Background: Targeting both PD-L1 and CTLA-4 may be synergistic immunotherapy approaches. CO.26 evaluated if dual inhibition leads to improved pt survival vs BSC alone in rmCRC. Methods: rmCRC pts were randomized 2:1 to D+T vs BSC. Treatment consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and supportive measures. Primary endpoint was overall survival (OS). Two-sided p < 0.10 was considered statistically significant. Cell-free (cf)DNA sequencing for MSI and TMB used GuardantOMNI panel and baseline plasma. Results: From 08/2016-06/2017, 180 pts were enrolled. Pt characteristics were balanced between arms. At median follow-up of 15.2 months (mos), median OS was 6.6 mos for D+T and 4.1 mos for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54 – 0.97). Progression free survival (PFS) was 1.8 mos vs 1.9 mos, respectively (HR 1.01, 90% CI 0.76 – 1.34). Disease control rate (DCR) was 22.6% for D+T and 6.6% for BSC (p = 0.006). cfDNA analysis was successful in 168/169 pts (99.4%). Two pts were MSI-high. In 166 MSS pts, OS HR was 0.66 (p=0.024; 90% CI 0.49-0.89). Excluding the MSI-H cases (TMB of 74.7 and 247.1 mts/Mb), mean TMB was 20.4 ± 16.3 mts/Mb (range: 0.96 – 114.0). In MSS pts, a pre-specified cutpoint of 20 mts/Mb stratified pts into high and low TMB groups but was not predictive for OS , PFS, or DCR (interaction p-values > 0.7). Using a minimum p-value approach, pts with TMB >28 mts/Mb (21% of MSS pts) had the greatest OS benefit (HR 0.34, 90% CI 0.18-0.63) for D+T (interaction p = 0.07). High TMB was associated with a trend in worse prognosis for OS in the BSC arm using both 20 mts/Mb (HR 1.26, 90% CI 0.76-2.12) and 28 mts/Mb (HR 2.59 90% CI 1.46-4.62) cutpoints. Conclusions: D+T significantly prolonged OS in pts with rmCRC. High TMB may select a group of MSS pts who benefit from D+T. Plasma TMB appeared prognostic in the BSC arm. This is the first study showing combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with MSS rmCRC. Updated results based on deaths in more than 90% of pts will be presented. Clinical trial information: NCT02870920.