First Case Report of a Dramatic Radiographic Response to a Checkpoint Inhibitor in a Patient With Proficient Mismatch Repair Gene Expressing Metastatic Colorectal Cancer

Metastatic colorectal cancer (mCRC) remains the second most common cause of cancer death in the United States, and therapeutic options are limited. Recently, the checkpoint inhibitor pembrolizumab was given the Food and Drug Administration breakthrough therapy designation for the treatment of patients with mCRC whose tumors demonstrate deficient mismatch repair gene (dMMR) expression (as evidenced by microsatellite instability-high [MSI-H]). The designation was based on a phase II study showing that in patients with dMMR, an objective response rate of 40% was seen, whereas in patients with proficient mismatch repair gene mCRCs, the response rate was 0%. To our knowledge, this is the first case of a patient with a proficient mismatch repair gene mCRC whose tumor demonstrated a dramatic response to a checkpoint inhibitor. Because this patient's tumor harbored amplification of both the PD-L1 and PD-L2 genes, the observed response was consistent with the presumed mechanism of action of checkpoint inhibitors. Checkpoint inhibitors are thought to activate a cytotoxic immune response that has been inhibited through tumor expression of PD-L1 and PD-L2. Given this result, dMMR in mCRC may not be the only predictor of responsiveness to checkpoint inhibition. As in non-small-cell lung cancer, PD-L1 or PD-L2 expression (or perhaps gene amplification) may also be predictors of checkpoint inhibitor efficacy.