PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

Abstract (PubMed)

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. We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab (anti-PD-1) in 41 patients with progressive metastatic carcinoma with and without mismatch-repair deficiency. Objective response rates were 40% and 71% (complete responses 0% and 8%) in the mismatch-repair-deficient colorectal cancer group and the mismatch-repair-deficient non-colorectal cancer group, respectively, compared with 0% in the mismatch-repair-proficient colorectal cancer group. Progression-free survival (PFS) at 20 weeks was 78% in mismatch-repair-deficient colorectal cancers, 67% in mismatch-repair-deficient other cancers, and 11% in mismatch-repair-proficient colorectal cancers. These data support the hypothesis that mismatch-repair status predicts clinical benefit from pembrolizumab regardless of tumor type.