Background: BOT promotes optimized T cell priming, activation and memory formation by strengthening antigen presenting cell/T cell co-engagement. As an Fc-enhanced next-generation anti–CTLA-4 antibody, BOT also promotes intratumoral regulatory T cell depletion and reduces complement fixation. We present results from patients with MSS CRC treated with BOT + BAL in an expanded phase 1a/1b study; NCT03860272. Methods: Patients (pts) with metastatic MSS CRC received BOT 1 or 2 mg/kg every 6 weeks (Q6W) + BAL 3 mg/kg every 2 weeks. Crossover from monotherapy to combination therapy was permitted (rescue) as well as fixed-dosing (150 mg BOT Q6W + 450 mg BAL every 3 weeks). Results: Fifty-nine combination pts were evaluable for efficacy/safety (treated as of 19 May 2022 with ≥1 Q6W imaging assessment), including one rescue and one fixed-dose pt. Median pt age was 57 (range, 25-83), 58% were female, and 76% received at least three prior lines of therapy including prior immunotherapy (34%). Median follow-up was 6.4 months (range, 1.6-29.5). In all pts, objective response rate (ORR) was 22% (95% CI, 12-35), disease control rate (DCR) was 73% (95% CI, 60-84), and median duration of response (DOR) was not reached (NR), with 9/13 responses ongoing. The 12-month overall survival (OS) rate was 61% (95% CI, 42-75), with median OS NR. Of the 13 responders, 9 had RAS mutations (7 KRAS, 2 NRAS), 0 had BRAF mutations, 0/10 had a TMB of ≥10 mutations/Mb, and 1/7 was PD-L1 positive (≥1% combined positive score). A subgroup analysis was conducted by the dose of BOT received . In 1 mg/kg pts (n=8), ORR was 38% (3/8; 95% CI, 9-76) and DCR was 100% (8/8; 95% CI, 63-100); in 2 mg/kg pts (n=50), ORR was 20% (10/50; 95% CI, 10-34) and DCR was 70% (35/50; 95% CI, 55-82). All grade treatment-related adverse events (TRAEs) occurred in 88% of pts, including grade 3 in 32%, and grade 4 in 2% of pts. Diarrhea/colitis was the only grade 3/4 TRAE occurring in more than three pts (15% grade 3, 2% grade 4). The most common grade 3 TRAEs outside of diarrhea/colitis were fatigue (5%) and pyrexia (5%). There were no grade 5 TRAEs reported. Fifteen percent of pts had a TRAE leading to discontinuation of BOT alone and 12% had a TRAE leading to discontinuation of both BOT + BAL. Conclusions: In heavily pretreated metastatic MSS CRC pts, BOT + BAL continues to demonstrate promising clinical activity with durable responses and was well tolerated with no new immune-mediated safety signals. A larger pt set, analyses by subgroup, and additional translational data will be presented at the meeting. A randomized phase 2 trial in MSS CRC pts is enrolling (NCT05608044). Clinical trial information: NCT03860272.