Background: Preclinical models support a combinatorial role of high-dose irradiation with immunotherapy. Multi-site stereotactic body radiotherapy (SBRT) with pembrolizumab (P) has been demonstrated as safe in advanced solid tumors. Here, we report extended follow-up of treated metastasis control (TMC), progression-free survival (PFS), overall survival (OS) and describe transcriptional changes associated with TMC, PFS and OS. Methods: Patients (pts) with AST received 3-5 SBRT doses (30-50 Gy total dose) to 2-4 metastases based on anatomic location. Pembrolizumab (200 mg IV Q3W) began one week following the final SBRT. Mets >65cc received partial-tumor SBRT. Response was measured by RECIST principles. TMC, PFS, and OS were estimated by Kaplan-Meier method. Pre- and post-SBRT biopsies from 24 pts were assayed via RNA microarray. Results: 68 pts (140 mets) were enrolled. 18 pts (21 mets) received partial tumor SBRT. Median volume of partially irradiated tumors was 121cc vs 7cc of fully irradiated (p=0.001). Median follow-up was 8.4 months (mo; range 1.1-24.2). 1-year TMC was 89.6%. At 12 mo TMC of partial versus full tumor irradiation was not significantly different (p=0.09). On multiple Cox regression, metastasis size, histology, volume of irradiated tumor and PD-L1 status were not predictive of TMC, PFS or OS. However, irradiated metastasis response predicted OS (HR = 0.37; 95% CI, 0.19-0.71; p = 0.003). Pts with irradiated met PR or CR had 17.8 mo median OS vs 9.1 and 3.4 in pts with mixed response or PD, respectively (p=0.005). Unsupervised transcriptional analysis of tumor biopsies demonstrated that the magnitude of DNA repair and innate/adaptive immune pathways induced in irradiated mets following SBRT was significantly associated with irradiated met response (p=0.009) and OS (p=0.007) to SBRT+P. Conclusions: Partial tumor SBRT+P approximates full tumor SBRT+P despite major differences in tumor volume. Transcriptional changes and clinical response of irradiated mets to SBRT+P are highly predictive of OS. Further research is needed to optimize immuno-radiotherapy. Clinical trial information: NCT02608385