Review of PD-1/PD-L1 Inhibitors in Metastatic dMMR/MSI-H Colorectal Cancer

Abstract

There are a wide range of therapies for metastatic colorectal cancer (CRC) available, but outcomes remain suboptimal. Learning the role of the immune system in cancer development and progression led to advances in the treatment over the last decade. While the field is rapidly evolving, PD-1, and PD-L1 inhibitors have a leading role amongst immunomodulatory agents. They act against pathways involved in adaptive immune suppression resulting in immune checkpoint blockade. Immunotherapy has been slow to impact the management of this patient population due to disappointing results, mainly when used broadly. Nevertheless, some patients with microsatellite-instability-high (MSI-H) or mismatch repair-deficient (dMMR) CRC appear to be susceptible to checkpoint inhibitors with objective and sustained clinical responses, providing a new therapeutic option for patients with advanced disease. This article provides a comprehensive review of the early and late phase trials with the updated data of PD-1/PD-L1 inhibitors alone or in combination with other therapies (immunotherapy, targeted therapy and chemotherapy). While data is still limited, many ongoing trials are underway, testing the efficacy of these agents in CRC. Current and future challenges of PD-1 and PD-L1 inhibitors are also discussed.

Molecular characterization of a large unselected cohort of metastatic colorectal cancers in relation to primary tumor location, rare metastatic sites and prognosis

“…The very poor prognosis for patients with MSI-H tumors is likely a combination of a more aggressive tumor and a poorer response to therapy. The very poor response to first-line treatment in patients with MSI-H tumors reported here, underlines the importance of evaluating immunotherapy upfront [26].…”

Remarkable Response of EGFR- and HER2-Amplified Metastatic Colon Cancer to Pyrotinib After Failed Multiline Treatments: A Case Report and Literature Review

“…A high TMB, as well as MSI-H as a predictive biomarker for response in mCRC, was revealed by previous studies, and patients carrying these characteristics are thought to be susceptible to immune checkpoint blockade (ICB) (20). The KEYNOTE-164 study evaluating pembrolizumab in MSI-H mCRC previously treated with more than one line of therapy showed that overall survival (OS) rates were 76% with a 41% PFS rate at 12 months (21).…”

Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives

“…In contrast, an MSI-stable or -low (MSS or MSI-L) phenotype (instability in <30% of microsatellites) indicates proficient MMR (pMMR) [1]. Lynch syndrome, an inherited syndrome caused by autosomal dominantly inherited germline mutations in one of the MMR genes (hMLH1, hMSH2, hMSH6, hPMS2, EPCAM), is seen in 3% of all CRC patients, whereas sporadic MSI-H status, most commonly due to inactivation of hMLH1, is seen in about 5-20% of all CRCs [2][3][4][5][6].…”