FDA approves first cancer treatment based on genetic makeup, not tumor location

immunotherapy drug
The U.S. Food and Drug has made the breakthrough step of approving a cancer therapy based not on the tumor's primary location, but on a specific genetic feature found in the cancer’s DNA.

Cancer has traditionally been identified by where in the body it develops. Breast cancer forms in the breast, lung cancer in the lungs, and so on. Even when a cancer metastasizes to a different part of the body, it is defined by its original location. If colorectal cancer travels to the brain, for instance, it is called metastatic colorectal cancer, not brain cancer. But many doctors, including Shayma Master Kazmi, MD, RPh, Medical Oncologist at our hospital in Philadelphia, call that old-school thinking. "We used to just think about cancers in terms of where they originated," Dr. Kazmi says. "Now we’re expanding our views on cancer to not be limited by where it starts, but to look at its blueprint, the way the cancer metastasizes, the way it grows, what makes the cancers tick."

Breakthrough treatment

The U.S. Food and Drug Administration (FDA) supported that perspective in May, when it made the breakthrough step of approving a cancer therapy based not on the tumor's primary location but on a specific genetic feature found in the cancer’s DNA. The approval allows the checkpoint inhibitor drug pembrolizumab (Keytruda®) to be used to treat patients with inoperable metastatic tumors that have one of two specific genetic features, called microsatellite instability-high (MSI-H) and mismatch repair deficiency (dMMR). These gene mutations make it difficult for the DNA in a cell to repair itself, which may lead to the type of unchecked cell growth that causes many tumors to form and grow. The decision marked the first time in its history the FDA approved a cancer treatment based on a genetic feature. “This critically important and paradigm-changing decision by the FDA is one more example of how future cancer treatments will be determined," says Maurie Markman, MD, president of Medicine & Science at Cancer Treatment Centers of America® (CTCA).

Checkpoint inhibitors like pembrolizumab are immunotherapy drugs designed to disrupt the communication, common between some cancer cells and disease-fighting T-cells, that allows cancer to hide from the immune system. Immune cells are almost like the body’s police force, scanning other cells as they pass certain checkpoints to determine whether they pose a threat that needs to be neutralized, like an infection or disease. But because cancer is made of the body’s own cells gone awry, some cancer cells are able to mask their threat, by sending deceptive signals to protein receptors, located on the immune cells’ surface, as they pass the checkpoints. Checkpoint inhibitors are so named because they work by blocking those receptors and exposing the cancer as harmful and ripe for attack. If not for these checkpoints, the immune system may attack healthy cells. The goal with checkpoint inhibitors is to keep those healthy cell protections intact while empowering the immune system to recognize cancer’s threat. But they don’t always work as designed, and scientists are still trying to figure out why.

'Huge first step'

"These drugs release the brake on the immune system so our T-cells can look for a foreign antigen," Dr. Markman says. "The question is: What's in the tumor cells that they will find when they release the brake? What are they attacking?" Pembrolizumab, for example, yields positive results about 20 percent of the time it’s used. While researchers don’t know why it works in some patients but not others, what they have discovered is that the MSI-H and/or dMMR defects are present in cancers in which the drug has shown positive results, regardless of where the tumor is located. In fact, these defects have been found in a number of patients, across cancer types. MSI-H has been detected in 15 percent of all colorectal tumors, as well as patients with bladder, breast, prostate and thyroid cancers. The defect has also been found in 90 percent of colorectal cancers in patients with Lynch syndrome, a genetic condition that elevates the risk for some cancers.

So far, the FDA has approved checkpoint inhibitors to treat several cancers, but only based on where they formed in the body—in the lung, bladder and kidney, for example. The drugs are also approved to treat Hodgkin lymphoma and metastatic melanoma. Dr. Kazmi says that by basing this new approval solely on a cancer's specific genetic feature, the FDA is taking "the first huge step" in changing how cancer may be treated in the future. "It is very exciting that the FDA is being so forward thinking by changing its views on traditional cancer treatment," she says. "We do not want to be limited by the origin of the cancer. We want to attack it at its core, its driving mechanism."

Learn more about why immunotherapy works for some patients but not others.