PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

TLDR

Somatic mutations can encode non‑self immunogenic antigens. The study aimed to evaluate the clinical activity of pembrolizumab in metastatic carcinomas with or without mismatch‑repair deficiency. Pembrolizumab was given IV at 10 mg/kg every 14 days to patients with mismatch‑repair‑deficient colorectal cancers, mismatch‑repair‑proficient colorectal cancers, and mismatch‑repair‑deficient non‑colorectal cancers. Pembrolizumab produced a 40 % immune‑related objective response rate and 78 % 20‑week progression‑free survival in mismatch‑repair‑deficient colorectal cancers, but no responses in mismatch‑repair‑proficient colorectal cancers; median progression‑free and overall survival were not reached in the deficient group versus 2.2 and 5.0 months in the proficient group, and high somatic mutation loads correlated with prolonged progression‑free survival. Funded by Johns Hopkins University and others; ClinicalTrials.gov NCT01876511.

Abstract

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, 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.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).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.).