BACKGROUND: Somatic mutations have the potential to encode "non-self" 
immunogenic antigens. We hypothesized that tumors with a large number of somatic 
mutations due to mismatch-repair defects may be susceptible to immune checkpoint 
blockade.
METHODS: We conducted a phase 2 study to evaluate the clinical activity of 
pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 
patients with progressive metastatic carcinoma with or without mismatch-repair 
deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per 
kilogram of body weight every 14 days in patients with mismatch repair-deficient 
colorectal cancers, patients with mismatch repair-proficient colorectal cancers, 
and patients with mismatch repair-deficient cancers that were not colorectal. 
The coprimary end points were the immune-related objective response rate and the 
20-week immune-related progression-free survival rate.
RESULTS: The immune-related objective response rate and immune-related 
progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 
patients), respectively, for mismatch repair-deficient colorectal cancers and 0% 
(0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient 
colorectal cancers. The median progression-free survival and overall survival 
were not reached in the cohort with mismatch repair-deficient colorectal cancer 
but were 2.2 and 5.0 months, respectively, in the cohort with mismatch 
repair-proficient colorectal cancer (hazard ratio for disease progression or 
death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with 
mismatch repair-deficient noncolorectal cancer had responses similar to those of 
patients with mismatch repair-deficient colorectal cancer (immune-related 
objective response rate, 71% [5 of 7 patients]; immune-related progression-free 
survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 
1782 somatic mutations per tumor in mismatch repair-deficient tumors, as 
compared with 73 in mismatch repair-proficient tumors (P=0.007), and high 
somatic mutation loads were associated with prolonged progression-free survival 
(P=0.02).
CONCLUSIONS: This study showed that mismatch-repair status predicted clinical 
benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns 
Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).