The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy

Abstract

Purpose: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy, which has demonstrated sensitivity to immune checkpoint inhibitor therapy. Here, we perform the largest genomics study in MCC to date to characterize the molecular landscape and evaluate for clinical and molecular correlates to immune checkpoint inhibitor response.

Experimental design: Comprehensive molecular profiling was performed on 317 tumors from patients with MCC, including the evaluation of oncogenic mutations, tumor mutational burden (TMB), mutational signatures, and the Merkel cell polyomavirus (MCPyV). For a subset of 57 patients, a retrospective analysis was conducted to evaluate for clinical and molecular correlates to immune checkpoint inhibitor response and disease survival.

Results: Genomic analyses revealed a bimodal distribution in TMB, with 2 molecularly distinct subgroups. Ninety-four percent (n = 110) of TMB-high specimens exhibited an ultraviolet light (UV) mutational signature. MCPyV genomic DNA sequences were not identified in any TMB-high cases (0/117), but were in 63% (110/175) of TMB-low cases. For 36 evaluable patients treated with checkpoint inhibitors, the overall response rate was 44% and response correlated with survival at time of review (100% vs. 20%, P < 0.001). Response rate was 50% in TMB-high/UV-driven and 41% in TMB-low/MCPyV-positive tumors (P = 0.63). Response rate was significantly correlated with line of therapy: 75% in first-line, 39% in second-line, and 18% in third-line or beyond (P = 0.0066). PD-1, but not PD-L1, expression was associated with immunotherapy response (77% vs. 21%, P = 0.00598, for PD-1 positive and negative, respectively).

Conclusions: We provide a comprehensive genomic landscape of MCC and demonstrate clinicogenomic associates of immunotherapy response.

Figure 1.. Genomic Landscape of Merkel Cell Carcinoma.

A) Distribution of Merkel cell carcinomas with high, intermediate and low tumor mutational burden (N = 317). B) Violin plots of the TMB distribution for the entire cohort and by molecular subgroup; the widest point occurs at the TMB with the largest number of samples. C) Genes most frequently affected by putatively pathogenic mutation in TMB-High Merkel cell carcinoma and D) TMB-Low Merkel cell carcinoma.

Figure 2.. Molecular subtypes of Merkel cell carcinoma.

A) Oncoprint of co-occurrence of TMB status, dominant mutational signature, viral status, and altered gene demonstrating mutual exclusivity of MCV integration and UV damage. Each column corresponds to one unique MCC specimen. Only alterations that are known or likely to be oncogenic are included. Tumors are sorted in descending order by TMB from the left. B) Clustering of prevalence of recurrent gene alterations in selected tumor types show that molecular subgroups of Merkel cell carcinoma cluster separately as compared to other tumor types. The TMB high subgroup clusters primarily with other neuroendocrine tumor types. The TMB low subgroup clusters primarily with other viral-driven tumor histologies.

Figure 3.. Response to treatment with immune checkpoint inhibitors and patient survival

A) Kaplan-Meier plot of overall survival in immunotherapy responders vs. those with progressive disease. Patients with favorable immunotherapy response have dramatically prolonged survival from the time of advanced/metastatic diagnosis compared to immunotherapy-treated patients without a good response. Patients were considered to be responders if they were assessed as having a complete response (CR), partial response (PR), or stable disease for at least six months. B) Relationship between tumor mutation burden, mutational signature, viral status (by NGS only), PD-L1 expression, PD-1 expression, response to therapy, and selected genomic alterations among 57 patients in clinical cohort.