1540 - Immuno-oncology therapy biomarkers differences between polyoma-virus positive and negative Merkel cell carcinomas

Background

Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) is detected in the majority of MCCs while MCPyV-negative cases are thought to arise through progressive accumulation of ultraviolet-light induced somatic mutations. In a non-selected cohort of stage IV MCC patients, treatment with Avelumab (an anti-PD-L1 monoclonal antibody), showed durable responses in less than a third of patients, regardless of their PD-L1 or MCV status. We hypothesized that there are significant differences in other predictors of response to I-O therapy in MCC related to their oncogenic origins.

Methods

48 MCC samples were analyzed for the presence of MCPyV using immunohistochemistry for detection of the large T-antigen (CM2B4 clone). Biomarkers of I-O therapy response included: expression of PD-L1 (IHC), total mutational burden (TMB) and microsatellite instability (MSI).

Results

Overall, MCPyV was detected in 18/48 cases using IHC (37.5%). In MCPyV-positive cases (N = 9) average TMB was 6/Mb (range 4-11/Mb), while MCPyV-negative cases (N = 21) had a significantly (p < 0.0001) higher average TMB of 25/Mb (range 4-68/Mb). No microsatellite instability was detected in any of the cases (0/22). The most commonly mutated gene in MCPyV-negative cohort was TP53 detected in 20 cases, with co-mutation of RB1 in 11 cases. Only one pathogenic mutation (ARID1A) was detected in any of the 9 MCPyV-positive cases. A single (MCPyV-positive) case exhibited PD-L1 expression in 5% of tumor cells.

Conclusions

MCPyV associated MCC was present in a significantly lower proportion of cases in our data set (37.5%) than has been reported in the general population (70-80%), potentially due to preselection of advanced disease cases. Successes of Avelumab therapy in MCC may be related to the high mutational load in MCPyV-negative cases and mediated through PD-L1+ immune cell infiltrate (IC) influence on effector (PD-1) lymphocytes, or some other mechanism. Further analysis of the status of these (and potentially other) biomarkers of response to immune check point inhibitors is recommended to refine the subgroups of patients responding to therapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Caris Life Sciences.

Funding

Caris Life Sciences.

Disclosure

Z. Gatalica: Leadership role: Caris Life Sciences. J. Xiu: Leadership role, employment: Caris Life Sciences. J. Swensen: Leadership role, employment: Caris Life Sciences. All other authors have declared no conflicts of interest.