PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Abstract

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.)

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

“…While being an adverse prognostic marker, a nonsynonymous NF1 mutation can be a favorable treatment‐predictive marker, by virtue of its association with increased mutational load. In particular, tumors with high mutational burden (or deficiency in the DNA mismatch repair pathway leading to such an increase) have recently been shown to respond better to immune checkpoint blockade agents (Le et al ., 2015; McGranahan et al ., 2016; Rizvi et al ., 2015; Van Allen et al ., 2015). Furthermore, NF1 ‐mutant melanomas have been found to be dependent on MAPK signaling and to respond to inhibitors targeting key players of this pathway (MEK, ERK) (Maertens et al ., 2013; Nissan et al ., 2014; Whittaker et al ., 2013).…”

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

“…However, PD-1 and PD-L1 blocking antibodies were proven unsuccessful in CRC, with the exception of MMR-deficient CRC. 23-25 , 27 , 28 The first aim of this study was to investigate whether the composition of the immune infiltrates and the intra-tumoral expression levels of inhibitory molecules in CRC metastases in the liver environment differ from those in primary CRC tumors and metastases outside the liver, which would suggest potential differences in sensitivity to checkpoint inhibitors among CRC tumors at different anatomical locations. The second objective was to determine whether targeting of inhibitory checkpoint pathways by antagonistic antibodies can enhance the functionality and anti-tumor responses of tumor-infiltrating T cells in LM-CRC.…”

“…22-25 In contrast, CRC patients hardly respond to PD-1 and PD-L1 blocking antibodies, 23-26 except for the minority of patients who are with mismatch repair (MMR)-deficient CRC. 27 , 28 A defective MMR enzyme system occurs in 10%-20% of CRC tumors and results in microsatellite instability, which is used as a molecular marker of MMR-deficiency. 29 It has been hypothesized that the observed difference in responsiveness to PD-1/PD-L1 blockade between MMR-deficient and MMR-proficient CRC is related to the higher numbers of somatic mutations in MMR-deficient tumors, due to the reduced ability to repair DNA damage.…”

“…The increased mutation rate may result in the presence of more mutation-encoded neo-antigens in the tumors, which elicit stronger anti-tumor T cell responses. 27 Indeed, MMR-deficient CRC tumors are characterized by denser CD8 + T cell infiltration. 30 They also have higher expression levels of inhibitory checkpoint molecules, probably to resist immune-mediated tumor elimination.…”

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

“…6,7 TMB is associated with clinical benefit to immune checkpoint blockade in patients with melanoma, lung, and colon cancer. 8–11 The role of TMB in tumor immunogenicity is less clear in breast cancer. While TMB is higher in estrogen receptor (ER)-negative tumors compared with ER-positive tumors, consistent evidence that mutational burden itself significantly correlates with TIL levels is lacking.…”