Real-World Impact of Immune Checkpoint Inhibitors in Metastatic Uveal Melanoma

Abstract

Uveal melanoma (UM) is the most common intraocular malignancy in adults and shows a high rate of metastatic spread. As randomized clinical trials with immune checkpoint inhibitors (ICI) have not been performed in patients with metastatic UM, we analyzed the real-world outcomes in a nationwide population-based study. Clinical data of patients with UM were extracted from the Danish Metastatic Melanoma database, a nationwide database containing unselected records of patients diagnosed with metastatic melanoma in Denmark. Survival before (pre-ICI, n = 32) and after (post-ICI, n = 94) the approval of first-line treatment with ICI was analyzed. A partial response to first-line treatment was observed in 7% of patients treated with anti-programmed cell death protein (PD)-1 monotherapy and in 21% with combined anti-cytotoxic T lymphocyte antigen (CTLA)-4 plus anti-PD-1 therapy. Median progression-free survival was 2.5 months for patients treated in the pre-ICI era compared to 3.5 months in the post-ICI era (hazard ratio (HR) 0.43; 95% confidence interval (CI) 0.28–0.67; p < 0.001). The estimated one-year overall survival rate increased from 25.0% to 41.9% and the median overall survival improved from 7.8 months to 10.0 months, respectively (HR 0.52; 95% CI 0.34–0.79; p = 0.003). Thus, the introduction of ICI as first-line treatment appears to have significantly improved the real-world survival of patients with metastatic UM, despite relatively low response rates compared to cutaneous melanoma. With the lack of therapies proven effective in randomized trials, these data support the current treatment with ICI in patients with metastatic UM.

The Role of Immune Checkpoint Blockade in Uveal Melanoma

“…None of the 24 patients treated with ipilimumab responded to the therapy. The median PFS was 3.0 months and the median OS was 9.9 months [115].…”

“…Bol et al [115] compared the efficacy of ipilimumab, pembrolizumab, and a combined therapy with ipilimumab and nivolumab in a retrospective population-based study including 86 patients. None of the 24 patients treated with ipilimumab responded to the therapy.…”

Uveal Melanoma

“…Recent reports on a specific inhibitor of the mutated form of GNAQ [7,8] must be confirmed and translated into clinical applications. Immune checkpoint blockers that have met considerable success in the treatment of several cancers, including cutaneous melanoma [9], show very low response rates in uveal melanoma (but see [10][11][12][13][14]), likely due to the low number of neo-antigens, a consequence of a very low mutational burden [15][16][17].…”

“…In the present thematic issue, the authors of 44 articles (31 original research articles [10,13,, 11 reviews [4,11,12,14,[47][48][49][50][51][52][53], one position paper [54], and one network report [55]) give insight into the current state of our understanding of uveal melanoma biology and clinics. They also discuss opportunities for the development of new therapeutics that will hopefully soon improve the survival rates of metastatic uveal melanoma patients.…”

“…Rossi and coworkers discuss the immunology of uveal melanoma in order to create a rationale for immunotherapy [11], and Schank and Hassel give an overview of immunotherapies for uveal melanoma [12]. Bol and coworkers present an interesting real-world perspective of therapy with immune checkpoint blockers in metastatic uveal melanoma that indicates some efficacy [13]. Fountain et al show that immune checkpoint blockers might be useful in the adjuvant setting and call for clinical trials [10].…”