Pembrolizumab Approved for Tumors with Specific Genetic Features. 


On May 23, the Food and Drug Administration (FDA) granted accelerated approval to the immunotherapy pembrolizumab (Keytruda®) for patients with solid tumors that have one of two specific genetic features known as mismatch repair deficiency and high microsatellite instability. The approval covers adult and pediatric patients whose cancer has progressed despite prior treatment and who have no alternative treatment options.

This is the first time that FDA has approved a cancer treatment based solely on the presence of a genetic feature in a tumor, rather than the patient’s cancer type.

“I think this is a step forward for precision medicine,” said James Gulley, M.D., Ph.D., head of the immunotherapy section of NCI’s Center for Cancer Research.

The approval provides another option for some patients who would not otherwise be candidates for treatment with pembrolizumab, such as those with pancreatic cancer, Dr. Gulley continued. But for some cancer types, he cautioned, only a small number of patients typically have these genetic features.

Mismatched DNA

The process of mismatch repair enables cells to correct mistakes in their DNA code that sometimes occur during DNA replication. It’s “like a spell-checker” for DNA, explained Dr. Gulley. Mismatch repair deficient (dMMR) cells, which lack this failsafe process, acquire multiple DNA mutations. Some dMMR cells acquire alterations in short, repetitive DNA sequences called microsatellites and are referred to as microsatellite instability-high (MSI-H).

Tumors that are dMMR and MSI-H are found in patients with Lynch syndrome, a genetic disorder caused by mutations in genes that control DNA mismatch repair. In addition, these genetic features can spontaneously occur in tumors and have been found in patients with several cancer types—most commonly colorectal, endometrial, and gastrointestinal cancers.

Compared with other tumors, dMMR and MSI-H tumors have a higher frequency of DNA mutations and, as a result, higher levels of abnormal antigens. Because immune cells attack cells that have abnormal antigens, researchers have hypothesized that immune cells may be more likely to recognize and attack dMMR and MSI-H tumor cells. Studies have suggested that this vulnerability, in turn, may make these tumors more susceptible to therapies like pembrolizumab that ramp up the immune response.

Regardless of Cancer Type

Patients with certain cancer types, like lung cancer and melanoma, typically have good responses to immune checkpoint inhibitors such as pembrolizumab. But not every patient with one of these cancer types responds well to the treatment. More recently, researchers have found that it’s the patients with tumors that have more DNA mutations, like dMMR and MSI-H tumors, that are most likely to respond.

So “why group tumors by cancer type,” when these genetic features are the more telling characteristic, remarked Dr. Gulley. What’s novel about the studies that led to the FDA approval, he explained, is that the investigators included any patient with a dMMR or MSI-H tumor, regardless of the cancer type.

The FDA approval is based on combined results from five single-arm clinical trials that evaluated the efficacy of pembrolizumab.

The investigators used standard lab tests to identify a total of 149 patients with 15 different types of cancer whose tumors were MSI-H or dMMR. All patients received one of two doses of pembrolizumab. Altogether, 40% of patients with MSI-H or dMMR tumors had measurable tumor shrinkage after treatment, and for 78% of these responders, their tumors shrank or stayed the same size for 6 or more months.

In an interim analysis of one of the five trials, the investigators reported that, among patients with colorectal cancer, 40% of those with dMMR tumors and 0% of those with mismatch repair-proficient tumors responded to the treatment. The FDA approval includes patients with colorectal cancer whose disease has progressed after treatment with certain chemotherapy drugs.

In a more recent analysis of the same study, the investigators evaluated 86 patients with dMMR tumors from 12 different cancer types. After several weeks of treatment with pembrolizumab, they found that 53% of the patients had measurable tumor shrinkage and 21% had no signs of cancer.

To estimate the fraction of patients whose tumors have these genetic features, the investigators then evaluated the mismatch repair status of more than 12,000 tumors from 32 different cancer types and found that about 5% were dMMR. This translates to approximately 60,000 cases of cancer in the United States each year, they noted.

Among the five clinical trials, common side effects included fatigue, itchy skin, diarrhea, and rash. Although not reported in the studies, pembrolizumab can also cause serious, sometimes life-threatening, inflammation in a number of organs.

With the FDA approval, dMMR and MSI-H are now definitively considered biomarkers for predicting a good response to treatment with pembrolizumab, Dr. Gulley said. Ongoing studies are examining whether they are also biomarkers for treatment with other immune checkpoint inhibitors, he added.

Having a biomarker to identify patients who are most likely to respond is “an area we have widely anticipated as being the next step in understanding how to better use immunotherapies,” said Dr. Gulley. “It’s a welcome first step, and there’s much more yet to be done.”

Under FDA’s accelerated approval, the drug manufacturer must verify and further describe the clinical benefit of the treatment. In one follow-up trial, called KEYNOTE-177, investigators will compare pembrolizumab with standard therapy for patients with dMMR or MSI-H colorectal tumors. The trial is currently recruiting participants.

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