Introduction
Pembrolizumab (Keytruda) is a humanized monoclonal antibody that targets the PD-1 immune checkpoint receptor found on T cells. Pembrolizumab functions by blocking the interaction between PD-1 and PD-L1/PD-L2, thereby preventing immune suppression mediated by tumors and restoring activity of anti-tumor T-cells.
On May 23, 2017, pembrolizumab received the first tissue-agnostic approval for use in treating cancers by the United States Food and Drug Administration (FDA). This represented a significant change in cancer treatment from being based solely on the site of origin of the cancer to being based on the presence of biomarkers. The first biologic indication for pembrolizumab’s use was for unresectable metastatic solid tumors with either:
High Microsatellite Instability (MSI-H)
Defective Mismatch Repair (dMMR)
The FDA’s approval was based on a pooled analysis of clinical trial data which demonstrated an overall objective response rate of 39.6% and durable responses across several different types of tumors.
The Importance of MSI-H/dMMR
Deficiencies in the DNA repair machinery lead to accumulation of multiple mutations in tumors that are classified as MSI-H or dMMR. This accumulation of mutations (or high mutational burden), in turn, leads to expression of neoantigens on the surface of these tumors, which makes them particularly susceptible to immune checkpoint inhibition.
Tumors exhibiting an MSI-H phenotype are most commonly seen in:
Colorectal carcinoma
Endometrial carcinoma
Gastric carcinoma
Certain pancreatic, biliary, and prostate carcinomas
Clinical and Scientific Implications
The first drug approval based solely on a molecular biomarker (rather than tumor site)
The establishment of a regulatory precedent for precision oncology
The expansion of treatment options for patients with limited treatment options
The expedited development of other immune checkpoint inhibitors
Subsequent to this regulatory milestone, there are now multiple tissue-agnostic therapies in clinical use. One example of tissue-agnostic therapy is Larotrectinib for the treatment of NTRK fusion-positive tumors.