This study investigates the clinical activity of pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, in patients with metastatic carcinoma, focusing on those with mismatch-repair deficiency. The study included 41 patients, divided into three cohorts: those with mismatch repair-deficient colorectal cancers, those with mismatch repair-proficient colorectal cancers, and those with mismatch repair-deficient non-colorectal cancers. The primary endpoints were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. Results showed a higher response rate and progression-free survival in patients with mismatch repair-deficient cancers compared to those with mismatch repair-proficient cancers. Specifically, the immune-related objective response rate was 40% in mismatch repair-deficient colorectal cancers and 0% in mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the mismatch repair-deficient colorectal cancer cohort but were 2.2 and 5.0 months, respectively, in the mismatch repair-proficient cohort. Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, compared to 73 in mismatch repair-proficient tumors, with high mutation loads associated with prolonged progression-free survival. The study concludes that mismatch-repair status predicts the clinical benefit of immune checkpoint blockade with pembrolizumab.This study investigates the clinical activity of pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, in patients with metastatic carcinoma, focusing on those with mismatch-repair deficiency. The study included 41 patients, divided into three cohorts: those with mismatch repair-deficient colorectal cancers, those with mismatch repair-proficient colorectal cancers, and those with mismatch repair-deficient non-colorectal cancers. The primary endpoints were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. Results showed a higher response rate and progression-free survival in patients with mismatch repair-deficient cancers compared to those with mismatch repair-proficient cancers. Specifically, the immune-related objective response rate was 40% in mismatch repair-deficient colorectal cancers and 0% in mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the mismatch repair-deficient colorectal cancer cohort but were 2.2 and 5.0 months, respectively, in the mismatch repair-proficient cohort. Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, compared to 73 in mismatch repair-proficient tumors, with high mutation loads associated with prolonged progression-free survival. The study concludes that mismatch-repair status predicts the clinical benefit of immune checkpoint blockade with pembrolizumab.