Background: SBRT is used to treat liver metastatic CRC, causing an increase in immunogenic antigen release and influx of responding immune cells. We hypothesize that radiation enhances the immunogenicity of MSS CRC and potentiates the effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients (pts) undergoing resection of their disease. Methods: Eligibility criteria include MSS CRC with resectable liver-confined metastatic disease. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management and adjuvant Pem. The primary objectives are to determine the safety/tolerability of this regimen and the recurrence free survival (RFS) at 1 year following clearance of metastatic disease. Correlative studies examined tumor infiltrating CD8+ T lymphocytes (TILs) and the accumulation and proteolysis of versican (VCAN), an immunoregulatory tumor matrix proteoglycan. 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. Results: 15 pts (median age 58.2 [range 38-69]) have been enrolled. All pts had prior FOLFOX. SBRT median dose was 50 Gy (40-60 Gy) to a single lesion targeted in all pts. No DLTs were observed. AEs included one case of biliary tract injury and biloma, not related to immunotherapy. No grade 3/4 immunotherapy-related AEs have occurred. 10 pts have completed a minimum follow-up of 1 year post resection. In the intention to treat analysis, the 1 year RFS was 70% (historic control 50%). 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. 4 pts had VPP cancers and all were recurrence free at 1 year. TILs in the radiated lesions were > 2 times as abundant as in the pre-treatment (tx) tissue for 50% of pts. 3 of 4 pts who had non-radiated lesions available for analysis had TILs > 2 times pre-tx in the non-radiated lesions indicating a potential abscopal effect. Conclusions: The combination of SBRT with Pem and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity and preliminary evidence of potential enhanced efficacy. Clinical trial information: NCT02837263.