Background: Microsatellite stable metastatic colorectal cancer (MSS mCRC) represents a high unmet need since there are currently no approved immunotherapy options. Since the inhibition of the transforming growth factor-β (TGF-β) pathway is known to contribute to the enhancement of immunotherapy efficacy, here, we report the results of vactosertib, a potent and selective TGF-β receptor I kinase inhibitor, combined with pembrolizumab in patients with MSS mCRC. Methods: In this phase 2, open label trial, patients have received vactosertib (300 mg BID, 5 days on / 2 days off) and pembrolizumab (200 mg, every 3 weeks) until confirmed progressive disease (PD), unacceptable toxicity or consent withdrawal. Patients with histologically confirmed mCRC who had disease progression after treatment with all available therapies including fluoropyrimidine and oxaliplatin or irinotecan were enrolled. Eligible patients were ≥19 years old, had ECOG status ≤1, and had no prior exposure to immunotherapy. The objectives were to evaluate the safety and efficacy (objective response rate (ORR) per RECIST v1.1). Results: Thirty-three patients with MSS mCRC were enrolled. Median age was 60 (range 33-72), 55% were male, median number of previous lines of chemotherapy was 3 (range 1-7), and 82% were consensus molecular subtype (CMS) 4. The ORR was 15.2% including 5 partial responses (PRs), 7 stable diseases, and 17 PDs as best overall responses; 12 patients remain on treatment. Among 5 patients with PR, 3 patients had confirmed PR and median duration of response was not reached yet. As of 04 Jan 2021, the most common treatment related adverse events (AEs) were increased amylase (21.2%), pruritus (21.2%), rash (21.2%), and increased lipase (18.2%). There were 3 treatment-related SAEs reported; drug induced pneumonitis (3%), nausea (3%), and vomiting (3%). Conclusions: The combination treatment with vactosertib and pembrolizumab showed favorable safety profile with promising efficacy in patients with MSS mCRC. Updated data including pharmacodynamic markers will be presented at the meeting. Clinical trial information: NCT03724851.