Usefulness of nivolumab plus ipilimumab immunotherapy for metastatic uveal melanoma

Abstract

A 53-year-old woman with known localized uveal melanoma presented with pain from a large destructive lesion of the left iliac bone. Biopsy confirmed metastatic melanoma, and positron emission tomography scan showed extensive osseous destruction. Because her uveal melanoma was successfully treated with brachytherapy 15 years earlier, next-generation sequencing was performed, and a GNAQ mutation proved the lesion to be of uveal origin. Uveal melanoma has a worse prognosis than cutaneous melanoma. We initiated treatment with the combination of nivolumab and ipilimumab, and after four cycles of treatment a positron emission tomography scan showed resolution of all prior lesions. The patient was then placed on maintenance therapy.

Although uveal melanoma is the most common primary intraocular malignancy in adults, it comprises <5% of all melanomas, with an approximate incidence rate in the USA of 1500 cases annually.^1,2 The rarity of uveal melanoma has prevented consensus regarding treatment of metastatic disease, and patients with metastatic uveal melanoma are routinely excluded from melanoma clinical trials because of the different tumor behavior and treatment response.^3,4 Uveal melanomas typically lack BRAF kinase mutations and do not benefit from BRAF/MEK inhibition and immunotherapy, but the efficacy of PD-1 and PD-L1 therapies in cutaneous melanoma has generated hope for these agents as potential treatment options for patients with melanoma of uveal origin.^5–7

CASE REPORT

A 53-year-old woman who had a uveal melanoma successfully treated without subsequent recurrence at age 38 presented with right-sided hip pain for 2 months. A computed tomography (CT) scan revealed a lesion in the iliac bone, and biopsy disclosed melanoma. Positron emission tomography imaging disclosed several osseous, liver, adrenal, and pulmonary metastases (Figure 1a, 1b). Next-generation sequencing identified a GNAQ mutation (c.626A > T, pQ209L), proving the lesion to be of uveal origin, and there were no alterations of BRAF, KIT, or NRAS.⁸ The patient was offered combination nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) intravenously every 3 weeks for four cycles, and radiation therapy was delivered to the left hip (15 fractions, 3750 cGy total dose). After the fourth cycle of immunotherapy, positron emission tomography/CT showed resolution of the metastases in the lungs, liver, and adrenal gland (Figure 1c, 1d). No active sites of disease were seen.

Figure 1.

(a, b) Initial positron emission tomography/CT scan showing extensive metastatic disease in the left ilium, T8, T11, liver, and left adrenal gland. (c, d) Posttreatment positron emission tomography/CT showing resolution of hypermetabolism of the osseous lesions as well as liver and adrenal metastases.

DISCUSSION

In January 2019, the National Comprehensive Cancer Network released guidance for treating metastatic uveal melanoma.⁹ Treatment of metastatic disease was presented in four main categories, with no therapy preferred over any other: clinical trial, immunotherapy, cytotoxic regimens, and targeted therapy. Cytotoxic regimens have been utilized for years but have a limited degree of activity.^10–13 Immunotherapeutic agents are generating interest for the treatment of uveal melanoma, primarily because of the response rates and survival benefits seen in the treatment of cutaneous melanoma. Currently available information suggests, unfortunately, that single-agent response rates for uveal melanoma are lower than what has been shown in the treatment of cutaneous melanoma.¹⁴ The combination of PD-1 and CTLA-4 drugs is therefore a logical approach to obtain a more robust response from currently available immunotherapeutic agents.