Uveal melanoma is the most common primary intraocular cancer in adults, most often affecting the choroid.¹ The available primary treatment options have historically included radiation, most commonly with plaque brachytherapy or proton beam radiotherapy, or enucleation.² Radiation has demonstrated local success rates upwards of 95%, but tumor size may limit which tumors are appropriate for globe-sparing treatment, particularly for plaque brachytherapy. Additionally, radiation-induced side effects can have a dramatic impact on the visual outcome even in the setting of successful treatment. Nearly 50% of patients end up with 20/200 vision or worse secondary to radiation retinopathy or radiation optic neuropathy.^1,2 As a result, there has been a goal to identify novel treatment approaches for primary uveal melanoma that have a reduced side effect profile. More importantly, metastatic disease occurs in nearly 50% of patients with uveal melanoma, and historically there have been no therapeutic options for metastatic uveal melanoma that increased life expectancy. This article will explore new approaches for primary disease and treatment for metastatic disease — some currently in clinical trials and others that are already approved by the US Food and Drug Administration (FDA).

Tumor size is a major determining factor of patient eligibility for plaque brachytherapy.³ The largest commercially available eye-plaque is 22 mm; given the recommendation for 2 mm margins, only lesions with a maximum largest basal diameter of about 18 mm can be treated unless a custom eye plaque is made.⁴ Custom eye plaques remain an option, but they introduce a greater potential for toxicity with the need for higher radiation doses to ophthalmic structures at risk.⁵ In efforts to offer globe preservation for patients with tumors at the upper size limit of commercially available plaques, staged eye plaque brachytherapy has been reported as a novel technique that uses a fractionated approach to maintain appropriate coverage without exceeding scleral dose constraints.⁴ With this technique, the dose needed for adequate tumor control is split into multiple fractions applied at different visits, which enables time for normal tissue repair in between applications.⁴

Ideaya Biosciences currently has a phase 2 clinical trial assessing the use of darovasertib, a protein kinase C (PKC) inhibitor with antineoplastic activity, as monotherapy for neoadjuvant and adjuvant uveal melanoma in cMET-driven and KRAS-mutation tumors, in addition to exploring darovasertib combined with crizotinib (Xalkori; Pfizer) to treat metastatic disease.⁶ This approach was ignited upon observing tumor shrinkage in 2 neoadjuvant uveal melanoma patients and can potentially improve current primary treatment paradigms in the future.⁶

Recent studies have evaluated the benefit of prophylactic anti-VEGF medications to prevent or reduce the development of radiation retinopathy.^7,8 Although prophylactic injections have not yet been evaluated in a prospective manner on a large scale, this is set to change in the new DRCR study, Protocol AL, where steroids and anti-VEGF medications will be evaluated.

NEW DRUG TREATMENTS

An alternative approach to reducing radiation side effects and maximizing visual outcomes involves using a different form of treatment. Belzupacap sarotalocan (bel-sar; also known as AU-011) is a papillomavirus-like particle drug conjugate from Aura Biosciences currently under investigation in a phase 2b/3 clinical trial. This treatment is for primary indeterminate lesions and small choroidal melanoma that have demonstrated growth over time. The nanoparticle selectively binds to modified heparin sulfate proteoglycans that are upregulated in tumor cells⁹ and works via direct cytotoxic effects on tumor cells and induction of long-term antitumor immunity.¹⁰

Bel-sar is administered by either an intravitreal or suprachoroidal injection followed by activation with infrared light. Specific drug delivery to malignant cells is enabled along with a proimmunogenic cell death that can generate long-term antitumor immunity.¹¹ To improve drug delivery, suprachoroidal space injection is the administration method under exploration for bel-sar, which provides targeted posterior segment delivery without affecting anterior segment tissues, offering potential safety benefits.¹² The suprachoroidal route of administration for bel-sar is believed to potentially improve bioavailability and reduce the dose needed which could yield a better benefit-risk profile.⁹

Metastatic disease occurs in up to 50% of patients with uveal melanoma and lack of effective therapies have resulted in a poor prognosis.¹³ Although treatment approaches have been limited, the first FDA-approved medication to treat metastatic uveal melanoma entered the market in 2022. Tebentafusp (Kimmtrak; Immunocore Ltd) is a bispecific fusion protein which targets gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain that redirects T cells to kill gp100-expressing tumor cells.¹⁴ This medication is restricted to HLA-A*02:01 positive patients, which occurs in about 50% of patients with metastatic uveal melanoma.¹⁵ The therapeutic benefit of tebentafusp has been associated with longer overall survival than control therapy among previously untreated patients, even in patients without radiographic evidence of disease regression. Circulating tumor DNA (ctDNA) refers to fragments of DNA from malignant tumors that are found in the bloodstream. Patients with increased overall survival on tebentafusp were noted to have better reduction or clearance of ctDNA, regardless of the radiographic tumor response.¹⁶ This suggests that early reduction of ctDNA may be a good indicator of future survival, and lack of radiographic response or increase in tumor size may not represent ineffective treatment as previously thought.

Although tebentafusp is the only FDA-approved medication on the market to treat metastatic uveal melanoma, several clinical trials are in progress with therapeutic options that display potential benefits. Darovasertib has been shown to lead to tumor regression,¹⁷ especially in combination with crizotinib, which works as an inhibitor of tyrosine kinase receptor, prevents the expression of oncogenic fusion proteins from activating gene expression, and impairs cell proliferation and survival.¹⁸ Investigator-reviewed data of the synergistic effects of darovasertib with crizotinib from phase 2 of the clinical trial reported tumor shrinkage in 89% of patients, an overall response rate of 50% as first-line treatment, and a 31% overall response rate as in any-line metastatic uveal melanoma.⁶ Interestingly, 5 patients with previously untreated primary uveal melanoma demonstrated a response to this treatment. Further investigations are under way to assess the effectiveness of this treatment for metastatic disease as well as for primary intraocular disease.

GENETIC APPROACHES

Although the prognosis for cutaneous melanoma has dramatically improved in response to the development and increased availability of checkpoint inhibitors, these medications have not improved the overall survival of patients with metastatic uveal melanoma. It has been suggested that a low tumor mutational burden and not having surface receptors regulated by any of the checkpoint inhibitors are potential reasons for why this class of medications has not shown a significant response in uveal melanoma. Further studies have demonstrated that uveal melanoma may express lymphocyte-activation gene 3 (LAG-3) receptors at a higher rate than programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). As a result, a clinical trial looking at the combination of nivolumab plus relatlimab (Opdualag; Bristol-Myers Squibb), a LAG-3 blocking antibody for metastatic uveal melanoma, has gotten under way.¹⁹ This combination acts on distinct immune checkpoints, contributing to T-cell exhaustion.²⁰

As the information around molecular prognostication has improved and the understanding of mutations that indicate increased risk has developed, a group of patients at increased risk for metastasis has been identified. As a result, there has been increased focus not only on identifying treatments for primary intraocular and metastatic disease but also in the neoadjuvant setting to reduce the risk of metastasis in patients with aggressive primary lesions. Sunitinib maleate (Sutent; Pfizer) is an oral multitarget tyrosine kinase inhibitor that is FDA approved to treat gastrointestinal stromal tumors, neuroendocrine tumors, and renal cell carcinoma²¹ and is now under investigation to treat high-risk patients with uveal melanoma. In a retrospective cohort study, adjuvant sunitinib was associated with a better overall survival when compared with institutional controls who shared the same risk factors.²² A phase 2 clinical trial assessing the effects of adjuvant sunitinib or valproic acid to prevent high-risk uveal melanoma from metastasizing is currently under way. Early results of this ongoing trial indicate that sunitinib tends to reduce the risk of metastasis, especially in younger patients.²³

CONCLUSION

Various therapeutic options are currently under investigation to treat patients with primary uveal melanoma, those at high-risk for metastasis, or those who have developed metastatic uveal melanoma. As a result, the prognosis of affected patients in the future may look brighter. Many of the current clinical trials are in phase 2, but the results are encouraging thus far. If these drugs prove to be effective and are approved for use, there is a potential to improve outcomes of patients for a disease that has historically had a dismal prognosis. RP

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