Developing the First Precision Medicine

In May 2017, the Food and Drug Administration (FDA) approved the first drug to treat tumors based on their genetic characteristics, regardless of where in the body the cancer originated. Until now, drugs have been approved based on their cell or tissue of origin, such as the breast or the lung. But pembrolizumab (Keytruda®) doesn’t target the genetic abnormalities of cancer cells specifically—it targets the immune system.

How did pembrolizumab become the first FDA-approved “tumor-agnostic” precision medicine drug? This historic accomplishment was enabled by more than three decades of NCI-funded research in cancer genetics and immunology. The drug is now available for patients with late-stage solid tumors with a genetic feature called microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). Whereas precision medicine has focused largely on developing and testing drugs that target the genetic abnormalities that drive cancer cell growth, this new precision medicine approach uses the genetic information in tumors as a biomarker, not a target, to identify patients who may benefit from treatment with pembrolizumab.

When the cells of the body divide, their DNA must be copied so each progeny cell receives a full complement. This process, known as DNA replication, is not always perfect and mistakes can be made. Normally, however, cells have ways of repairing these mistakes. In cells with dMMR, genes responsible for a DNA repair process known as mismatch repair are mutated. This DNA repair defect can be inherited (as it is in a condition called Lynch syndrome), or the defect can happen by chance (sporadically). The failure of cells with dMMR to repair mistakes made in DNA replication leads to the accumulation of hundreds to thousands of mutations, some of which can cause cancer.

Lynch syndrome is named after NCI-funded researcher Henry T. Lynch, M.D., who discovered the syndrome in the early 1970s by studying affected families that demonstrated an increased risk of colorectal and several other types of cancer. In the 1990s, several NCI-funded research teams investigating the genetics of hereditary colorectal cancer determined that mutations in mismatch repair genes play a key role in this syndrome. Two of these teams were led by Richard Kolodner, Ph.D., of the Ludwig Institute for Cancer Research, and Bert Vogelstein, M.D., of Johns Hopkins University.

In addition to hereditary and sporadic colorectal cancers, dMMR is associated with some cancers of the uterus, ovary, prostate, stomach, small intestine, biliary tract, and pancreas.

Scientists have found that cancers with many mutations, such as lung cancer and melanoma, are more likely to respond to pembrolizumab and other immunotherapy drugs than cancers with low numbers of mutations. Researchers hypothesized that tumors with dMMR—because of their high number of mutations—might also respond to these drugs, including pembrolizumab.

One trial, led by Johns Hopkins researcher Dung Thi Le, M.D., was funded in part by several NCI grants, including a Cancer Center Support Grant and a Specialized Program of Research Excellence Award. Forty-one patients were enrolled in this trial, 32 of whom had colorectal cancer. Forty percent of patients with dMMR colorectal cancer responded to treatment, compared with 0% in patients without the defect.

These results and other data led FDA to grant pembrolizumab accelerated approval for the treatment of dMMR cancers. This approval is significant because targeting genetic characteristics, rather than where the cancer originates in the body, opens up new options for patients who might otherwise not be considered candidates for a drug. Furthermore, this example demonstrates that decades of NCI-funded research in different areas, including cancer genetics and immunology, has resulted in a whole greater than the sum of its parts for patients.