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Clinical and Experimental Ophthalmology 2016; 44: 509–519 doi: 10.1111/ceo.12688

Review Evolving systemic targeted therapy strategies in uveal melanoma and implications for ophthalmic management: a review Amanda YL Goh1 and Christopher J Layton DPhil(Oxon) FRANZCO1,2,3 1

School of Medicine, University of Queensland, 2 Gallipoli Medical Research Institute and 3 Ophthalmology Department, Greenslopes Private Hospital, Brisbane, Queensland, Australia

ABSTRACT Uveal melanoma (UM) is the most common primary ocular tumour in adults. Despite good local control of the primary tumour with current methods, survival after the development of metastasis has remained poor over the last 30 years. After cutaneous melanoma, UM is the most common type of melanoma, and an ongoing debate exists regarding whether these conditions should be considered separate entities, particularly in the context of targeted therapy, where many of the initial trials for patients with metatatic cutaneous melanoma excluded metastatic UM. This paper will review the recent and ongoing investigations designed to validate systemic targeted therapy and immunotherapy in patients with metastatic UM and suggests ways in which these developments may affect management of UM by ophthalmologists in the near future.

Key words: choroidal melanoma, cutaneous melanoma, immunotherapy, targeted therapy, uveal melanoma.

INTRODUCTION Uveal melanoma (UM) is the most common primary ocular tumour in adults,1 with an incidence of approximately seven per million in Australia.2 The condition can arise in any part of the uveal tract; however, the vast majority originate from the choroid.3 With currently available treatment, approxi-

mately 50% of patients ultimately develop metastases, and patients with metastatic UM (MUM) have a very poor median overall survival between 2 and 15 months.4,5 Survival has remained virtually unchanged for the last 30 years despite significant improvement in local tumour control rates, which are now greater than 90% over a 5-year period.3,6 Metastases in UM have the highest predilection for the liver (93%), with other common sites being the lungs (24%) and bones (16%).3 As such, the prognostic benefits offered by earlier recognition and systemic treatment are now becoming more recognized.7 In many ways, knowledge of the biology and development of treatment for UM has been, and continues to be, partly dependent upon cutaneous melanoma (CM). Over 90% of melanomas are cutaneous, with UM accounting for only 5%.5 This is considered the most likely reason for the disparity in evidence between these two conditions in terms of risk factors, cytogenetics, signalling pathways and efficacy of treatment. Although initial studies of systemic therapies for CM excluded UM, a significant body of data is beginning to appear concerning which agents may also be able to treat MUM. Historically, attempts to enhance UM therapy have concentrated on establishing and refining local ophthalmic methods to remove the primary tumour. Although enucleation was traditionally the mainstay of treatment, recent decades have seen a shift towards more conservative methods after the Collaborative Ocular Melanoma Study reports, which showed that in moderately sized tumours (defined as an apical

j Correspondence: Dr Christopher J Layton, Gallipoli Medical Research Institute, Lower Lobby, Greenslopes Private Hospital, Newdegate Street, Greenslopes QLD 4120, Australia. Email: [email protected] Received 14 August 2015; accepted 17 November 2015. Competing/conflicts of interest: None declared. Funding sources: None declared. © 2015 Royal Australian and New Zealand College of Ophthalmologists

510 height of 2.5–10.0 mm and a basal diameter less than 16.0 mm), plaque brachytherapy could be employed with similar outcomes.8 Today, the majority of patients are treated with either of these two methods, with factors including tumour size, extent of local advancement, possibility of complications and patient preferences determining the treatment choice. Other less commonly used modalities targeting the primary tumour include photocoagulation therapy,9 transpupillary thermotherapy,10 internal resection (endoresection),11 proton beam irradiation,12 gamma-knife radiosurgery,13 and for advanced tumours that extend extrasclerally, orbital exenteration.14 Arguably, the most significant limitation to the current treatment of MUM is the lack of effective systemic therapy.1,15 Unfortunately, the development of multiple successful treatment modalities for local control has not impacted significantly on survival rates.15 This has prompted new interest in the natural history of UM, which was previously unknown because of the early establishment of safe enucleation techniques as the treatment of choice. Although fewer than 4% of patients are reported to have detectable metastases at the time of diagnosis,16 it is becoming increasingly acknowledged that subclinical “micrometastases” have often formed several years prior to the time of diagnosis.17 This phenomenon provides an explanation for the poor survival outcome even with successful local treatment,17,18 highlighting the need for earlier, more sensitive detection of metastases and effective systemic therapies for UM. Therefore, many primary UM tumours may be more accurately conceptualized as a manifestation of systemic disease, rather than an ocular mass in isolation, and thus ideally should be treated accordingly with a combination of both ophthalmic (local) and systemic approaches, in the way that numerous other solid tumours are currently managed.7 In the past, this approach to the treatment of UM has been strictly limited by its resistance to standard chemotherapy and the absence of effective systemic treatment.1,15 However, the growing knowledge of the mechanisms underlying metastatic transformation in these tumours has led clinicians and researchers to broaden their perspective on potential targets in systemic treatment and prophylactic, primary and adjuvant therapies for UM.7 As this is one of the most rapidly changing fields in medicine with many emerging therapies directed at new targets, an updated discussion on recent and ongoing developments in systemic therapies for MUM will be presented here. It could be anticipated that these potential molecular targets and novel therapeutic agents may alter the standard of care for UM management at its primary presentation. It can also be anticipated that the developing conceptualization of UM as a systemic disease and

Goh and Layton the development of novel targeted therapy for MUM may place new demands on ophthalmic clinicians to have an understanding of molecular prognostic indicators and the availability of systemic therapies for MUM in the near future.

RELATIONSHIP TO CUTANEOUS MELANOMA AND ITS SYSTEMIC THERAPIES

The uveal tract is the second most common site of melanomas, but is the site of only 5% of all melanomas, with the vast majority (over 90%) being cutaneous (CM).5 Along with their shared origin from neural crest melanoblasts, UM and CM both have high rates of metastasis which then imply a mean survival of only 2–15 months.5,19 Their prognoses are most dependent on similar parameters of tumour size – Breslow thickness and largest tumour diameter – in CM and UM, respectively.5 The most commonly used treatments for these two tumours is local control; however, once metastasized, both are resistant to conventional chemotherapy.5 CM and UM also share several cytogenetic features; however, these are present in different frequencies; for instance, monosomy 3, the most prognostically significant chromosomal abnormality in UM, is present in 50% of UM but only (25%) of CM tumours.5 There is debate in the literature regarding whether the differences between these two tumours can be merely attributed to their locations. Although both tumours are known to frequently metastasize, CM typically spreads haematogenously and lymphogenously, the latter of which is not usually observed in UM. It is thought that the absence of ocular lymphatic drainage contributes to the predilection of UM to disseminate via the haematogenous route5, accounting for its spread to the liver (93%) and in some cases, also the lungs (24%) and bones (16%).20 Typically, CM metastasizes locally in its early stages, ultimately involving multiple sites, particularly the lungs (51%), lymph nodes, subcutaneous tissue, liver and bones;19 in contrast, UM often presents with distant micrometastases at diagnosis.17 In addition, their distinctive locations may explain some differences in predisposing factors; because ultraviolet radiation exposure is higher in the skin than the uveal tract, this may account for the fact that its role in the tumorigenesis of UM is not as prominent in CM.5 Other known risk factors for CM include a family history of melanoma, higher number of melanocytic naevi and fair skin type, the last of which also predisposes to UM. Individuals with light coloured irises and oculodermal melanocytosis are also at increased risk of UM.5 In view of these similarities and differences, there is divided opinions on whether CM and UM should © 2015 Royal Australian and New Zealand College of Ophthalmologists

Systemic targeted therapy in uveal melanoma be regarded as separate entities, especially when devising targeted therapy.5,15 For example, the genetic differences between the two entities recently became clinically relevant with the development of agents targeting two key mutations in components of the mitogen-activated protein kinase (MAPK) pathway, BRAF and NRAS. These agents are beginning to revolutionize the management of the cutaneous variant of melanoma, but unfortunately, this therapeutic success has not extended to UM, in which these mutations are rarely present.21–23 Instead, a majority of primary UM tumours, as well as liver metastases, achieve constitutive MAPK signalling via alternative, yet still potentially targetable mutations, and in this respect UM mirrors CM.23

BASIC

CONSIDERATIONS IN

UM

PROGNOSIS AND

TUMORIGENESIS

Although cytogenetic abnormalities remain one of the most widely recognized molecular abnormalities in UM, the advent of gene expression profiling has led to the characterization of UM into Class I (lowgrade) and Class II (high-grade) tumours, based on their molecular signatures of RNA expression. This categorization strongly correlates with 92-month survival rates of 95 and 31% for Class I and II tumours respectively24 and has been found to be a more reliable predictor of metastatic risk than clinical, histopathologic and chromosomal factors.25–27 This and similar risk stratification tools have implications for future management of UM, where patients may be categorized to assess their suitability for conservative treatment, entry into clinical trials of novel agents, adjuvant therapy and/or treatment with newly approved therapies.6,24 One such test assigns a Class I or II status to a tumour sample collected by fineneedle aspiration, according to its RNA expression levels of the selected 15 genes: CDH1, ECM1, E1F1B, FXR1, HTR2B, ID2, LMCD1, LTA4H, MTUS1, RAB31, ROBO1 and SATB1.26,27 With considerable developments in molecular technology and next generation genome sequencing, the tumorigenesis of UM has become increasingly characterized over the last few years, and modern approaches have allowed the development of a variety of therapies which can specifically inhibit important contributors to tumour transformation, growth, prognosis or metastasis.

CURRENT APPROACHES TO SYSTEMIC THERAPY IN UM Standard chemotherapy It has been well recognized for many years that UM tumours, both primary and metastatic, are essentially resistant to standard chemotherapy.28 Reported response rates of UM to chemotherapy are as low as 0–15%15 and responders have a very limited © 2015 Royal Australian and New Zealand College of Ophthalmologists

511 extended survival in MUM.1,15 This has arguably been one of the major limitations to successful MUM management, and therefore, there is currently intensive activity focused on developing and trialling targeted systemic therapies, many of which will be explored in the succeeding texts.

Therapeutic targeting in UM BAP1 The most significant and widely known chromosomal abnormality is full or partial loss of chromosome 3 (the former referred to as monosomy 3), which is found in around 50% of UM tumours.3,5,6,15,18 Other common abnormalities correlated with prognosis are loss of chromosomes 1p, 6q and 8p, as well as polysomy of chromosome 8q.3,5 Monosomy 3 is strongly associated with increased metastatic risk and poorer survival, attributed to the numerous critical genes it carries, some of which are amenable to targeted therapy. One such gene is BRCA1 associated protein 1 (BAP1) at chromosome 3p21.1.29,30 BAP1 is a tumour suppressor gene encoding a histone H2A ubiquitin hydrolase, which regulates cell differentiation, cell cycle arrest and DNA repair.31,32 Inactivation or loss-of-function mutations in BAP1 are thought to be late events in UM progression and have a strong correlation with Class II status,29 the presence of metastases,31,33 and therefore poorer survival. Agents that counteract the downstream effects of BAP1 deletion such as H2A hyperubiquitination may therefore also be of therapeutic value.31,32 One class of such agents is histone deacetylase (HDAC) inhibitors; several of which have been observed in UM cell lines, and in vivo tumours in mice to inhibit growth, and reprogram high-grade (Class II) UM cells to shift towards a more differentiated (Class I) phenotype.32 Based on these pre-clinical findings, a phase II trial is underway to evaluate a HDAC inhibitor, vorinostat, in patients with MUM (NCT01587352). Interestingly, although the majority of BAP1 mutations arise sporadically, several familial UM cases possess germline mutations of the gene. These inherited syndromes are associated with a strong family history of malignancy clusters including melanocytic tumours (particularly CM) and nonmelanocytic tumours (i.e. mesothelioma).34–36 It is possible that HDAC inhibitors, if found to be clinically active, may be of particular benefit to this subgroup for not only their UM tumours, but also simultaneous treatment of the other malignancies to which they are predisposed because of BAP1 aberrations.

GNAQ/GNA11 Although aberrations in BRAF and NRAS are generally not present in UM,21 the same downstream

512 effects of increased MAPK pathway signalling occurs through alternative targetable mutations in other parts of the pathway (Fig. 1). In around 85% of primary UM tumours and liver metastases, constitutive activation of the MAPK pathway results from mutually exclusive mutations in G protein α subunit genes, GNAQ or GNA11,37–39 found in either codons 183 or more commonly, 209, of the Ras-like domain.40 Changes in these proto-oncogenes are thought to be early events in UM development and key players in tumorigenesis.41 While the exact mechanism by which they cause MAPK pathway activation is not clear, constitutive protein kinase C (PKC) activation has been implicated.37,42,43 Wu et al. showed that a PKC inhibitor, enzastaurin, exhibited stronger antiproliferative and apoptotic effects on UM cell lines with GNAQ mutations than those without and was associated with reduced extracellular signalregulated kinase 1/2 phosphorylation – a marker involved in MAPK pathway activation43 (Fig. 1). A more recent study also showed the PKC inhibitors, AEB071 and AHT956, reduced both PKC and MAPK pathway signalling in all cell lines with GNAQ/ GNA11 mutations, yet had little effect in those without GNAQ/GNA11 mutations.37 Furthermore, strong synergism between AEB071, a PKC inhibitor, and PD0325901, which inhibits MEK, a component of the MAPK pathway (Fig. 1), led to enhanced

Goh and Layton apoptosis of UM cells with GNAQ/GNA11 mutations compared with monotherapy. This combination caused tumour growth reduction and regression in a mouse xenograft model. MEK inhibition alone with TAK733, a novel mitogen-activated protein kinase kinase 1/2 inhibitor, has also been shown to cause cytotoxicity to a greater degree in UM cell lines with a positive GNAQ/GNA11 mutational status.44 These preclinical studies support not only therapeutic potential for MEK inhibitors, but also PKC inhibitors, for MUM. At present, a substantial proportion of ongoing clinical trials for MUM are targeting these pathways. One of the few that have been completed was a randomized, multicenter phase II trial involving 101 patients with MUM, which demonstrated selumetinib, a mitogen-activated protein kinase kinase 1/2 inhibitor, improved response rates and progression-free survival of 14% and 15.9 weeks respectively, compared with chemotherapy with either temozolomide or dacarbazine (0% response rate, 7 weeks progression-free survival).45 Tumour shrinkage was observed in almost half of the patients receiving selumetinib, compared with no objective response with chemotherapy, and a trend towards improved overall survival was also observed.45 Based on these findings, an international phase III trial (SUMIT) on the efficacy of selumetinib in combination with dacarbazine as systemic therapy in an estimated 128

Figure 1. A simplified diagram of the cellular components leading to activation of mitogen-activated protein kinase (MAPK) pathway. The main targets of extracellular signal-regulated kinase have been illustrated; however, other downstream pathways exist. GPCR, G-protein coupled receptor; Gαq, alpha subunit of Gq protein; PLC-β, phospholipase C-β; PIP2, phosphatidylinositol 4,5-biphosphate; DAG, diacylglycerol; PKC, protein kinase C; MEK, mitogen-activated protein kinase kinase; RSK, ribosomal s6 kinase; MNK, mitogen-activated protein kinase-interacting kinase; MSK, mitogen-activated and stress-activated protein kinase. © 2015 Royal Australian and New Zealand College of Ophthalmologists

Systemic targeted therapy in uveal melanoma patients with MUM is currently ongoing (NCT01974752)46, and selumetinib monotherapy is now in phase II trials (NCT01143402). Another MEK inhibitor, trametinib, is also in phase II trials both as monotherapy and in combination with an Akt/PKB (protein kinase B) inhibitor, GSK2141785, for MUM (NCT01979523). Agents targeting other aspects of the MAPK pathway are the focus of many new clinical UM trials. Preliminary data from a phase I trial of the previously mentioned oral PKC inhibitor, AEB071 (NCT01430416), suggested some clinical activities in MUM with 47% of the 118 patients involved achieving stable disease and a median progression-free survival of 15.4 weeks with reasonable safety characteristics.47 Combination treatment of AEB071 with MEK inhibitor, MEK162 (NCT01801358), and phosphoinositide 3-kinase inhibitor, BYL719 (NCT02273219), in patients with pre-treated MUM are also being studied. Because of the cross-talk between the MAPK pathway and phosphoinositide 3-kinase /Akt pro-survival pathway and the effectiveness of combined inhibition in vitro suggests further investigation for in vivo and clinical outcomes is warranted.48 Trials evaluating this dual therapy in patients with MUM are anticipated in the near future.

IGF-1 It is widely known amongst all medical specialties that MUM has a propensity of spreading to the liver; however, the reason behind this tropism is not fully known. Over the past 15 years, there has been a developing consensus that growth factors in the hepatic environment contribute.3,49–51 One such growth factor is insulin-like growth factor 1 (IGF-1), which is primarily produced in the liver and has been shown to promote cell proliferation and tumorigenesis not only in UM but in numerous other malignancies.52 IGF-1 signalling, in conjunction with epidermal growth factor (EGF) signalling, can induce UM cell migration and invasion, and therefore increase metastatic potential.51 The levels of IGF-1 receptor (IGF-1R) expression are found to vary amongst UM tumours;49,51 however, its upregulation, when present, may serve as an important clinical prognostic parameter,49,50 as it is more strongly associated with increased mortality than more commonly used prognostic markers, such as tumour cell type and diameter.50 Because dissemination to the liver is strongly associated with a poorer prognosis in MUM,53 the potential benefit of IGF-1 inhibitors to prevent liver metastases is under investigation. Studies in human UM-derived cell lines have shown that cyclolignan picropodophyllin (PPP), an IGF-1R inhibitor, hinders cell survival, growth, invasion and migration.51,54 © 2015 Royal Australian and New Zealand College of Ophthalmologists

513 Picropodophyllin was also demonstrated to cause tumour regression and reduction in incidence of liver micrometastases from UM xenografts in mice.54 A further study of a similar design also reported picropodophyllin-inhibited expression of vascular endothelial growth factor (VEGF), which promotes angiogenesis in UM tumours.50 Chattopadhyay et al. reported that IMC-A12 (cixutumumab), a monoclonal antibody against IGF-1R, was able to block IGF-1 downstream activity and reduce migration in UM cell lines, and concluded that IGF-1R is a potentially useful target for UM therapy.55 If these findings translate into clinical outcomes, IGF-1R inhibitors may be valuable in managing both MUM and primary UM tumours by reducing the potential for dissemination. A phase II trial (NCT01413191) has been completed on cixutumumab in patients with MUM, but results are yet to be published.

Receptor tyrosine kinases – VEGF and others Although VEGF has been implicated in the induction of angiogenesis by primary tumours, and thereby allowing growth and creating an avenue for metastasis,56 established systemic anti-angiogenic therapies have failed to produce significant clinical responses in patients with UM to date.1,56,57 However VEGF inhibitors have produced positive results in animal models,58 and some investigators still feel that there may be a clinical advantage offered by these agents. This has led to a phase II trial testing the humanized anti-VEGF monoclonal antibody, bevacizumab, with temozolomide in patients with chemonaïve MUM (NCT01217398). Another anti-VEGF monoclonal antibody, ranibuzimab, is also in phase I trials (NCT00765921). Other anti-angiogenic agents, such as an oral VEGF receptor (VEGFR) inhibitor, axitinib, have also attracted some attention as a candidate MUM therapy, supported by phase II results of it having single-agent clinical activity in patients with metastatic melanoma, and interestingly, one out of the three patients with MUM experienced a partial response.59 A phase II study is underway for patients with advanced or recurrent melanoma, including both cutaneous and intraocular types, which may further elucidate potential benefits of this anti-angiogenic agent in MUM management (NCT01533948). In addition to its anti-angiogenic properties via VEGFR blockade, sunitinib also acts as an antiproliferative agent by inhibiting platelet-derived growth factor receptor (PDGFR), c-KIT, FMS-like tyrosine kinase 3 (FLT-3) and RET.60 A pilot study on sunitinib malate reported one partial response, seven of stable disease and two of progressive disease outcomes, with 80% overall clinical benefit for Stage

514 IV UM with at least 10% c-KIT expression.61 Findings from a more recent pilot study were consistent with this; one partial response, 12 stable disease outcomes and 65% overall clinical benefit in 20 patients with MUM treated with sunitinib monotherapy was observed.60 It has been commented that these modest, but not significant, responses and a lack of improvement in overall survival suggest sunitinib and other c-KIT-targeting agents have no clear role in MUM as monotherapy.62 However, sunitnib monotherapy continues to be investigated in phase II trials for MUM (NCT01551459), as well as for UM with high risk of metastatic disease (NCT02068586). Ongoing trials also reflect interest in sunitnib combined with other agents, such as temozolomide in a phase I/II trial for late-stage CM, mucosal and ocular melanoma (NCT01005472) and cisplatin and tamoxifen citrate (NCT00489944) as adjuvant therapy for UM with high metastatic risk. Sorafenib is another multi-receptor tyrosine kinase inhibitor with actions on VEGFR, PDGFR, cKIT and FLT-3 and RAF kinases in the MAPK pathway.63 A case series of sorafenib-treated patients with MUM following fotemustine chemotherapy showed favourable results with reduced levels of tumour markers, partial responses and disease stabilization in three of seven patients.64 A more recent study also reported very similar results with this combination 65; however, no objective responses or clinical improvement have been observed when sorafenib was used in combination with other standard chemotherapeutic agents, such as carboplatin and paclitaxel.66,67 Currently, phase I trials are hoping to determine the efficacy of sorafenib in combination with a different chemotherapeutic agent, lenalidomide,68 liver Yttrium-90 radioembolization (NCT01893099), and also as monotherapy in a large phase II trial for patients with MUM (NCT01377025).

Immunotherapy in UM UM arises in an immunologically privileged site, and therefore, it is postulated that its immunogenicity may be higher than other tumours, possibly rendering it more vulnerable to immunotherapy.62 The aim of this approach is to create an immunogenic environment surrounding the tumour or metastases, increasing its recognition and destruction by the immune system. Because of recent successful use of immunotherapy for CM,69–71 there has been great interest in its role in the treatment of MUM, particularly antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1), with some studies yielding promising results.

Goh and Layton

CTLA-4 Ipilimumab is a humanized monoclonal antibody against CTLA-4 present on the surface of activated T lymphocytes, but unfortunately the major clinical trials that demonstrated improved overall survival in patients with metastatic CM both excluded ocular melanoma.69,70 However, over the past few years, there has been a growing body of knowledge on the efficacy of ipilimumab, from other trials which have included MUM. Ipilimumab has been reported as clinically effective in some cases of pre-treated MUM72,73 independent of poor prognostic factors (e. g. advanced age and presence of metastases) and in an apparent dose-dependent manner.74 A retrospective analysis by Moser et al. noted that although not statistically significant, ipilimumab-treated patients had a longer median overall survival of 28 months compared with 13 months if untreated.57 Another retrospective study also found that outcomes with ipilimumab were favourable when compared with those reported for other systemic therapies in patients with MUM.62 A recently completed study (GEM1) on ipilimumab monotherapy in MUM included 32 newly diagnosed patients in a multicentre phase II trial and reported an overall survival rate of 9.8 months, with a disease control rate of approximately 50%, and stable disease in 38.71% of patients.75 This study has been critiqued as having selection bias towards patients with better performance status and prognosis, based on the high dose (10 mg/kg ipilimumab) that was tolerated by the participants, and other phase II trials have failed to show these positive effects in other patient cohorts.76 Nevertheless, the GEM1 findings suggest that immunotherapy may offer an efficacious treatment for individuals with MUM in the near future, with implications for treatment paradigms in the ophthalmic care of UM. Ipilimumab (NCT02158520) and another CTLA-4 inhibitor, tremelimumab (CP-675,206) (NCT01034787) remain in phase II trials for patients with MUM. A phase 0 trial of ipilimumab in combination with liver Yttrium-90 radioembolization is also underway (NCT01730157).

PD-1 Nivolumab and pembrolizumab are monoclonal antibodies directed against PD-1, a co-inhibitory receptor located on T cells that reduces their anti-tumour activity.15 The pivotal trials demonstrating their efficacy in metastatic CM both indicated UM as an exclusion criterion,77,78 and as such, it remains uncertain whether clinical improvements afforded by these agents extend to UM. Despite its location in an immunoprivileged site, PD-L1, the activating ligand of PD-1, is constitutively expressed on several cell © 2015 Royal Australian and New Zealand College of Ophthalmologists

Systemic targeted therapy in uveal melanoma

515

Table 1. Current clinical trials for targeted therapy and immunotherapy for patients with uveal melanoma (UM) or metastatic uveal melanoma (MUM) registered on ClinicalTrials.gov Target TARGETED THERAPY Protein kinase C (PKC) PKC and Phosphoinositide 3-kinase (PI3K) Mitogen-activated protein kinase kinase (MEK) MEK and Protein kinase B (Akt/PKB) Multi-Receptor Tyrosine Kinases

Vascular endothelial growth factor (VEGF)

VEGF receptor (VEGFR) Histone deacetylase (HDAC) Anaplastic lymphoma kinase Glycoprotein NMB Mammalian target of rapamycin (mTOR) and somatostatin IMMUNOTHERAPY Cytotoxic T-lymphocyteassociated protein 4 (CTLA-4)

Programmed cell death 1 (PD-1) PD-1 and CTLA-4 Interleukin-2

Interferon-alpha 2b

Intervention

Condition

Design

ClinicalTrials.gov Identifier No. Investigation

AEB071

MUM

Phase I

NCT01430416

Safety and efficacy

AEB071 with BYL719

MUM

Phase I

NCT02273219

Safety and efficacy

Selumetinib with dacarbazine vs. placebo with dacarbazine Selumetinib vs. dacarbazine or temozolomide Trametinib with/without GSK2141795 Sunitinib vs. dacarbazine Sunitinib vs. valproic acid Sunitinib malate with temozolomide Sunitinib malate, cisplatin and tamoxifen citrate Sorafenib vs. placebo Sorafenib with lenalidomide

MUM

Phase III

NCT01974752

Efficacy

MUM

Phase II

NCT01143402

Efficacy

Stage IV or Recurrent MUM MUM High-risk UM Stage IIIC and IV UM, CM or MM High-risk UM

Phase II

NCT01979523

Efficacy

Phase II Phase II Phase I/II

NCT01551459 NCT02068586 NCT01005472

Safety and efficacy Efficacy Safety and efficacy

Phase II

NCT00489944

Safety and efficacy

Phase II Phase I

NCT01377025 NCT01183663

Efficacy Safety and efficacy

Sorafenib with hepatic Yttrium-90 radioembolization Bevacizumab with temozolomide Ranibuzimab with proton beam irradiation Axitinib Vorinostat

Crizotinib Glembatumumab vedotin Everolimus (RAD001) with pasireotide (SOM230)

MUM Advanced cancer (including UM) MUM with liver metastases MUM

Phase I

NCT01893099

Safety and efficacy

Phase II

NCT01217398

Safety and efficacy

Newly diagnosed UM

Phase I

NCT00765921

Safety and efficacy

Stage III/IV or Recurrent Phase II UM or CM UM with extraocular Phase II extension, Stage IV or Recurrent UM UM with Class II status Phase II

NCT01533948

Efficacy

NCT01587352

Efficacy

NCT02223819

Safety and efficacy

Phase II

NCT02363283

Efficacy

Phase II

NCT01252251

Safety and efficacy

Phase 0

NCT01730157

Safety and efficacy

Stage IV or Recurrent UM MUM

Ipilimumab with hepatic Yttrium-90 radioembolization Ipilimumab vs. paclitaxel with bevacizumab Tremelimumab (CP-675,206) Pembrolizumab

MUM with liver metastases Stage IV MUM, CM or MM Stage III/IV UM Stage III/IV UM

Phase II

NCT02158520

Efficacy

Phase II Phase II

NCT01034787 NCT02359851

Safety and efficacy Efficacy

Ipilimumab with nivolumab Aldesleukin (IL-2) with tumour-infiltrating lymphocyte vs. cyclophosphamide with tumour-infiltrating lymphocyte Recombinant IFN-alpha 2b with dacarbazine

MUM MUM

Phase II Phase II

NCT01585194 NCT01814046

Safety and efficacy Safety and efficacy

UM with Monosomy 3 and/or 8q amplification

Phase II

NCT01100528

Efficacy

© 2015 Royal Australian and New Zealand College of Ophthalmologists

516 lines derived from primary UM tumours as well as their metastases.79 Such findings warrant the ongoing phase II trials on nivolumab in combination with ipilimumab (NCT01585194), and pembrolizumab (NCT02359851) in patients with MUM.

IL-2 Interleukin-2 (IL-2) is another agent that modulates the immune system to increase its reactivity towards tumour cells; however, its exact mechanism of action is not known.80 IL-2 has established efficacy in selected patients with metastatic CM,81,82 however has not been recommended for UM as responses were not as favourable.83 Nevertheless, there is a phase II trial underway involving the use of highdose IL-2 as an enhancing agent for immune-related biological treatments, such as autologous tumourinfiltrating lymphocyte therapy, rather than its direct anti-tumour effects (NCT01814046).

Current clinical trials Therefore, although the initial studies of therapies for metastatic CM excluded MUM, ophthalmologists should be aware of the intensive investigation into the mechanisms of UM tumorigenesis and how this has led to promising results in validating targeted therapies and immunotherapy for MUM. Developments in this field have now progressed to clinical trials for a number of systemically administered agents, as summarized in Table 1, with some findings suggesting that for the first time, effective systemic therapy for MUM is likely to appear as a viable therapeutic option in the near future.

IMPLICATIONS OF SYSTEMIC TARGETED THERAPY OF UM AND STRATEGIES FOR FUTURE OPHTHALMIC MANAGEMENT

An understanding of UM tumourigenesis with its associated implications for therapeutic targeting means that rather than only having access to methods to achieve local control, diagnosing and treating ophthalmologists can now begin to obtain information concerning specific tumour mutations in each of their patients. There is, in our view, a good possibility that the intensive research into systemic therapies for UM detailed in this manuscript will yield new, approved UM treatments, and this has extensive implications for ophthalmic practice in the near future. At present, local control of UM in clinical practice is often obtained without obtaining a tissue diagnosis in keeping with the results of the Collaborative Ocular Melanoma Study studies, and perhaps the two largest changes in practice demanded by these new therapies are the likely need for ophthalmologists to obtain tumour tissue through extraocular or vitreoretinal

Goh and Layton approaches at the time of diagnosis, and the need to consider systemic therapy as part of initial treatment planning. Tissue processing and sequencing of the tumour genomic profile not only allow risk stratification and assistance in patient selection for therapy of clinical trials, but is also likely to be required to identify which targeted agent or combination of agents is most likely to be effective in systemic therapy. If UM at diagnosis proves to be best considered as the ocular component of a systemic disease, future studies will clarify if immediate adjunctive targeted treatment with appropriate agents at the time of diagnosis, rescue therapy once metastases are identified, or a combination of the two approaches yields the greatest benefits to patients.

CONCLUSION This review details the extensive recent and ongoing investigations into the tumourigenesis of UM and the resulting development of systemic targeted therapy and immunotherapy. The emerging option of effective systemic therapy in UM, coupled with a developing understanding of UM as a systemic disease, may highlight the need for ophthalmic clinicians to familiarize themselves with the newer molecular prognostic markers, therapeutic targets and potential strategies when considering the incorporation of systemic therapy into future practice.

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