Histologic and Immunologic Factors Associated with Response to Immune Checkpoint Inhibitors in Advanced Sarcoma

Abstract Purpose: To characterize factors associated with response to immune checkpoint inhibitors (ICI) in advanced sarcoma. Experimental Design: This is a retrospective study with a cohort of 216 patients with advanced sarcoma treated with ICI between 2016 and 2023 at Stanford Health Care. Overall survival, progression-free survival (PFS), objective response rates (ORR) per RECIST criteria, and reason for ICI discontinuation were analyzed across histologic subtypes, ICI regimens, tumor mutational burden, and PD-L1 expression. Results: The overall ORR in the cohort was 16.7%. The histologic subtypes with the highest ORR were Kaposi sarcoma (KS, 66.7%), alveolar soft part sarcoma (ASPS, 50%), angiosarcoma (33.3%), myxofibrosarcoma (MFS, 28.6%), and undifferentiated pleomorphic sarcoma (UPS, 27.8%). The subtypes with the lowest ORR were osteosarcoma (0%), synovial sarcoma (0%), and liposarcoma (3.7%). The subtypes with the highest median PFS were KS (median not reached), ASPS (median not reached), MFS (27.4 months), and UPS (11.3 months). The ORR for sarcomas with PD-L1 ≥ 1% was 27.8% (P = 0.02), whereas the ORR for sarcomas with tumor mutational burden ≥10 mutations per megabase of DNA was 28.6% (P = 0.20). Conclusions: ORR and PFS were highly variable across sarcoma histologic subtypes. In this large analysis, KS, ASPS, angiosarcoma, MFS, and UPS demonstrated the highest ORR and longest PFS while osteosarcoma, synovial sarcoma, and liposarcoma had the lowest ORR and shortest PFS. PD-L1 expression was also associated with increased ORR. Our findings provide further insight into understanding the sarcoma histologic and immunologic factors that correspond with response to ICI.