Tumor-agnostic drug development in dMMR/MSI-H solid tumors

Mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) represents a distinct phenotype among solid tumors characterized by frequent frameshift mutations resulting in the generation of neoantigens that are highly immunogenic. Seminal studies identified that dMMR/MSI-H tumors are exquisitely sensitive to immune checkpoint inhibitors, which has dramatically improved outcomes for patients harboring dMMR/MSI-H tumors. Nevertheless, many patients develop resistance to single-agent immune checkpoint blockade, prompting the need for improved therapeutic options for this patient population. In this review, we highlight key studies examining the efficacy of PD1 inhibitors in the metastatic and neoadjuvant setting for patients with dMMR/MSI-H tumors, describe resistance mechanisms to immune checkpoint blockade, and discuss novel treatment approaches that are currently under investigation for dMMR/MSI-H tumors.