Response to Anti-PD-1 in Uveal Melanoma Without High-Volume Liver Metastasis

Abstract

Background: Uveal melanoma (UM) is an uncommon melanoma subtype with poor prognosis. Agents that have transformed the management of cutaneous melanoma have made minimal inroads in UM. Methods: We conducted a single-arm phase II study of pembrolizumab in patients with metastatic UM and performed bioinformatics analyses of publicly available datasets to characterize the activity of anti-PD-1 in this setting and to understand the mutational and immunologic profile of this disease. Results: A total of 5 patients received pembrolizumab in this study. Median overall survival was not reached, and median progression-free survival was 11.0 months. One patient experienced a complete response after one dose and 2 others experienced prolonged stable disease (20% response rate, 60% clinical benefit rate); 2 additional patients had rapidly progressing disease. Notably, the patients who benefited had either no liver metastases or small-volume disease, whereas patients with rapidly progressing disease had bulky liver involvement. We performed a bioinformatics analysis of The Cancer Genome Atlas for UM and confirmed a low mutation burden and low rates of T-cell inflammation. Note that the lack of T-cell inflammation strongly correlated with MYC pathway overexpression. Conclusions: Anti-PD-1-based therapy may cause clinical benefit in metastatic UM, seemingly more often in patients without bulky liver metastases. Lack of mutation burden and T-cell infiltration and MYC overexpression may be factors limiting therapeutic responses.ClinicalTrials.gov identifier: NCT02359851.

Copyright © 2019 by the National Comprehensive Cancer Network.

Figures

Figure 1A

Progression-free survival

Figure 1B:

Overall survival

Figure 2. Non-synonymous tumor mutational load comparing skin cutaneous metastatic and uveal melanoma.

The vertical axis shows the total number of predicted protein-changing somatic mutations (single nucleotide variants and small insertions/deletions). Each data point represents one sample. The non-T cell-inflamed (blue), intermediate (green) and T cell-inflamed (red) tumor group are shown on the horizontal axis.

Figure 3A. MYC gene and target molecule expression by T cell-inflamed gene signature in uveal melanoma.

Top to bottom: annotation bar showing the non-T cell-inflamed (blue), intermediate (green) and T cell-inflamed (red) tumor group of uveal melanoma samples from TCGA database; boxplot showing the expression distribution of 21 annotated MYC signaling target molecules (CDC25A, CDK2, ECSIT, FASN, FSTL1, FUT3, GGH, HMGA1, IMPA2, IRS1, JARID2, LAMB2, MAG, MYC, MYH7, PYCR1, RTN2, RUVBL1, SLC16A1, SOX9, TKT) defined in Ingenuity Knowledgebase™ (QIAGEN Inc.) based on experimental evidence; small heatmap panel showing the expression pattern of MYC gene; larger heatmap panel showing the expression pattern of T cell-inflamed gene signature. The color key of the heatmaps are shown to the right corner of the heatmaps, with blue indicating lower expression, and red indicating higher expression.

Figure 3B. MYC gene expression in the non-T cell-inflamed (blue), intermediate (green) and T cell-inflamed (red) tumor group.

P-value was computed using two-sided Student’s t-test comparing non-T cell-inflamed group with intermediate and T cell-inflamed groups combined due to limited number of samples in the T cell-inflamed tumor group.