Background: SBRT is a standard treatment option for oligometastatic CRC and is associated with an increase in immunogenic antigen release and influx of immune cells. We hypothesized that radiation would enhance the immunogenicity of pMMR CRC and potentiate the effectiveness of PD-1 blockade. This phase Ib study examined the safety and efficacy of the sequential combination of SBRT and Pem in patients (pts) undergoing resection of their disease. Additionally, the accumulation and proteolysis of versican (VCAN), an immunoregulatory tumor matrix proteoglycan was examined as a novel immunotherapy biomarker. Proteolysis of VCAN results in the release of an immunostimulatory fragment, versikine. Cancers with low VCAN and high versikine (VCAN proteolysis predominant (VPP)) are hypothesized to respond better to immunotherapies. Methods: Eligibility criteria included resectable liver-confined metastatic pMMR CRC. Prior surgery and systemic chemotherapy were allowed. Subjects received sequential SBRT and cycle 1 of Pem prior to operative management and adjuvant Pem. The primary objectives were to determine the safety/tolerability of this regimen and the recurrence free survival (RFS) at 1 year following operative management. Correlative studies examined tumor infiltrating CD8+ T lymphocytes (TILs), VCAN, and versikine using immunohistochemistry. Results: 15 pts (median age 61.5 [range 39-69], 26% female) were enrolled. All pts had prior FOLFOX. The number of liver lesions ranged from 1-6. SBRT median dose was 50 Gy (40-60 Gy) to 1-2 liver lesions. Grade 3/4 AEs included one case of biliary tract injury and biloma, and one case of G3 hypophosphatemia. No grade 3/4 immune-related AEs occurred. All pts completed a minimum follow-up of 1 year post resection (median follow-up 41 months [range 15-64]). In the intention to treat analysis, the 1 year RFS was 67% (historic control 50%), 40% of patients remained cancer free, and 67% of pts are still alive. 2 of 3 pts with BRAF V600E mutations have had early recurrences. 2 pts had VCAN high tumors and both recurred prior to 1 year. 6 pts had VPP cancers and 83% were recurrence free at 1 year and 66% are currently without evidence of cancer. Conclusions: The combination of SBRT with Pem was well tolerated with no signal of increased immunotherapy-related toxicity. This study met its primary endpoint and this regimen deserves further investigation in confirmatory studies. Additionally, VCAN accumulation and proteolysis are promising biomarkers in this setting. Clinical trial information: NCT02837263.