A phase 2 trial evaluated pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, in 41 patients with progressive metastatic cancer, including those with mismatch-repair (MMR) deficient and proficient tumors. The study found that patients with MMR-deficient tumors had significantly higher response rates and progression-free survival compared to those with MMR-proficient tumors. Specifically, 40% of patients with MMR-deficient colorectal cancer had an immune-related objective response, while none of the MMR-proficient colorectal cancer patients did. Similarly, patients with MMR-deficient noncolorectal cancers had high response rates comparable to those with MMR-deficient colorectal cancer. Whole-exome sequencing revealed that MMR-deficient tumors had a much higher number of somatic mutations, which correlated with improved progression-free survival. The study concluded that MMR status is a key predictor of clinical benefit from PD-1 blockade. The results suggest that tumors with high mutational loads, such as those with MMR deficiency, are more responsive to immune checkpoint inhibitors. The study also highlighted the importance of tumor mutational burden in determining the effectiveness of immunotherapy. Safety assessments showed that adverse events were generally manageable, with some cases of thyroid dysfunction and pancreatitis. The findings support the use of MMR status as a biomarker for selecting patients who may benefit from PD-1 inhibitors. The study underscores the role of immune system recognition of tumor mutations in the effectiveness of immunotherapy.A phase 2 trial evaluated pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, in 41 patients with progressive metastatic cancer, including those with mismatch-repair (MMR) deficient and proficient tumors. The study found that patients with MMR-deficient tumors had significantly higher response rates and progression-free survival compared to those with MMR-proficient tumors. Specifically, 40% of patients with MMR-deficient colorectal cancer had an immune-related objective response, while none of the MMR-proficient colorectal cancer patients did. Similarly, patients with MMR-deficient noncolorectal cancers had high response rates comparable to those with MMR-deficient colorectal cancer. Whole-exome sequencing revealed that MMR-deficient tumors had a much higher number of somatic mutations, which correlated with improved progression-free survival. The study concluded that MMR status is a key predictor of clinical benefit from PD-1 blockade. The results suggest that tumors with high mutational loads, such as those with MMR deficiency, are more responsive to immune checkpoint inhibitors. The study also highlighted the importance of tumor mutational burden in determining the effectiveness of immunotherapy. Safety assessments showed that adverse events were generally manageable, with some cases of thyroid dysfunction and pancreatitis. The findings support the use of MMR status as a biomarker for selecting patients who may benefit from PD-1 inhibitors. The study underscores the role of immune system recognition of tumor mutations in the effectiveness of immunotherapy.