling circuit, which controls the size of organs in mammals. This pathway, which operates independently from the MAPK and PI3K/Akt pathway, is also dependent on the activity of Gα proteins and has been shown to be upregulated in activating mutations of GNAQ.
Cell Cycle Disruptions
Healthy melanocytes produce Bcl-2, an antiapoptotic factor that is important in inhibiting apoptosis. However, mutations in the major tumor suppressor genes retinoblastoma (Rb) and p53 (TP53) can allow melanocytes to enter the cell cycle and proliferate. Alterations in upstream mediators, such as cyclin D1, which phosphorylates Rb and inactivates its tumor suppressor function, allows cells to enter the cell cycle. Further upstream epigenetic modifications, such as methylation of the CDK2NA gene promoter region, impairs the production of p16, which exerts an important inhibition of Cyclin D1, of Rb, and cell cycle initiation. Increased MDM2, a key inhibitor of p53 that causes cellular proliferation, has also been observed in UM.
Changes in cytogenetics have been associated with invasion and metastasis, including monosomy 3, trisomy 8, and loss of chromosome 6q. The BRCA-associated protein-1 (BAP1), a deubiquitinating enzyme, is involved in regulating the cell cycle, cellular differentiation, and DNA repair. The loss of inactivating tumor suppressor genes such as BAP1 on chromosome 3p21.1 is postulated to be associated with metastasis in UM.
In contrast, mutations associated with disomy 3 (EIF1AX and SF3B1) are associated with low-grade UM and a better prognosis. Other genes predictive of metastatic UM include CDH1, ECM1, FXR1, HTR2B, ID2, LMCD1, LTA4H, MTUS1, RAB31, ROBO1, and SATB1.
Through gene expression profiling (GEP) of UM, three different prognostic classes of disease have been delineated.
|Class||Metastatic Risk||5-year metastatic risk||Associated genes|
|Class 1A||Low||2%||EIF1AX, SF3B1|
|Class 1B||Intermediate||21%||EIF1AX, SF3B1, CDH1/RAB31|
A GEP test for UM prognostication (DecisionDx®-UM) has been developed.
The cancer-testis antigen PRAME (preferentially expressed antigen in melanoma) is a biomarker for increased metastatic risk in Class 1 and Class 2 UMs. It is an independent prognostic biomarker for metastasis in UM.
|Class||5-year metastasis rate|
Cellular Adhesion Molecules
Disruptions in cellular adhesion molecules are implicated in the mechanism of metastasis in many cancer types through mediating detachment of cells from the primary tumor and attachment of disseminated cells to components of the extracellular matrix or the vascular endothelium. UMs express various integrins and attachment molecules, including a1b1, a2b2, a3b1, a5b1, avb3, intercellular adhesion molecule-1 (ICAM-1), neural cell adhesion molecule, and vascular cell adhesion molecule-1. Loss of expression of ICAM-1, in particular, is associated with an increased risk of metastasis.
Matrix metalloproteins (MMPs) are zinc-dependent endopeptidases that degrade extracellular matrix and are important components in the invasion and metastasis of UM. In UM, increased expression of MMP-2 and MMP-9 have been observed as well as expression of MMP inhibitors such as tissue inhibitor of metalloproteases (TIMP-2). Inappropriate activation or inhibition of MMPs are associated with tumor progression.
Local Therapy to the Eye
Enucleation was previously the standard treatment for UM. However, the Zimmerman-McLean-Foster Hypothesis theorized that elevated intraocular pressure could facilitate dissemination of malignant cells through the vortex veins into systemic circulation. The benefits of enucleation were evaluated in the Collaborative Ocular Melanoma Study (COMS), where no long-term survival differences were observed in patients treated with enucleation or iodine-125 (125I) brachytherapy. UM can therefore be managed conservatively except when the eye is rendered painful or when vision is not salvageable. This occurs in large and extensive melanomas or melanomas with associated retinal detachment or vitreous hemorrhage.
Many indications for resection exist, including:
- Iridociliary tumors of indeterminate pathology with suspicious features.
- Iridociliary tumors with rapid growth.
- Situations where plaque brachytherapy or proton beam radiotherapy are not available.
- Thick ciliary body and choroidal tumors that require dangerously high radiation dosages.
Two surgical resection techniques exist: “Exoresection” and “endoresection”
- Exoresection (transscleral resection via partial lamellar sclerouvectomy (PLSU)). Exoresection is more appropriate for anteriorly located tumors.50 Adjunctive plaque radiotherapy or proton beam radiotherapy can be done after exoresection.
- Endoresection (transretinal resection via pars plana vitrectomy). Endoresection is more suitable for posterior tumors but carries increased surgical risks. One such theoretical risk is intraoperative dissemination of tumor cells that can lead to recurrence. The use of neoadjuvant irradiation to destroy tumor cells prior to endoresection has been controversial.
Photodynamic Therapy (PDT) involves intravenous administration of a photosensitive dye (a photosensitizer) that pools within the tumor vasculature and generates toxic reactive oxidative species when activated by a specific wavelength of light. These chemotoxic reactive oxidative species cause endothelial changes and subsequent thrombosis of the tumor. The use of PDT with verteporfin, a second-generation photosensitizer, has shown short-term tumor control while circumventing the risks of radiation retinopathy in small melanomas, but long-term tumor control rates are lower.
Transpupillary thermotherapy (TTT) ablates tumor cells using focused thermal energy. TTT is not considered a primary treatment of small UMs due to high recurrence rates. Presently, it is used for residual or recurrent disease following other primary treatments. It is not recommended in cases of melanoma with multiple high-risk features, such as visual changes, subretinal fluid, or close proximity to the optic disc.
Radiotherapy induces DNA damage, causing tumor cell death and proliferation arrest. Plaque brachytherapy, charged-particle therapy including proton beam radiotherapy, and stereotactic radiosurgery are all means of delivering localized radiation therapy to the eye. The goal of radiotherapy is to destroy the tumor while preserving vision and minimizing complications. Complications of radiation therapy include cataract formation, retinal and choroidal vasculopathy, and optic neuropathy. In addition, the irradiated tumor may become ischemic, resulting in macular edema, serous retinal detachment, retinal ischemia, rubeosis, and neovascular glaucoma.
Plaque brachytherapy involves suturing a radioactive plaque to the sclera to deliver focal radiation to the tumor. The most commonly used radioisotopes include iodine-125 (125I), ruthenium-106 (106Ru), and Palladium-103 (103Pd). 125I emits gamma radiation, which penetrates deeper into tumors, but increases toxicity to the eye. Ruthenium emits beta radiation, which may result in less toxicity to surrounding structures. Intraocular radiation toxicity includes optic nerve atrophy and maculopathy.
Proton beam therapy
Proton beam therapy (PBT) applies focused radiation to a targeted area. It is used in medium- to large-sized tumors or for tumors in regions inaccessible to plaque brachytherapy such as the optic disc and fovea. The physical properties of the proton beam limits collateral damage to surrounding structures due to the Bragg peak, where the most destructive ionizing radiation occurs immediately before the location particles stop travelling. This allows precise delivery of ionizing radiation. PBT is a well-established treatment option but is not easily accessible for many centers.
Stereotactic radiosurgery, such as gamma(γ) knife and CyberKnife®, utilizes high-dose γ radiation delivered over a small, well-defined 3-dimensional area with minimal exposure to surrounding tissue. Its high precision makes this approach is useful for tumors near the macula and optic disc. Additionally, stereotactic radiosurgery is noninvasive and requires only one procedure, unlike plaque brachytherapy which necessitates two separate, invasive operations. One study found that stereotactic radiosurgery is effective in posterior UM while allowing for good visual outcomes. Similarly, the CyberKnife® robotic radiosurgery system additionally can accurately track tumors, thereby precisely delivering repeated radiation to a focused area.
Tissue factor is a transmembrane cytokine receptor expressed on sub-endothelial tissues that binds to factor VII and initiates the extrinsic coagulation cascade. It is upregulated in UM and postulated to contribute to tumor angiogenesis, growth, and metastasis. Treatment with ICON-1, a human immunoconjugate (ICON) fusion protein that is composed of the Fc domain of the human IgG and a structurally modified human factor VII, is under investigation in a phase I trial in patients with UM (NCT02771340).
Human papillomavirus (HPV) induces tumor growth through heparan sulfate modifications found on cancerous cells. Currently under investigation, intravitreal AU-011 is a novel photosensitive recombinant papillomavirus-like particle (VLP) that binds to the atypically expressed heparan sulfate and destroys cancer cells when activated by a 690 nm wavelength of light without affecting healthy tissue (NCT03052127). Early data demonstrates reduction in tumor thickness and preservation of vision.
Locoregional treatments of liver metastasis
Resection of metastatic nodules
In colon and other types of cancers, hepatectomy is the best prognosis-maximizing strategy in patients with liver-limited metastasis. However, hepatectomy in UM patients offers limited response and is rarely indicated as most present with multiple liver metastases involving both liver lobes.
Hepatic intra-arterial chemotherapy
Metastases are disseminated through and perfused by the hepatic artery. Through hepatic intra-arterial (HIA) chemotherapy, medication is delivered through an indwelling hepatic artery catheter, directly to metastatic liver cells to chemotherapy. Metastatic hepatic cells are thus exposed to maximum medication levels while minimizing toxicity of unaffected hepatic tissue supplied by the portal veins. In a phase III open label randomized trial, HIA-administered fotemustine yielded a statistically significant increase in PFS (4.5 months) compared to patients treated intravenously (3.5 months), but no improvement to OS was observed in either group. HIA administration of melphalan, an alkylating nitrogen mustard, has also been used safely in patients with metastatic UM. The efficacy of other HAI regimens, including the combination of cisplatin, vinblastine, and dacarbazine, is comparable to other HAI regimens.
Intra-arterial hepatic chemoembolization
Hepatic transarterial chemoembolization (TACE) combines hepatic artery embolization with chemotherapy infusion. Hepatic artery embolization deprives metastatic cells significant perfusion, causing tumor ischemia. Additionally, direct administration of medication maximizes tumor exposure to chemotherapy while minimizing systemic chemotherapy-related toxicity. Various chemotherapeutic medications have been used to embolize the hepatic artery to treat metastatic UM, including cisplatin, thiotepa, and lipiodol. Another study concluded that the efficacy of TACE with BCNU (1,3-bis[2-chloroethyl]-1-nitrosuourea) is superior to conventional systemic chemotherapy.
Trans-arterial hepatic immunoembolization
Immunoembolization involves hepatic artery embolization using immune-stimulating agents such as granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) rather than chemotherapeutic agents, as in chemoembolization. GM-CSF is a glycoprotein produced by T-cells that simulates immune cells such as macrophages and dendritic cells. Therefore, in addition to inducing tumor ischemia, immunoembolization may also attract and stimulate immune cells, facilitate antigen uptake, and enhance systemic immunity against tumor cells. A double-blinded, randomized, phase II study reported an OS of 21.5 months and elevated interleukin (IL)-6 and IL-8 levels in 52 patients with UM and hepatic metastases who received GM-CSF. The authors concluded that the robust inflammatory responses delayed progression of extrahepatic systemic metastases.
Selective Internal Radiation Therapy
Selective internal radiation therapy (SIRT), also referred to as microsphere radioembolization or transarterial radioembolization (TARE), involves inserting variously sized radioactive microspheres into the hepatic artery, thereby occluding and depriving metastatic tissue from perfusion. These microspheres also deliver localized 90yttrium (90Y), a high-energy, pure β-emitter, to hepatic tumors, unlike whole-liver doses in external beam radiation therapy that can cause fatal radiation hepatitis. Various clinical trials have found that 90Y resin microspheres are a safe and effective salvage therapy for patients with limited pretreatment burden hepatic metastases or unresectable liver metastases from UM. A clinical trial investigating radioactive 90Y microspheres (SIR-Sphere®) in UM with hepatic metastasis is ongoing (NCT01473004).
Drug-eluting bead microspheres are designed to occlude vessels and expose metastatic tumors to localized, controlled, and sustained dosages of chemotherapeutic medications. Doxorubicin- and irinotecan-eluting beads have demonstrated efficacy in the treatment metastatic UM.
Isolated hepatic perfusion
Isolated hepatic perfusion (IHP) is a procedure where hepatic blood flow is segregated from the systemic vasculature through cannulation and clamping of the hepatic artery and inferior vena cava and joining this circulation to an extracorporeal circuit. Having a distinct circulation, highly potent chemotherapies can be administered specifically to the liver while bypassing systemic circulation, thereby reducing undesirable systemic effects. However, this surgical procedure is complex and extensive, thereby limiting its availability. It is also associated with considerable morbidity and mortality due to veno-occlusive disease and hepatotoxicity. The role of IHP in metastatic liver UM is being studied in the randomized multicenter phase III SCANDIUM trial (NCT01785316).
Systemic chemotherapy is reserved for metastatic UM although there is currently no standard therapy for metastatic UM. Effective treatments for metastatic cutaneous melanoma are generally ineffective in metastatic uveal melanoma. Various chemotherapeutic agents have been evaluated, including dacarbazine, temozolomide, treosulfan, and fotemustine.
Dacarbazine chemotherapy is ineffective with a response rate below 1% and no improvement in survival. Another clinical trial assessing bleomycin, vincristine, lomustine, and dacarbazine (BOLD regimen) with interferon-a2, demonstrated 20 of 24 (83%) patients exhibiting disease progression while two (8.3%) remained stable with a PFS of 1.9 months and OS of 10.6 months. In addition, liver metastases from UM had a lower response rate (10%) than metastases from cutaneous melanoma (33%) when patients are treated with the “Dartmouth combination” (dacarbazine, carmustine, cisplatin, and tamoxifen). Higher response rates and median survival have been reported with chemotherapy administration directly into the hepatic artery in a highly selected group of patients.
Temozolomide, a triazene analog of dacarbazine, is a cytotoxic alkylating agent that has demonstrated minimal efficacy in metastatic UM. A phase II trial of temozolomide in 14 enrolled patients with metastatic UM, demonstrated no complete or partial responses and only 2 patients were able to achieve stable disease. The investigators concluded that temozolomide is not effective in the treatment of metastatic UM. A recent phase II trial of bevacizumab and temozolomide as first-line treatment in patients with metastatic UM revealed a 6-month PFR (progression free rate) of 23%.
Treosulfan, a bifunctional sulfonate alkylating cytotoxic agent, has poor efficacy against metastatic UM. A phase II study of cisplatin, gemcitabine, and treosulfan reported no response in 17 patients with a median PFS and OS of 7 months and 7.7 months, respectively. A prospective phase II clinical trial of dacarbazine and treosulfan for metastatic UM revealed no responses with a PFS of 12 weeks and median OS of 30 weeks.
The safety and efficacy of IV fotemustine was evaluated in 25 patients with metastatic UM. In one study, 9 patients were found to have stable disease with a median survival duration of 13.9 months and a 1-year survival rate of 60%.
Adjuvant therapy is additional treatment that follows a primary treatment modality, such as surgical resection followed by chemotherapy or radiotherapy. This approach to treat metastatic UM has been evaluated in numerous studies, but at present, no effective adjuvant therapy decreases the risk of metastasis or improves OS. No survival difference was found in patients treated with adjuvant dacarbazine or bacilli Calmette-Guérin (BCG). The phase III randomized multicenter FOTEADJ trial evaluating adjuvant IV fotemustine for UM was terminated early due to futility; there were no differences in the 3-year metastasis-free survival and OS between the two groups. Treatment with systemic adjuvant interferon (IFN) in various nonrandomized clinical trials also did not improve survival in patients with UM. Adjuvant crizotinib, a tyrosine kinase inhibitor (TKI), demonstrated positive results but minimally impacted tumor size. A clinical trial investigating crizotinib in high-risk UM following definitive therapy is ongoing (NCT02223819). Treatment with adjuvant sunitinib, a TKI that inhibits c-Kit, VEGFR1, VEGFR2, IGFR1, and PDGFRb, in a retrospective study in patients with confirmed monosomy 3 and 8q and large tumor size (T3 or T4) and/or DecisionDx-UM Class 2 (high-grade) UM demonstrated encouraging results. A randomized phase II clinical trial of adjuvant sunitinib versus valproic acid for high-grade UM is currently underway (NCT02068586).
Mutations in GNAQ or GNA11 are common in UM, resulting in constitutive activation of the MAPK and PI3K/Akt pathways. Therapies directed against downstream effectors such as MEK, Akt, and protein kinase C are being investigated.
MAPK, PI3K/Akt, KIT
c-Kit and c-Met are both RTKs that are implicated in angiogenesis, metastasis, cell motility, cell growth, and inhibition of apoptosis in metastatic UM. They are associated with an increased risk of hepatic tumor proliferation and differentiation due to hepatocyte growth factor/scatter factor (HGF/SF), which are produced in high quantities in the liver. Thus, targeting the interaction between RTKs and HGF/SF has been an area of interest for the treatment of metastatic UM.
Crizotinib is a TKI that has demonstrated prevention of metastasis in an animal metastatic UM model. Inhibition of c-Met, EGFR, and IGFR1 inhibits proliferation of uveal UM cells. A phase II clinical trial of crizotinib for high-risk UM is currently underway (NCT02223819).
The efficacy of sunitinib malate, a nonselective c-Kit inhibitor, with dacarbazine has been studied in the randomized multicenter phase II SUAVE clinical trial in 74 patients with metastatic UM. However, PFS and OS were not improved with sunitinib as an overall response rate of 0% and 8% were observed in the sunitinib and dacarbazine arms and it was concluded that sunitinib did not provide clinical benefit in patients with metastatic UM.
Cabozatinib (XL184), an oral RTK inhibitor that inhibits c-Met and VEGFR2, has been shown to inhibit HGF-induced migration and invasion of melanoma cells. A randomized phase II discontinuation trial of 23 patients treated with cabozatinib for metastatic UM revealed a median OS of 12.6 months and a median PFS of 4.8 months, suggesting some clinical benefit in patients with metastatic UM.
The efficacy of sorafenib (BAY439006), an oral multikinase inhibitor that impairs tumor growth by acting on both tumor and tumor vasculature cells, was found to be clinically positive in the phase II STREAM clinical trial (median survival = 14.8 months, median PFS = 5.5 months (placebo median PFS = 1.9 months, p = 0.0079)).
Selumetinib (AZD6244, ARRY-142886) is a highly selective MEK1/2 inhibitor that has been used in combination therapy but has not demonstrated positive results. In a randomized, open-label phase II clinical trial, selumetinib versus chemotherapy (temozolomide or dacarbazine) did not improve overall survival. Furthermore, in the randomized, phase III, double-blinded SUMIT clinical trial, selumetinib with dacarbazine did not significantly improve PFS.
Trametinib (GSK1120212) is a reversible selective, allosteric inhibitor of MEK1/MEK2 activation and kinase activity that demonstrated no objective responses and a median PFS of 1.8 months in a multicenter phase 1 clinical trial in 16 patients with primary UM. A randomized phase II clinical trial of trametinib with or without the Akt inhibitor GSK2141795 is currently in progress (NCT01979523).
Binimetinib (MEK162, ARRY-162, ARRY-438162) is a MEK inhibitor that is currently being studied in a phase Ib/II clinical trial in patients with UM (NCT01801358).
Imatinib mesylate is an inhibitor of the RTK of c-kit, bcr-abl, and PDGFR. A phase II multicenter single-arm clinical trial investigating the efficacy of imatinib in 25 patients with c-kit-positive metastatic UM did not improve PFS.
A phase II study of ulixertinib (BVD-523), an ERK1/2 inhibitor, is currently underway in patients with metastatic UM (NCT03417739).
PKC, an upstream activator of the MAPK pathway, is a potential target in the treatment of UM. Sotrastaurin (AEB071) has been shown to exert antitumor activity in UM cell lines with GNAQ mutations through selectively inhibiting growth by targeting the PKC/ERK1/2 and PKC/NF-kB pathways. The synergistic antitumor effects of sotrastaurin with BYL719, a selective PI3Ka inhibitor, has been shown in UM cell lines harboring GNAQ and GNA11 mutations. A phase I clinical trial on the efficacy and safety of sotrastaurin (NCT01430416) and combination of AEB071 with BYL719 (NCT02273219) is currently ongoing. Another PKC inhibitor, LXS196, is being studied in a phase I clinical trial (NCT02601378).
Oblimersen, a bcl-2 anti-sense oligonucleotide, interrupts the Bcl-2/Bcl-XL interactions with pro-death proteins (Bim), leading to Bax translocation, cytochrome c release, and subsequent apoptosis. This medication has demonstrated efficacy against advanced cutaneous melanoma. An open label phase II of combination oblimersen, paclitaxel, and carboplatin is currently underway (NCT01200342).
Bortezomib is a tripeptide that inhibits the activity of proteasomes by binding to the catalytic site of the 26S proteasome and has demonstrated efficacy against multiple myeloma in the SUMMIT, CREST, and APEX trials. It can induce a proapoptotic state by reducing antiapoptotic proteins such as Bcl-2 while stabilizing proapoptotic proteins such as p53 and Bcl-2 associated X protein (BAX). In phase II trials, bortezomib has been observed to enhance the sensitivity of melanoma cells to various chemotherapeutics, rather than directly destroying cancer cells. An open label phase II study of bortezomib, paclitaxel, and carboplatin is currently underway (NCT00288041)).
Chaperone proteins, or chaperonins, play important roles in protein folding and suppression of protein aggregation. Disruptions of chaperone proteins may allow for toxic accumulations of atypically folded proteins. These abnormal proteins are then tagged and cleared through the ubiquitin-proteasome pathway. Heat-shock protein 90 (Hsp90) is a molecular chaperone protein that interacts with RTKs and components of the MAPK and PI3K/Akt pathway. Ganetespib (STA-9090) is a second-generation Hsp90 inhibitor that has been shown to produce significant cytotoxicity and antitumor activity against various hematological and solid tumor cell lines. In a phase II trial of ganetespib in 17 patients with metastatic UM, only one partial response, four stable disease, 11 progressive disease, and 1 withdrawal were observed.
Invasion and metastasis
Vitaxin, a humanized monoclonal antibody that binds to avb3, triggers an antibody-dependent cellular cytotoxic reaction and blocks tumor growth. Volociximab, an a5b1 anti-integrin monoclonal antibody is also being evaluated in patients with metastatic melanoma. This treatment has not been evaluated in patients with UM and its efficacy remains unknown.
A clinical study by the National Cancer Institute of Canada Clinical Trials Group found that the MMP inhibitor, marimastat (BB-2516), only exhibits limited activity in patients with metastatic malignant melanoma. However, no such trial has yet been performed in patients with metastatic UM.
Lenalidomide, a derivative of thalidomide, exhibits antiangiogenic effects directed against fibroblast growth factor 2 (FGF2). However, no significant responses were observed in a phase II randomized clinical trial that evaluated the efficacy and safety of low-dose (5 mg) versus high-dose (25 mg) oral lenalidomide in 16 evaluable patients with metastatic UM.
Aflibercept (VEGF Trap) is a soluble decoy fusion protein derived from the VEGFR that selectively inhibits VEGF and has demonstrated efficacy in both cutaneous and UM in a multicenter phase II clinical trial. Of the 41 enrolled patients, 9 of the patients had primary UM. Despite an observed response rate of 0%, a median PFS of 5.7 months was obtained with an OS of 19 months.
Sorafenib, as mentioned above, has anti-neovascular activity due to inhibition of the RTK of VEGFR).
A clinical trial assessing the efficacy of AZD2171 (cediranib), an inhibitor of the VEGFR RTK, is underway (NCT00243061).
Immunotherapy refers to the use of the host immune system to treat cancer. Various immunotherapies exist for cancer, including cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either stimulate cells or block immune checkpoint pathways. An antitumor immune response can be generated through the production of cytokines.
The eye is an immune-privileged site and can be responsive to T-cell based therapy. A promising target for cutaneous melanoma is the cytotoxic T lymphocyte-associated protein 4 (CTLA4). Ipilimumab (humanized anticytotoxic T-lymphocyte antigen-4 monoclonal (anti-CTLA4) antibody) has been shown to improve OS in patients with advanced cutaneous melanoma. However, in a trial investigating ipilimumab for metastatic UM, no objective responses were observed but ended with 3 of 13 (23%) patients achieving stable disease. In the Spanish Melanoma Group (GEM) study, a median OS of 9.8 months was obtained after receiving ipilimumab 10 mg/kg every 3 weeks for 4 doses followed by a maintenance dose every 12 weeks. One of 13 (7.7%) treatment-naïve patients achieved a partial response and six (46.2%) attained stable disease. Ipilimumab was found to have very limited activity against metastatic UM in the phase II Dermatologic Cooperative Oncology Group (DeCOG) study. Another study investigating ipilimumab plus dacarbazine for metastatic UM revealed promising result.
An open-label, multicenter phase 2 study on the efficacy of fully humanized anti-CTLA4 monoclonal antibody, tremelimumab, was terminated due to the initial poor response.
UM can avoid immune surveillance through the production of indoleamine-pyrrole-2,3-dioxygenase (IDO) and the programmed death-ligand 1 (PD-L1). PD-L1 is expressed on the cell surface of some UM cells and binds to the programmed death receptor-1 (PD-1) on T-lymphocytes. This interaction results in the inhibition of T cell proliferation and activity in peripheral tissues. Nivolimumab and pembrolizumab are two anti-PD-1 receptor antibodies that have shown efficacy against advanced cutaneous melanoma. However, treatment of metastatic UM with pembrolizumab, nivolumab, or atezolizumab, yielded poor PFS and OS results in a clinical trial. A multicenter phase II clinical trial of pembrolizumab in patients with advanced UM is in progress (NCT02359851).
High densities of CD3+ T cells in tumor microenvironments have been correlated with longer survival in many solid cancers. However, the T cell response to cancer antigens is typically poor as tumor cells can deactivate cancer-reactive T cells. To improve the T-lymphocyte response to cancer antigens, immune mobilizing monoclonal T cell receptors (TCRs) against cancer (ImmTAC) have been developed. ImmTAC molecules are bispecific biologics that are composed of a monoclonal high-affinity T cell receptor (mTCR) fused to an anti-CD3 single-chain antibody fragment (scFv). The mTCR presents the cancer-associated or cancer-specific antigen of interest and the scFv engages polyclonal T cells, thus activating cytotoxic T cells to destroy tumor cells. IMCgp100, a specific ImmTAC that targets the gp100-derived peptide in complex with HLA-A*201 on the surface of melanoma cells, has been evaluated in patients with metastatic UM in a phase I study. Encouraging OS and PFS data were found and the medication was well tolerated (NCT02570308). IMCgp100 versus investigator’s choice of dacarbazine, pembrolizumab, or ipilimumab in treatment-naïve patients with metastatic UM was recently initiated (NCT03070392).
Tumor infiltrating lymphocytes
A subset of tumor infiltrating lymphocytes (TILs) demonstrated robust activity against UM. In an attempt to determine if transfer of such reactive TILs could induce tumor regression, a phase II study was conducted (NCT01814046) in 21 patients with metastatic UM treated with lympho-depleting chemotherapy (cyclophosphamide, fludarabine) followed by a single infusion of autologous TILs and high-dose interleukin-2 (IL-2). Of the 20 evaluable patients, 7 (35%) had objective tumor regression (6 partial responses, 1 complete response).
Glembatumumab vedotin (CDX-011) is an antibody-drug conjugate that is directed against glycoprotein NMB (GPNMB), a transmembrane protein found in various tumors, including UM, that is conjugated via a cathepsin B-sensitive valine-citrulline linkage to the cytotoxic agent monomethyl auristatin E (MMAE). CDX-011 IgG2 component binds to the GPNMB antigen, which is expressed on 86% of UMs. The entire conjugate is taken into the target cell via endocytosis. The antibody-drug conjugate is mobilized through endosomes or lysosomes where the drug is eventually released through cleavage of the valine-citrulline linkages, allowing dispersion of the cytotoxic MMAE at the target tissue. Results from a single metastatic UM trial (NCT02363283) revealed that out of the 31 enrolled and evaluable patients, 61% disease control rate, despite a low objective response rate of 6%. In addition, 17/31 (55%) patients achieved stable disease.
Various studies have found that PRAME-specific CD8+ T cells could recognize and lyse PRAME-positive malignant cells. As a potential therapeutic target, clinical trials evaluating PRAME-TCR (T cell receptor) gene therapy are currently underway for patients with various cancers that could eventually be evaluated in advanced UM as well.
UM has been studied extensively at the epigenetic level. Histone deacetylase (HDAC) regulates transcription of various transcriptional factors involved in tumor initiation and progression through deacetylation of histones, thus modifying the structure of DNA and chromatin. HDAC inhibitors induce cell-cycle arrest through increasing overall histone acetylation, which increases activity of transcriptional factors and transcription of tumor-suppressor genes. HDAC inhibitors include valproic acid, trichostatin A, panobinostat (LBH-589), vorinostat, suberoylanilide hydroxamic acid (SAHA), depsipeptide, tenovin-6, JSL-1, MC1568, and MC1575. In a multicenter phase II clinical trial of vorinostat in advanced UM, the investigators concluded that vorinostat did not yield a beneficial response.
Bromodomains are important amino acid domains of transcription factor complexes that serve key functions in epigenetic modifications. Bromodomain and extra-terminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT) share a similar structure and BRD4, in particular, has been implicated in various cancers. BRD4 stimulates the positive transcription elongation factor (P-TEFb) complex, and upregulates expression of growth promoting genes such as c-Myc, which is important in the pathogenesis of UM. JQ1, a BRD4 competitive inhibitor, has shown cytotoxicity in UM mouse models with GNAQ and GNA11 mutations. Similarly, PLX51107, a novel BRD4 inhibitor, has demonstrated high cytotoxic activity in UM cell lines at nanomolar concentrations. A recent phase 1 study of mivebresib (ABBV-075), a pan-BET inhibitor, in 10 patients with UM achieved an OS of 7.4 (95% CI: 0.9-3.6) and PFS of 2.0 months (95% CI: 1.8 – 11.0).
UM is the most common primary intraocular malignancy. Enucleation is most commonly used for large tumors and radiotherapy for select tumors. Adjuvant therapy and systemic therapy has not demonstrated efficacy in decreasing the risk of metastasis and improving outcomes. Existing systemic treatments used for cutaneous melanoma are not effective against UM. Metastasis occurs most frequently to the liver via hematogenous spread. Locoregional treatment of liver metastases can be offered with variable efficacy. There is no consensus on follow-up, but annual history and physical examinations under an ophthalmologist or oncologist are recommended.
- Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology. 2011;118(9):1881-1885.
- Collaborative Ocular Melanoma Study Group. Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report no. 15. Arch Ophthalmol. 2001;119(5):670-676.
- Woodman SE. Metastatic uveal melanoma: biology and emerging treatments. Cancer J. 2012;18(2):148-152.
- Treatment (Ocular) | Melanoma Research Foundation. Melanoma Research Foundation. https://melanoma.org/patients-caregivers/ocular-melanoma/treatment-ocular/. Accessed August 7, 2019.
- Onken MD, Worley LA, Long MD, et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49(12):5230-5234.
- Griner EM, Kazanietz MG. Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer. 2007;7(4):281-294.
- Ueda Y, Hirai S-I, Osada S-I, Suzuki A, Mizuno K, Ohno S. Protein Kinase C δ Activates the MEK-ERK Pathway in a Manner Independent of Ras and Dependent on Raf. Journal of Biological Chemistry. 1996;271(38):23512-23519. doi:10.1074/jbc.271.38.23512
- Ambrosini G, Musi E, Ho AL, de Stanchina E, Schwartz GK. Inhibition of mutant GNAQ signaling in uveal melanoma induces AMPK-dependent autophagic cell death. Mol Cancer Ther. 2013;12(5):768-776.
- Murga C, Laguinge L, Wetzker R, Cuadrado A, Gutkind JS. Activation of Akt/Protein Kinase B by G Protein-coupled Receptors A ROLE FOR α AND βγ SUBUNITS OF HETEROTRIMERIC G PROTEINS ACTING THROUGH PHOSPHATIDYLINOSITOL-3-OH KINASEγ. J Biol Chem. 1998;273(30):19080-19085.
- Ballou LM, Chattopadhyay M, Li Y, Scarlata S, Lin RZ. Gαqbinds to p110α/p85α phosphoinositide 3-kinase and displaces Ras. Biochemical Journal. 2006;394(3):557-562. doi:10.1042/bj20051493
- Golebiewska U, Scarlata S. Gαq Binds Two Effectors Separately in Cells: Evidence for Predetermined Signaling Pathways. Biophys J. 2008;95(5):2575-2582.
- Georgescu M-M. PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control. Genes Cancer. 2010;1(12):1170-1177.
- Mouriaux F, Kherrouche Z, Maurage C-A, Demailly F-X, Labalette P, Saule S. Expression of the c-kit receptor in choroidal melanomas. Melanoma Res. 2003;13(2):161-166.
- Feng X, Degese MS, Iglesias-Bartolome R, et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell. 2014;25(6):831-845.
- Johansson P, Aoude LG, Wadt K, et al. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. Oncotarget. 2016;7(4). doi:10.18632/oncotarget.6614
- Moore AR, Ceraudo E, Sher JJ, et al. Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma. Nat Genet. 2016;48(6):675-680.
- Brantley MA Jr, Harbour JW. Deregulation of the Rb and p53 pathways in uveal melanoma. Am J Pathol. 2000;157(6):1795-1801.
- Singh AD, Croce CM, Wary KK, et al. Familial uveal melanoma: absence of germline mutations involving the cyclin-dependent kinase-4 inhibitor gene (p16). Ophthalmic Genet. 1996;17(1):39-40.
- Coupland SE, Anastassiou G, Stang A, et al. The prognostic value of cyclin D1, p53, and MDM2 protein expression in uveal melanoma. J Pathol. 2000;191(2):120-126.
- Yu H, Mashtalir N, Daou S, et al. The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression. Mol Cell Biol. 2010;30(21):5071-5085.
- Harbour JW, Onken MD, Roberson EDO, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330(6009):1410-1413.
- Abdel-Rahman MH, Pilarski R, Cebulla CM, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet. 2011;48(12):856-859.
- Field MG, Harbour JW. Recent developments in prognostic and predictive testing in uveal melanoma. Curr Opin Ophthalmol. 2014;25(3):234-239.
- Martin M, Maßhöfer L, Temming P, et al. Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat Genet. 2013;45(8):933-936.
- Harbour JW, Roberson EDO, Anbunathan H, Onken MD, Worley LA, Bowcock AM. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet. 2013;45(2):133-135.
- Onken MD, Worley LA, Tuscan MD, Harbour JW. An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn. 2010;12(4):461-468.
- Harbour JW. A prognostic test to predict the risk of metastasis in uveal melanoma based on a 15-gene expression profile. Methods Mol Biol. 2014;1102:427-440.
- Field MG, Durante MA, Decatur CL, et al. Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas. Oncotarget. 2016;7(37):59209-59219.
- Gezgin G, Luk SJ, Cao J, et al. PRAME as a Potential Target for Immunotherapy in Metastatic Uveal Melanoma. JAMA Ophthalmol. 2017;135(6):541-549.
- Ikeda H, Lethé B, Lehmann F, et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity. 1997;6(2):199-208.
- Epping MT, Bernards R. A causal role for the human tumor antigen preferentially expressed antigen of melanoma in cancer. Cancer Res. 2006;66(22):10639-10642.
- Field MG, Decatur CL, Kurtenbach S, et al. PRAME as an Independent Biomarker for Metastasis in Uveal Melanoma. Clin Cancer Res. 2016;22(5):1234-1242.
- Anastassiou G, Schilling H, Djakovic S, Bornfeld N. Expression of VLA-2, VLA-3, and αv integrin receptors in uveal melanoma: association with microvascular architecture of the tumour and prognostic value. Br J Ophthalmol. 2000;84(8):899-902.
- Anastassiou G, Schilling H, Stang A, Djakovic S, Heiligenhaus A, Bornfeld N. Expression of the cell adhesion molecules ICAM-1, VCAM-1 and NCAM in uveal melanoma: a clinicopathological study. Oncology. 2000;58(1):83-88.
- Baker JK, Elshaw SR, Mathewman GE, et al. Expression of integrins, degradative enzymes and their inhibitors in uveal melanoma: differences between in vitro and in vivo expression. Melanoma Res. 2001;11(3):265-273.
- Overall CM, Kleifeld O. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6(3):227-239.
- Zimmerman LE, McLean IW, Foster WD. Does enucleation of the eye containing a malignant melanoma prevent or accelerate the dissemination of tumour cells. Br J Ophthalmol. 1978;62(6):420-425.
- Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Arch Ophthalmol. 2006;124(12):1684-1693
- Puusaari I, Heikkonen J, Summanen P, Tarkkanen A, Kivelä T. Iodine brachytherapy as an alternative to enucleation for large uveal melanomas. Ophthalmology. 2003;110(11):2223-2234. doi:10.1016/s0161-6420(03)00661-4
- Gunduz K, Bechrakis N. Exoresection and endoresection for uveal melanoma. Middle East African Journal of Ophthalmology. 2010;17(3):210. doi:10.4103/0974-9233.65494
- Damato B. Intrascleral recurrence of uveal melanoma after transretinal “endoresection.” British Journal of Ophthalmology. 2001;85(1):110e - 110. doi:10.1136/bjo.85.1.110e
- Bechrakis NE, Foerster MH. Neoadjuvant Proton Beam Radiotherapy Combined With Subsequent Endoresection of Choroidal Melanomas. International Ophthalmology Clinics. 2006;46(1):95-107. doi:10.1097/01.iio.0000195856.31324.00
- Canal-Fontcuberta I, Salomão DR, Robertson D, et al. CLINICAL AND HISTOPATHOLOGIC FINDINGS AFTER PHOTODYNAMIC THERAPY OF CHOROIDAL MELANOMA. Retina. 2012;32(5):942-948. doi:10.1097/iae.0b013e31825097c1
- Fabian ID, Stacey AW, Papastefanou V, et al. Primary photodynamic therapy with verteporfin for small pigmented posterior pole choroidal melanoma. Eye. 2017;31(4):519-528. doi:10.1038/eye.2017.22
- Fabian ID, Stacey AW, Al Harby L, Arora AK, Sagoo MS, Cohen VML. Primary photodynamic therapy with verteporfin for pigmented posterior pole cT1a choroidal melanoma: a 3-year retrospective analysis. British Journal of Ophthalmology. 2018;102(12):1705-1710. doi:10.1136/bjophthalmol-2017-311747
- Singh AD. Enucleation Following Transpupillary Thermotherapy of Choroidal Melanoma: Clinicopathologic Correlations. Archives of Ophthalmology. 2003;121(3):397. doi:10.1001/archopht.121.3.397
- Mashayekhi A, Shields CL, Rishi P, et al. Primary Transpupillary Thermotherapy for Choroidal Melanoma in 391 Cases. Ophthalmology. 2015;122(3):600-609. doi:10.1016/j.ophtha.2014.09.029
- Damato B, Kacperek A, Errington D, Heimann H. Proton beam radiotherapy of uveal melanoma. Saudi Journal of Ophthalmology. 2013;27(3):151-157. doi:10.1016/j.sjopt.2013.06.014
- AlMahmoud T, Quinlan-Davidson S, Pond G, Deschênes J. Outcome analysis of visual acuity and side effect after ruthenium-106 plaque brachytherapy for medium-sized choroidal melanoma. Middle East African Journal of Ophthalmology. 2018;25(2):103. doi:10.4103/meajo.meajo_198_16
- Zorlu F, Selek U, Kiratli H. Initial results of fractionated CyberKnife radiosurgery for uveal melanoma. Journal of Neuro-Oncology. 2009;94(1):111-117. doi:10.1007/s11060-009-9811-x
- Sikuade MJ, Salvi S, Rundle PA, Errington DG, Kacperek A, Rennie IG. Outcomes of treatment with stereotactic radiosurgery or proton beam therapy for choroidal melanoma. Eye. 2015;29(9):1194-1198. doi:10.1038/eye.2015.109
- Kurup G. CyberKnife: A new paradigm in radiotherapy. Journal of Medical Physics. 2010;35(2):63. doi:10.4103/0971-6203.62194
- Walker TM. Expression of Angiogenic Factors Cyr61 and Tissue Factor in Uveal Melanoma. Archives of Ophthalmology. 2002;120(12):1719. doi:10.1001/archopht.120.12.1719
- Factor VII-targeting Immunoconjugate Protein ICON-1 (Concept Id: C4287686) - MedGen - NCBI. https://www.ncbi.nlm.nih.gov/medgen/925218. Accessed August 7, 2019.
- Kines RC, Varsavsky I, Choudhary S, et al. An Infrared Dye–Conjugated Virus-like Particle for the Treatment of Primary Uveal Melanoma. Molecular Cancer Therapeutics. 2018;17(2):565-574. doi:10.1158/1535-7163.mct-17-0953
- Schefler AC. 6-month results of a phase 1b-2 prospective multicenter clinical trial of a novel targeted therapy (AU-011) for the treatment of choroidal melanoma. Presented at the: American Society of Retina Specialists annual meeting; July 2018; Vancouver, British Columbia.
- Sugihara K, Uetake H. Therapeutic strategies for hepatic metastasis of colorectal cancer: overview. Journal of Hepato-Biliary-Pancreatic Sciences. 2012;19(5):523-527. doi:10.1007/s00534-012-0524-8
- Aoyama T, Mastrangelo MJ, Berd D, Nathan FE, Shields CL, Shields JA, Rosato EL, Rosato FE, Sato T. Protracted survival after resection of metastatic uveal melanoma. Cancer. 2000;89(7):1561-1568.
- Avril MF, Aamdal S, Grob JJ, et al. Fotemustine Compared With Dacarbazine in Patients With Disseminated Malignant Melanoma: A Phase III Study. Journal of Clinical Oncology. 2004;22(6):1118-1125. doi:10.1200/jco.2004.04.165
- Leyvraz S, Piperno-Neumann S, Suciu S, et al. Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial. Ann Oncol. 2014;25(3):742-746.
- Pingpank JF, Hughes MS, Alexander HR, et al. A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma. Journal of Clinical Oncology. 2010;28(18_suppl):LBA8512-LBA8512. doi:10.1200/jco.2010.28.18_suppl.lba8512
- Boone BA, Perkins S, Bandi R, et al. Hepatic artery infusion of melphalan in patients with liver metastases from ocular melanoma. J Surg Oncol. 2018;117(5):940-946.
- Melichar B, Voboril Z, Lojík M, Krajina A. Liver metastases from uveal melanoma: clinical experience of hepatic arterial infusion of cisplatin, vinblastine and dacarbazine. Hepatogastroenterology. 2009;56(93):1157-1162.
- Daniels JR, Sternlicht M, Daniels AM. Collagen chemoembolization: pharmacokinetics and tissue tolerance of cis-diamminedichloroplatinum(II) in porcine liver and rabbit kidney. Cancer Res. 1988;48(9):2446-2450.
- Carrasco CH, Wallace S, Charnsangavej C, Papadopoulos NE, Patt YZ, Mavligit GM. Treatment of hepatic metastases in ocular melanoma. Embolization of the hepatic artery with polyvinyl sponge and cisplatin. JAMA. 1986;255(22):3152-3154.
- Agarwala SS, Panikkar R, Kirkwood JM. Phase I/II randomized trial of intrahepatic arterial infusion chemotherapy with cisplatin and chemoembolization with cisplatin and polyvinyl sponge in patients with ocular melanoma metastatic to the liver. Melanoma Research. 2004;14(3):217-222. doi:10.1097/01.cmr.0000129377.22141.ea
- Patel K, Sullivan K, Berd D, et al. Chemoembolization of the hepatic artery with BCNU for metastatic uveal melanoma: results of a phase II study. Melanoma Research. 2005;15(4):297-304. doi:10.1097/00008390-200508000-00011
- Damato B, Patel I, Campbell IR, Mayles HM, Douglas Errington R. Local tumor control after 106Ru brachytherapy of choroidal melanoma. International Journal of Radiation Oncology*Biology*Physics. 2005;63(2):385-391.
- Sato T. Locoregional Management of Hepatic Metastasis From Primary Uveal Melanoma. Seminars in Oncology. 2010;37(2):127-138. doi:10.1053/j.seminoncol.2010.03.014
- Valsecchi ME, Terai M, Eschelman DJ, et al. Double-Blinded, Randomized Phase II Study Using Embolization with or without Granulocyte–Macrophage Colony-Stimulating Factor in Uveal Melanoma with Hepatic Metastases. Journal of Vascular and Interventional Radiology. 2015;26(4):523-532.e2. doi:10.1016/j.jvir.2014.11.037
- Ingold JA, Reed GB, Kaplan HS, Bagshaw MA. RADIATION HEPATITIS. Am J Roentgenol Radium Ther Nucl Med. 1965;93:200-208.
- . Sato T, Eschelman DJ, Gonsalves CF, et al. Immunoembolization of Malignant Liver Tumors, Including Uveal Melanoma, Using Granulocyte-Macrophage Colony-Stimulating Factor. Journal of Clinical Oncology. 2008;26(33):5436-5442. doi:10.1200/jco.2008.16.0705
- Gonsalves CF, Eschelman DJ, Sullivan KL, Rani Anne P, Doyle L, Sato T. Radioembolization as Salvage Therapy for Hepatic Metastasis of Uveal Melanoma: A Single-Institution Experience. American Journal of Roentgenology. 2011;196(2):468-473. doi:10.2214/ajr.10.4881
- Eldredge-Hindy H, Ohri N, Anne PR, et al. Yttrium-90 Microsphere Brachytherapy for Liver Metastases From Uveal Melanoma. American Journal of Clinical Oncology. 2016;39(2):189-195. doi:10.1097/coc.0000000000000033
- Poon RTP, Tso WK, Pang RWC, et al. A Phase I/II Trial of Chemoembolization for Hepatocellular Carcinoma Using a Novel Intra-Arterial Drug-Eluting Bead. Clinical Gastroenterology and Hepatology. 2007;5(9):1100-1108. doi:10.1016/j.cgh.2007.04.021
- Fiorentini G, Aliberti C, Del Conte A, et al. Intra-arterial hepatic chemoembolization (TACE) of liver metastases from ocular melanoma with slow-release irinotecan-eluting beads. Early results of a phase II clinical study. In Vivo. 2009;23(1):131-137.
- Tan AL, Eschelman DJ, Gonsalves CF, Frangos A, Sato T. Treatment of bulky uveal melanoma (UN) hepatic metastases with doxorubicin eluting beads (DEBDOX) followed by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) TACE: an initial experience. Journal of Vascular and Interventional Radiology. 2014;25(3):S45. doi:10.1016/j.jvir.2013.12.107
- Nam HC, Jang B, Song MJ. Transarterial chemoembolization with drug-eluting beads in hepatocellular carcinoma. World Journal of Gastroenterology. 2016;22(40):8853. doi:10.3748/wjg.v22.i40.8853
- Reddy SK, Kesmodel SB, Alexander HR Jr. Isolated hepatic perfusion for patients with liver metastases. Ther Adv Med Oncol. 2014;6(4):180-194.
- Olofsson R, Ny L, Eilard MS, et al. Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial): study protocol for a randomized controlled trial. Trials. 2014;15(1). doi:10.1186/1745-6215-15-317
- Spagnolo F, Caltabiano G, Queirolo P. Uveal melanoma. Cancer Treat Rev. 2012;38(5):549-553.
- Kivelä T, Suciu S, Hansson J, et al. Bleomycin, vincristine, lomustine and dacarbazine (BOLD) in combination with recombinant interferon alpha-2b for metastatic uveal melanoma. European Journal of Cancer. 2003;39(8):1115-1120. doi:10.1016/s0959-8049(03)00132-1
- Albert DM, Ryan LM, Borden EC. Metastatic ocular and cutaneous melanoma: a comparison of patient characteristics and prognosis. Arch Ophthalmol. 1996;114(1):107-108.
- Pons F, Plana M, Caminal JM, et al. Metastatic uveal melanoma: is there a role for conventional chemotherapy? - A single center study based on 58 patients. Melanoma Res. 2011;21(3):217-222.
- Bedikian AY, Papadopoulos N, Plager C, Eton O, Ring S. Phase II evaluation of temozolomide in metastatic choroidal melanoma. Melanoma Res. 2003;13(3):303-306.
- Piperno-Neumann S, Diallo A, Etienne-Grimaldi M-C, et al. Phase II Trial of Bevacizumab in Combination With Temozolomide as First-Line Treatment in Patients With Metastatic Uveal Melanoma. Oncologist. 2016;21(3):281-282.
- Schmittel A, Schuster R, Bechrakis NE, et al. A two-cohort phase II clinical trial of gemcitabine plus treosulfan in patients with metastatic uveal melanoma. Melanoma Res. 2005;15(5):447-451.
- O’Neill PA, Butt M, Eswar CV, Gillis P, Marshall E. A prospective single arm phase II study of dacarbazine and treosulfan as first-line therapy in metastatic uveal melanoma. Melanoma Res. 2006;16(3):245-248.
- Spagnolo F, Grosso M, Picasso V, Tornari E, Pesce M, Queirolo P. Treatment of metastatic uveal melanoma with intravenous fotemustine. Melanoma Res. 2013;23(3):196-198.
- Triozzi PL, Singh AD. Adjuvant Therapy of Uveal Melanoma: Current Status. Ocul Oncol Pathol. 2014;1(1):54-62.
- Yang J, Manson DK, Marr BP, Carvajal RD. Treatment of uveal melanoma: where are we now? Ther Adv Med Oncol. 2018;10:1758834018757175.
- McLean IW, Berd D, Mastrangelo MJ, et al. A randomized study of methanol-extraction residue of bacille Calmette-Guerin as postsurgical adjuvant therapy of uveal melanoma. Am J Ophthalmol. 1990;110(5):522-526.
- Desjardins L, Dorval T, Lévy C, et al. Randomised study on adjuvant therapy by DTIC in choroidal melanoma. Ophtalmologie. 1998;12(3):168-173.
- Piperno-Neumann S, Rodrigues MJ, Servois V, et al. A randomized multicenter phase 3 trial of adjuvant fotemustine versus surveillance in high risk uveal melanoma (UM) patients (FOTEADJ). J Clin Orthod. 2017;35(15_suppl):9502-9502.
- Richtig E, Langmann G, Schlemmer G, et al. [Safety and efficacy of interferon alfa-2b in the adjuvant treatment of uveal melanoma]. Ophthalmologe. 2006;103(6):506-511.
- Voelter V, Schalenbourg A, Pampallona S, et al. Adjuvant intra-arterial hepatic fotemustine for high-risk uveal melanoma patients. Melanoma Res. 2008;18(3):220-224.
- Lane AM, Egan KM, Harmon D, Holbrook A, Munzenrider JE, Gragoudas ES. Adjuvant interferon therapy for patients with uveal melanoma at high risk of metastasis. Ophthalmology. 2009;116(11):2206-2212.
- Wu X, Zhou J, Rogers AM, et al. c-Met, epidermal growth factor receptor, and insulin-like growth factor-1 receptor are important for growth in uveal melanoma and independently contribute to migration and metastatic potential. Melanoma Res. 2012;22(2):123-132.
- Valsecchi ME, Orloff M, Sato R, et al. Adjuvant Sunitinib in High-Risk Patients with Uveal Melanoma: Comparison with Institutional Controls. Ophthalmology. 2018;125(2):210-217.
- Ren X, Hu B, Colletti L. Stem cell factor and its receptor, c-kit, are important for hepatocyte proliferation in wild-type and tumor necrosis factor receptor-1 knockout mice after 70% hepatectomy. Surgery. 2008;143(6):790-802.
- Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 2012;12(2):89-103.
- Surriga O, Rajasekhar VK, Ambrosini G, Dogan Y, Huang R, Schwartz GK. Crizotinib, a c-Met inhibitor, prevents metastasis in a metastatic uveal melanoma model. Mol Cancer Ther. 2013;12(12):2817-2826.
- Sacco JJ, Nathan PD, Danson S, et al. Sunitinib versus dacarbazine as first-line treatment in patients with metastatic uveal melanoma. J Clin Orthod. 2013;31(15_suppl):9031-9031.
- Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2(3):270-287.
- Daud A, Kluger HM, Kurzrock R, et al. Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma. Br J Cancer. 2017;116(4):432-440.
- Scheulen ME, Kaempgen E, Keilholz U, et al. STREAM: a randomized discontinuation, blinded, placebo-controlled phase II study of sorafenib (S) treatment of chemonaive patients (pts) with metastatic uveal melanoma (MUM). J Clin Oncol. 2017;35(15 suppl):abstr - 9511.
- Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA. 2014;311(23):2397-2405.
- Carvajal RD, Piperno-Neumann S, Kapiteijn E, et al. Selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma: a phase III, multicentre, randomised trial (SUMIT). J Clin Oncol. 2018;36(12):1232-1239.
- Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):782-789.
- Nathan PD, Marshall E, Smith CT, et al. A Cancer Research UK two-stage multicenter phase II study of imatinib in the treatment of patients with c-kit positive metastatic uveal melanoma (ITEM). J Clin Orthod. 2012;30(15_suppl):8523-8523.
- Wu X, Li J, Zhu M, Fletcher JA, Hodi FS. Protein kinase C inhibitor AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the PKC/Erk1/2 and PKC/NF-κB pathways. Mol Cancer Ther. 2012;11(9):1905-1914.
- Musi E, Ambrosini G, De Stanchina E, Schwartz GK. The phosphoinositide 3-kinase α selective inhibitor BYL719 enhances the effect of the protein kinase C inhibitor AEB071 in GNAQ/GNA11-mutant uveal melanoma cells. Mol Cancer Ther. 2014;13(5):1044-1053.
- Richardson PG, Barlogie B, Berenson J, et al. Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma:: final time-to-event results from the SUMMIT trial. Cancer. 2006;106(6):1316-1319.
- Jagannath S, Barlogie B, Berenson JR, et al. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. British Journal of Haematology. 2008. doi:10.1111/j.1365-2141.2008.07359.x
- Lee SJ, Richardson PG, Sonneveld P, et al. Bortezomib is associated with better health-related quality of life than high-dose dexamethasone in patients with relapsed multiple myeloma: results from the APEX study. Br J Haematol. 2008;143(4):511-519.
- Orlowski RZ, Kuhn DJ. Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res. 2008;14(6):1649-1657.
- Triozzi PL, Eng C, Singh AD. Targeted therapy for uveal melanoma. Cancer Treat Rev. 2008;34(3):247-258.
- Faingold D, Marshall J-C, Antecka E, et al. Immune expression and inhibition of heat shock protein 90 in uveal melanoma. Clin Cancer Res. 2008;14(3):847-855.
- Shah S, Luke JJ, Jacene HA, et al. Results from phase II trial of HSP90 inhibitor, STA-9090 (ganetespib), in metastatic uveal melanoma. Melanoma Res. 2018;28(6):605-610.
- Zeldis JB, Heller C, Seidel G, et al. A randomized phase II trial comparing two doses of lenalidomide for the treatment of stage IV ocular melanoma. J Clin Oncol. 2009;27(15S):e20012-e20012.
- Moser JC, Pulido JS, Dronca RS, McWilliams RR, Markovic SN, Mansfield AS. The Mayo Clinic experience with the use of kinase inhibitors, ipilimumab, bevacizumab, and local therapies in the treatment of metastatic uveal melanoma. Melanoma Res. 2015;25(1):59-63.
- Tarhini AA, Frankel P, Margolin KA, et al. Aflibercept (VEGF Trap) in inoperable stage III or stage iv melanoma of cutaneous or uveal origin. Clin Cancer Res. 2011;17(20):6574-6581.
- Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14:73.
- Pereira PR, Odashiro AN, Lim L-A, et al. Current and emerging treatment options for uveal melanoma. Clin Ophthalmol. 2013;7:1669-1682.
- Piulats Rodriguez JM, Ochoa de Olza M, Codes M, et al. Phase II study evaluating ipilimumab as a single agent in the first-line treatment of adult patients (Pts) with metastatic uveal melanoma (MUM): The GEM-1 trial. J Clin Orthod. 2014;32(15_suppl):9033-9033.
- Zimmer L, Vaubel J, Mohr P, et al. Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma. PLoS One. 2015;10(3):e0118564.
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517-2526.
- Joshua AM, Monzon JG, Mihalcioiu C, Hogg D, Smylie M, Cheng T. A phase 2 study of tremelimumab in patients with advanced uveal melanoma. Melanoma Res. 2015;25(4):342-347.
- Algazi AP, Tsai KK, Shoushtari AN, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016;122(21):3344-3353.
- Boudousquie C, Bossi G, Hurst JM, Rygiel KA, Jakobsen BK, Hassan NJ. Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells. Immunology. 2017;152(3):425-438.
- Middleton MR, Steven NM, Evans TJ, et al. Safety, pharmacokinetics and efficacy of IMCgp100, a first-in-class soluble TCR-antiCD3 bispecific t cell redirector with solid tumour activity: Results from the FIH study in melanoma. J Clin Orthod. 2016;34(15_suppl):3016-3016.
- Sato T, Nathan PD, Hernandez-Aya LF, et al. Intra-patient escalation dosing strategy with IMCgp100 results in mitigation of T-cell based toxicity and preliminary efficacy in advanced uveal melanoma. J Clin Orthod. 2017;35(15_suppl):9531-9531.
- Rothermel LD, Sabesan AC, Stephens DJ, et al. Identification of an Immunogenic Subset of Metastatic Uveal Melanoma. Clin Cancer Res. 2016;22(9):2237-2249.
- Chandran SS, Somerville RPT, Yang JC, et al. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study. Lancet Oncol. 2017;18(6):792-802.
- Bouchard H, Viskov C, Garcia-Echeverria C. Antibody–drug conjugates—A new wave of cancer drugs. Bioorg Med Chem Lett. 2014;24(23):5357-5363.
- Patel S, Lewis KD, Olencki T, Hernandez-Aya L, Joseph R, Williamson S, Chandra S, Shirai K, Carter B, Moscow J. A phase II study of CDX-011 (Glembatumumab vedotin) for metastatic uveal melanoma. Presented at the: 14th international congress of the Society for Melanoma Research; October 2017; Brisbane, Australia.
- Buder K, Gesierich A, Gelbrich G, Goebeler M. Systemic treatment of metastatic uveal melanoma: review of literature and future perspectives. Cancer Med. 2013;2(5):674-686.
- Álvarez-Rodríguez B, Latorre A, Posch C, Somoza Á. Recent advances in uveal melanoma treatment. Med Res Rev. 2017;37(6):1350-1372.
- Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol. 2010;3:5.
- Landreville S, Agapova OA, Matatall KA, et al. Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res. 2012;18(2):408-416.
- Moschos MM, Dettoraki M, Androudi S, et al. The Role of Histone Deacetylase Inhibitors in Uveal Melanoma: Current Evidence. Anticancer Res. 2018;38(7):3817-3824.
- Haas NB, Quirt I, Hotte S, et al. Phase II trial of vorinostat in advanced melanoma. Invest New Drugs. 2014;32(3):526-534.
- Dey A, Nishiyama A, Karpova T, McNally J, Ozato K. Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription. Mol Biol Cell. 2009;20(23):4899-4909.
- French CA, Miyoshi I, Aster JC, et al. BRD4 Bromodomain Gene Rearrangement in Aggressive Carcinoma with Translocation t(15;19). Am J Pathol. 2001;159(6):1987-1992.
- Zeng L, Zhou M-M. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 2002;513(1):124-128.
- Yang Z, He N, Zhou Q. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol Cell Biol. 2008;28(3):967-976.
- Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains. Nature. 2010;468(7327):1067-1073.
- Ambrosini G, Sawle AD, Musi E, Schwartz GK. BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells. Oncotarget. 2015;6(32):33397-33409.
- Ambrosini G, Schwartz GK. Abstract 4462: Cytotoxic effects of a novel BRD4 inhibitor in uveal melanoma cells with Gnaq/11 mutations. Cancer Res. 2016;76(14 Supplement):4462-4462.
- Patel SP, Wolff JE, Mostorino RM, Chen X, McKee MD, Piha-Paul SA. Uveal melanoma patients (pts) treated with abbv-075 (mivebresib), a pan-inhibitor of bromodomain and extraterminal (BET) proteins: Results from a phase 1 study. J Clin Orthod. 2018;36(15_suppl):e14585-e14585.