Predictors of immunotherapy benefit in Merkel cell carcinoma

Abstract

Merkel cell carcinoma is a rare cancer for which immune checkpoint blockade is standard-of-care for recurrent/metastatic disease. However, not all patients benefit from immunotherapy. A greater understanding of molecular mechanisms and predictive biomarkers are unmet needs. We retrospectively analyzed electronic health records and next-generation sequencing data of 45 patients treated at our institution from 2013 to 2020 to understand clinical and genomic correlates of benefit from immunotherapy. Our cohort predominantly included individuals with stage III disease at primary disease diagnosis and individuals with stage IV disease at recurrent/metastatic disease diagnosis. Most received immunotherapy as first-line treatment. 43% experienced objective response (median duration of response 24.2 months, 95% confidence interval 8.8-not reached). Median overall survival was 15.5 months (95% confidence interval 9.0-28.7) (median follow-up 25.2 months). Less advanced stage at primary disease diagnosis and shorter disease-free interval between completion of initial treatment and recurrence were each associated with greater odds of response (odds ratio of 0.06, p = 0.04 for stage; odds ratio 0.75, p = 0.05 for disease-free interval). Single-nucleotide variants in ARID2 and NTRK1 were associated with response (p = 0.05, without Bonferroni correction), while none of Merkel cell polyomavirus status, total mutational burden, ultraviolet mutational signatures, and copy-number alterations predicted outcomes. Patients with shorter disease-free interval may be particularly suitable immunotherapy candidates. Our molecular findings point to ARID2 and NTRK1 as potential predictive markers and/or therapeutic targets (e.g., with Trk inhibitors), although this association needs to be confirmed in a larger sample.

Keywords: Merkel cell carcinoma; cancer; genomics; immunotherapy; precision medicine.

Figure 1. Survival outcomes in patients with Merkel cell carcinoma treated with an immune checkpoint inhibitor.

(A) Overall survival (in months) among 45 patients with Merkel cell carcinoma treated with an immune checkpoint inhibitor. Dotted lines represent 95% confidence intervals. (B) Overall survival among patients with Merkel cell carcinoma based on response to immune checkpoint inhibitor. CI = confidence interval, HR = hazard ratio.

Figure 2. Mutational landscape by response to immune checkpoint inhibitor.

Mutational plot showing the most frequently mutated genes (top-to-bottom, ≥15%) ordered by response and by total number of SNVs, with gene frequency listed at left (%), and Fisher exact test p values (response versus no response) at right. Asterisks denote values less than 0.05 (significant before Bonferroni correction, for which cutoff for significance is 0.0001 for our panel of 447 genes). The bar graph at top shows the total number of panel single nucleotide variants detected per sample by mutation signature. Blank MCPyV and TMB denote unknown values. LR = locoregional recurrence; MCPyV = Merkel cell polyomavirus status; MR = metastatic recurrence; P = primary site; SNV = single nucleotide variant; TMB = total mutational burden in mutations per Mb.

Figure 3. Copy-number variants by response to immune checkpoint inhibitor.

Copy-number variants arranged by chromosomal band loci. Each column represents an individual tumor and corresponding gene loci. Chart at top shows total number of genes with copy number variants per sample. Patient samples presented by response and in order of descending total number of CNVs. CNV = copy-number variant.