Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab

Abstract

Purpose: We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre-and on-treatment.Patients and Methods: Pretreatment (n ¼ 78) and 8-week ontreatment (n ¼ 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti-PD-1 response.Results: Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8 þ CD3 þ PD-1 þ ) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumorinfiltrating T cells at baseline correlated with a better progression-free survival (PFS).Conclusions: We show that quantitative assessments of CD8 þ CD3 þ PD-1 þ T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti-PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.

Differential quantities of immune checkpoint-expressing CD8 T cells in soft tissue sarcoma subtypes

“…In addition, densities of intratumoral CD8+ T cells at baseline correlated with a better progression-free survival. 21 GIST, a subtype that is mostly studied separately from other STS subtypes, was not included in the aforementioned clinical studies. In silico analyses using this STS subtype have demonstrated gene expression patterns associated with immune checkpoint inhibitor responses.…”

Sarcoma treatment in the era of molecular medicine

“…In addition, recent profiling studies of immune checkpoints expression in STSs and bone sarcomas revealed their correlation with poor clinical outcomes and provide rationales for their targeting (Dancsok et al , 2019; Orth et al , 2020). In fact, a new study revealed a positive correlation between immune infiltration and response to anti‐PD‐L1 therapy in sarcoma (Keung et al , 2020). Similarly, a gene expression study in 608 tumors across STS subtypes established a classification between immune‐low, immune‐high, and vascularized phenotypes (Petitprez et al , 2020).…”

4-1BB is a target for immunotherapy in patients with undifferentiated pleomorphic sarcoma

“…Two landmark translational studies have now been published on the SARC028 trial of pembrolizumab, focused on UPS and DDLS. Baseline tumour biopsies indicated responders had higher infiltration of T lymphocytes and a higher percentage of PD-L1 + macrophages, as well as effector memory and regulatory T cells 15 . Petitprez et al carried out analyses across a number of STS cohorts, identifying five sarcoma immune classes with histological subtypes evenly distributed across the most immune rich classes.…”

“…Sarcomas are not a single disease entity but rather a group of cancers with diverse biology and consequently diverse responses to therapy. There is evidence to suggest that patients with undifferentiated pleomorphic sarcomas (UPS) in particular may be more responsive to anti-PD-1 therapy than patients with other sarcoma subtypes 12,15 . Not only is UPS the most common subtype amongst patients with ESTS, it is also associated with the highest rates of systemic relapse and poorest survival outcomes 4 .…”