Abstract

e23523 Background: Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the sarcoma cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in patients with advanced cancer. Methods: Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2 nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-PFS rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling and monocyte/lymphocyte ratio (sum of cells derived from the monocytic lineage including monocytes, macrophages and myeloid dendritic cells, divided by sum of lymphocytes) were computed both on tumor and blood. Results: 61 highly pretreated (median of 5 prior lines) patients with advanced sarcomas (leiomyosarcoma: 28% and other types; 32 men [53%]; median age, 47 years [range, 37-55 years]) were enrolled in two centers (France; Spain) from 03/2020 to 04/2021. All but one received atezolizumab and 56/61 (92%) received SBRT. The most frequently irradiated site was lung (n = 36/72 lesions; 50%). Treatment-related G3 (no G4-5) toxicity was observed in one (2%) patient. Median OS and PFS were respectively 12.2 [95%CI:7-18.4] and 2.5 months [95%CI:1.2-2.6], including five (8.2%) patients with PFS > 1 year. Best overall responses consisted of PR (n = 3;5%) and SD (n = 36; 60%). Altogether, 182 (n = 86 paraffin; n = 96 freshly frozen) sequential tumor biopsies from 35 patients were successfully analyzed. None (0%) of the biopsies harbored tertiary-lymphoid structures. Tumor RNA sequencing analysis using independent immune deconvolution technics including CIBERSORTabs, EPIC and xCELL revealed an increased tumor infiltration of monocytic lineage-derived cells in patients who rapidly progressed. Differential gene expression analysis showed a significant upregulation of genes implicated in immunosuppression in unressponsive tumors. Unresponsive tumors were enriched with immune chemoattractants. We found higher monocyte/lymphocyte ratio in unresponsive patients compared to patients who had stable disease or tumor response both in the tumor and in the blood. Matched blood and tumor monocyte/lymphocyte ratios were significantly correlated in this population. Conclusions: This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying patients with advanced sarcomas most likely to respond to immuno-radiotherapy. Clinical trial information: NCT02992912 .