Clinical Presentation and Workup

Approximately two-thirds of patients present due to changes in their vision; approximately a third are asymptomatic and the disease is discovered on routine eye examination. A comprehensive eye examination is absolutely vital to the evaluation and staging of patients, and this is detailed in the NCCN Guidelines recommendations.

“Biopsy is typically not performed to confirm diagnosis unless the clinical diagnosis is in question. However, a biopsy may be performed for prognostic purposes through molecular testing,” Dr. Barker said.

There are 2 primary staging systems for uveal melanoma, and both are based on tumor height and largest base diameter. The first staging system was the Collaborative Ocular Melanoma Study (COMS), followed by the AJCC staging system. In the COMS staging system, tumors are described as either small, medium, or large, whereas in the AJCC system they are staged as T1, T2, T3, or T4. Some overlap exists between the COMS small and medium categories and the AJCC T1 and T2 categories, and between the COMS large category and AJCC T3 and T4 categories. The AJCC system also incorporates the extent of primary tumor involvement through T-stage modifiers. Presence of ciliary body involvement or extraocular extension of the primary tumor is associated with T-stage modifiers A, B, C, D, or E.

COMS Trials Inform Treatment

The COMS was a series of landmark trials that helped define the management of primary uveal melanoma (Figure 1). These findings have informed the new NCCN Guidelines for Uveal Melanoma.

The first COMS study, conducted in the late 1980s, elucidated the natural history of small uveal melanomas and determined the safety of observation, with treatment at the time of tumor growth. The second trial of medium-sized tumors randomized patients to definitive plaque brachytherapy or enucleation, the standard treatment. The third trial randomized patients with large uveal melanomas to

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The Collaborative Ocular Melanoma Study (COMS) helped define primary tumor management.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5S; 10.6004/jnccn.2018.0042

The COMS small tumor trial showed that melanoma-related mortality was low for this subset (<4% approximately 8 years after diagnosis) and that the growth of small uveal melanomas is rare (≈30% at 5 years).² Characteristics that predicted for growth are programmed into the risk assessment of these patients.³ Tumors that grow are primarily treated with RT or laser therapy.

The COMS medium tumor trial, conducted during a 10-year span, found no difference in overall survival between patients randomized to definitive plaque brachytherapy or enucleation, and no difference in cancer mortality.⁴ Survival at 5 years was approximately 80%, and approached 60% at 12 years. Predictors of melanoma-related mortality included advanced age and larger tumor size.

“A series of investigations found that quality of life, however, was different between the 2 groups,”⁵ Dr. Barker added. “Patients preserved vision if they underwent brachytherapy versus enucleation. However, patients treated with brachytherapy tended to have more anxiety than those who underwent enucleation.”

Finally, the COMS large tumor trial found no difference in survival between neoadjuvant RT followed by enucleation, or enucleation alone⁶; 5-year survival was approximately 60% and 10-year survival approached 40%. Again, predictors of melanoma-specific mortality included advanced age and larger tumors. The study did find a lower risk for orbital recurrence in patients who received neoadjuvant RT, but this difference was not clinically significant; thus, neoadjuvant RT is not part of standard management. Particle beam therapy may be an alternative to enucleation in select patients with large tumors, but this was not studied by the COMS group.

Management of primary uveal melanoma is predominantly based on tumor size. The NCCN Guidelines give several options for any given size tumor, generally including RT, laser therapy, and surgical removal, with some additional adjuvant options in select situations.

“In this day and age, enucleation is only being performed for large tumors,” Dr. Barker indicated. As for risk assessment, he said the data are insufficient for the use of composite measures, therefore, “we generally look at variables in isolation.”

Genomics and Other Factors Associated With Risk of Metastasis

Cutaneous and uveal melanomas are different genetically in that cutaneous disease harbors far more mutations, and these are different from those in uveal melanoma. “As I mentioned, genomic testing is predictive in cutaneous melanoma. For instance, the BRAF mutation is a predictor of response to RAF inhibition. In addition, the overall number of mutations seen in cutaneous melanoma may be a predictor of the response to therapy,” Dr. Barker noted. “On the other hand, in uveal melanomas, specific genomic alterations are not associated with response to treatment, but they are associated with prognosis and the probability of metastasis.”

Along with gene expression profile and specific genetic alterations (eg, BAP1 is associated with worse survival than EIFAX1, which is associated with virtually no risk), other risk factors for metastasis include certain clinical factors (T stage and T-stage modifiers, ciliary body involvement, extraocular extension), histopathologic factors (spindle vs epithelioid cell type), and cytogenetics (status of chromosomes 3, 5, and 8). These factors can be used in risk stratification.

Follow-Up Imaging and Treatment of Metastases

Although whole-body imaging is recommended for surveillance in patients with high-risk cutaneous melanoma, uveal melanoma recurrence most often occurs in the liver (Figure 2). For this reason, surveillance of patients with high-risk uveal melanoma should include specific imaging of the liver.

“The NCCN Guidelines recommend surveillance according to risk for metastasis. These risk groups help clinicians identify how often imaging should be performed in their surveillance strategy,” Dr. Barker stated.

For distant metastasis, no single systemic therapy has proven to be most effective for uveal melanoma. Thus, the NCCN Guidelines encourage clinical trial participation when possible. Although drugs that are effective in cutaneous melanoma are far less effective for uveal disease, they can still be considered. Liver-directed therapy is also part of management, which includes resection, ablation, chemoembolization, radioembolization, and regional perfusion.

Second-Line Therapies for Advanced Disease

With the approval of PD-1 checkpoint inhibitors and targeted agents for first-line treatment of advanced/metastatic disease, the direction for second-line therapy is less certain because most of the data for these agents come from studies of previously untreated patients.

“Despite the rapid pace of development of novel therapies for melanoma, for second-line treatment of advanced disease it doesn't take long to feel we are back at the beginning—with not many options and questionable choices,” she said.

Dr. Salama then listed several factors to consider when selecting second-line therapy, including disease characteristics (eg, mutation status of BRAF, and perhaps NRAS and KIT), prior therapies (eg, response, setting, and timing of relapse), and prior toxicities. “Generally, you can switch classes. Sometimes you can go back to the same agent, particularly if there has been a long disease-free interval or lack

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Follow-up imaging after treatment of the primary tumor is based on most likely site of metastatic recurrence.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5S; 10.6004/jnccn.2018.0042

Among the systemic therapy options in the second or subsequent line of treatment are anti–PD-1 as monotherapy if not given for initial treatment (ie, nivolumab, pembrolizumab); ipilimumab alone or with nivolumab; targeted therapy based on BRAF or KIT mutation status; high-dose interleukin-2; and best supportive care.

Checkpoint Inhibitors in the Second Line

“Many patients have already received anti–PD-1 in the frontline,” Dr. Salama noted. “We've tried to list many of the same agents as for the frontline, highlighting the issue of switching class if possible and potentially looking at other agents.”

It is reasonable for patients with a good performance status progressing on anti–PD-1 therapy to consider dual checkpoint inhibitors. If at least 3 months have elapsed since frontline therapy was discontinued, reintroduction of the same agent or class should be considered, the NCCN Guidelines state.

Prospective data in the frontline setting are very limited, but pembrolizumab after progression on ipilimumab has shown some benefit.⁷ “However, now that patients receive anti–PD-1 agents in the frontline, we have no [relevant] data for the second-line setting,” she continued. “What is available are some retrospective series, overall with small numbers of patients.”

Some retrospective studies have found modest benefit for ipilimumab after anti–PD-1, and perhaps slightly higher activity for the combination of ipilimumab and anti–PD-1. Although the response rate is approximately 60% in the first-line setting, these series suggest that the activity of dual checkpoint inhibition is diminished in the second-line setting, Dr. Salama said.

Another concern is increased toxicity with dual therapy, which appears to be similar irrespective of disease setting. In a study from Memorial Sloan Kettering Cancer Center, 91% of patients on ipilimumab/nivolumab had a clinically significant adverse event, two-thirds sought emergency medical care, and many were hospitalized.⁸

Targeted Therapies in the Second Line

Sequencing also involves targeted agents, and again, the data for guidance are scarce. In a study of 274 patients with BRAF-mutated metastatic melanoma, those receiving a BRAF inhibitor in the frontline and ipilimumab in the second-line had no clinical responses.⁹ More recent studies have evaluated sequencing with anti–PD-1 agents. In a retrospective study of 114 patients, no differences in survival were shown between patients receiving either BRAF/MEK-targeted therapy or anti–PD-1 agents first, but subsequent anti–PD-1 therapy given after ipilimumab showed some evidence of diminished efficacy versus the reverse, Dr. Salama said.¹⁰

Regarding choice of drugs and whether they should be given in combination or sequenced, there are still no definitive directives. Currently, agents being investigated in clinical trials include concurrent BRAF/MEK inhibition plus an anti–PD-1 or the sequential administration of an BRAF/MEK inhibitor before an anti–PD-1 (+ ipilimumab) or the reverse. “We probably have more questions than answers at this point,” Dr. Salama acknowledged.

To help determine the best sequence for BRAF-mutated metastatic melanoma, the randomized phase III ECOG-ACRIN EA6134 study will compare dabrafenib/trametinib and ipilimumab/nivolumab on progression, and the same in reverse sequence (ClinicalTrials.gov identifier: NCT02224781).

Extrapolating From the First-Line Setting

“Meanwhile, the choice of second-line therapy is largely extrapolated from the first-line setting,” Dr. Salama concluded (Figure 3). “There's no perfect treatment…switching the class of agent is usually the best course. The main factors we now consider are clinical when selecting a therapy. No perfect therapy exists, even in the frontline. Based on all these factors, we have to choose a therapy that best fits patients' clinical needs.”

Anti–PD-1 monotherapy produces high response rates but can take some time to work; responses can

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How to choose therapy in 2018? Largely extrapolated from the first-line setting.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5S; 10.6004/jnccn.2018.0042