Background: In studies reported to date, no objective responses have been observed with PD-1 inhibitors in advanced/metastatic CRC (mCRC) pts with microsatellite stable (MSS)/mismatch repair proficient (pMMR) tumors. About 95% of mCRC pts have this phenotype; additional strategies are needed to improve effectiveness of immunotherapies in these pts. Entinostat (ENT), an oral, class I-selective histone deacetylase inhibitor, enhances anti-PD-1 activity by downregulation of immunosuppressive cell types in the tumor microenvironment in vivo and has shown promising activity with pembrolizumab (PEMBRO) in pts with melanoma and lung cancer. This study evaluates the safety and efficacy of ENT + PEMBRO in MSS/pMMR CRC pts. Methods: This study is a multi-cohort, Simon 2-stage, phase II trial. Main eligibility criteria for pts in the CRC cohort are: documented MSS/pMMR status, ≥1 prior regimen in the metastatic setting, and no prior anti-PD-(L)1 therapy. All pts received ENT 5 mg PO QW + PEMBRO 200 mg IV Q3W. The primary endpoint is objective response rate (ORR) as assessed by irRECIST. Results of the first stage are reported. Results: 16 pts were enrolled in Stage I with a median age of 58 (range 36-68) and 4 lines of prior therapy. Median follow up is 4.7 mos. To date, 2 pts had documented pseudoprogression (1 subsequently became a confirmed PR). As of data cutoff, 6 pts (1 PR, 5 SD) remain on study (median time on treatment of 18 wks). Common ( > 15%) treatment-related AEs include fatigue (37.5%), arthralgia (18.8%), and increased alkaline phosphatase (18.8%). Grade 3/4 related AEs were observed in 3 patients, and two deaths occurred on study – one due to sepsis secondary to cholangitis and the other due to progression. Serial blood and pre-treatment biopsies were obtained in all pts, with paired post-treatment biopsies in a subset of pts. Evaluation of PD-L1 expression, gene expression, myeloid and lymphoid compartments in biospecimens is in progress. Conclusions: ENT + PEMBRO demonstrates acceptable safety and encouraging preliminary activity in a small cohort of MSS/pMMR CRC pts, a patient population in which objective responses have not been reported with PD-(L)1 monotherapy. Clinical trial information: NCT02437136