What are the treatment options and prognoses for different types of ocular melanoma, including uveal and conjunctival melanoma?

Treatment and Prognosis of Ocular Melanoma

Uveal Melanoma Treatment

Metastatic Uveal Melanoma - HLA-A*02:01-Positive Patients

HLA-A*02:01-positive patients with metastatic uveal melanoma should be treated with tebentafusp (20 mg on day 1,30 mg on day 8, then 68 mg weekly until progression). 1

• This represents the only FDA-approved systemic therapy with proven survival benefit for metastatic uveal melanoma 1
• Tebentafusp demonstrated significant improvements in overall survival (HR 0.51; 95% CI, 0.37-0.71) and progression-free survival (HR 0.73; 95% CI, 0.58-0.94) 1
• The 1-year overall survival benefit is clinically meaningful despite substantial grade 3-4 adverse events, which become more manageable over time 1
• Higher disease control rates with tebentafusp may explain improved survival despite low objective response rates 1

Metastatic Uveal Melanoma - All Other Patients

For patients who are not HLA-A*02:01-positive or otherwise ineligible for tebentafusp, enrollment in clinical trials is strongly recommended as no specific systemic therapy can be recommended. 1

• No standard systemic therapy has demonstrated survival benefit in this population 1
• Historical chemotherapy approaches (selumetinib, dacarbazine) showed progression-free survival improvements but no overall survival benefit 1
• The SUMIT trial confirmed that selumetinib plus dacarbazine provided no significant benefit over placebo plus dacarbazine (PFS HR 0.78, P=0.32; OS HR 0.75, P=0.40) 1

Primary Uveal Melanoma Treatment

Primary uveal melanoma achieves local control in >90% of patients using radiation therapy, enucleation, or local resection, tailored to tumor size and location. 2, 3

• Radiation options include plaque brachytherapy (iodine-125, ruthenium-106, palladium-103) or teletherapy (proton beam, stereotactic radiosurgery) 4
• Conservative eye-preserving treatments are increasingly utilized 5, 3
• Treatment selection depends on tumor size, location (iris vs. ciliary body vs. choroid), and patient preferences 6

Conjunctival Melanoma Treatment

Conjunctival melanoma should be treated with wide local excision combined with adjuvant therapy including brachytherapy, cryotherapy, or topical chemotherapy. 5

• Standard approach is surgical excision with adjuvant modalities 5
• For metastatic disease, treatment follows cutaneous melanoma guidelines (see below) 5

Mucosal Melanoma Treatment

Patients with unresectable/metastatic mucosal melanoma should be offered the same systemic therapies as cutaneous melanoma: anti-PD-1 monotherapy (nivolumab or pembrolizumab), combination immunotherapy (nivolumab plus ipilimumab), or BRAF/MEK inhibitors if BRAF V600 mutant. 1

• This recommendation is based on expert consensus given the rarity of mucosal melanoma and lack of dedicated trials 1
• Clinical trial enrollment remains strongly encouraged 1
• One small phase II trial suggested benefit from temozolomide plus cisplatin in the adjuvant setting, but results are not considered generalizable 1

Prognosis

Uveal Melanoma Prognosis

Despite excellent local control rates (>90%), uveal melanoma carries a guarded long-term prognosis with 40-50% of patients developing distant metastases, predominantly in the liver. 4, 2

• Metastatic disease remains the leading cause of death among uveal melanoma patients 5
• Survival rates have remained essentially unchanged despite improvements in local treatment 4, 5
• Iris melanomas have significantly better prognosis than ciliary body or choroidal melanomas 7, 4
• Small, well-differentiated iris melanomas may remain localized for years with minimal metastatic potential 7
• Recent cytogenetic and genetic advances enable identification of tumors with high metastatic potential, though this has not yet translated to improved survival 5

Conjunctival Melanoma Prognosis

Conjunctival melanoma prognosis is poor once metastatic disease develops, with no effective systemic therapy historically available. 5

• Incidence is increasing among white adults 5
• Most cases originate from primary acquired melanosis 5
• Metastatic disease carries similarly poor prognosis as uveal melanoma 5

Key Prognostic Factors Across Ocular Melanomas

• Tumor location: Anterior segment (iris) tumors have better prognosis than posterior segment 7, 4
• Tumor size: Smaller tumors have lower metastatic potential 7
• Differentiation: Well-differentiated tumors carry better prognosis 7
• Invasion: Absence of vascular, lymphatic, or extraocular invasion indicates lower metastatic risk 7
• Early detection: Smaller tumors treated earlier may improve outcomes 4

Critical Clinical Pitfalls

• Do not use cutaneous melanoma immunotherapy regimens for uveal melanoma unless the patient is ineligible for tebentafusp and enrolled in a clinical trial, as uveal melanoma has distinct biology and poor response to standard checkpoint inhibitors 1, 2
• Always check HLA-A*02:01 status in all patients with metastatic uveal melanoma to identify tebentafusp candidates 1
• Avoid adjuvant systemic therapy for uveal melanoma outside clinical trials, as no adjuvant therapy has demonstrated benefit 1