Patterns of Response to Immune Checkpoint Inhibitors in Sarcomas With High Tumor Burden and/or Mismatch Repair Deficiency.

Abstract

Purpose: Immune checkpoint inhibitors (ICIs) are frequently used to treat metastatic solid tumors characterized by high tumor mutational burden (TMB) and/or mismatch repair (MMR) deficiency. Most of the literature on their benefit is about carcinomas and melanomas, but little is known about their effects on sarcomas in these settings. In this study, we examined the response pattern to ICI-based therapy in sarcomas with those characteristics.

Methods: Patients treated in our institution with ICI-based therapy for sarcomas with high TMB and/or MMR deficiency were identified. We analyzed the main outcome of interest, radiologic response to therapy, alongside clinical information including treatment type and duration, histologic diagnosis, germline and somatic MMR deficiency, and ultraviolet A (UVA) mutational signature.

Results: Among 17 patients identified, TMB ranged from 9 to 151 mut/Mb. Radiologic response was observed in 6 patients. TMB of responding patients ranged from 15-75 mut/Mb. The only responding case of MMR deficiency was seen in the one patient diagnosed with Lynch syndrome. By contrast, none of the five cases of sporadic MMR deficiency responded. The three complete responses were seen in MMR-proficient tumors associated with UVA signature and high TMB.

Conclusion: Overall, sarcomas with MMR deficiency and/or high TMB show a heterogeneous pattern of responses to ICI-based therapy. Other cellular and molecular factors, such as histology, germline factors, and mutation signatures, likely contribute to the response to ICI treatment in sarcomas.