FDA Approval: Pembrolizumab — tissue-agnostic (MSI-H) for Cancer

The approval that stopped asking where the cancer started

On 23 May 2017, FDA granted accelerated approval to pembrolizumab, sold as Keytruda. It covered solid tumors carrying one of two genetic features. NCI described what was new. This was the first time the agency approved a cancer treatment based on a feature of the tumor alone, rather than the organ it grew in.

Until then, an approval read "for lung cancer" or "for melanoma." This one read, in effect, "for any solid tumor that looks like this."

The spell-checker that stopped working

Cells copy their DNA constantly, and copying makes mistakes. A system called mismatch repair catches them. NCI's James Gulley described it as a spell-checker for DNA.

When that system fails, the cell is called mismatch repair deficient, written dMMR. Errors pile up. Some of them land in short repeating stretches of DNA called microsatellites. A tumor with many such errors is called microsatellite instability-high, or MSI-H.

Here is why that matters to the immune system. More mutations mean more abnormal proteins on the tumor's surface. Immune cells hunt for exactly that kind of abnormality. Researchers reasoned that these tumors should be easier for an unleashed immune system to see.

Pembrolizumab does the unleashing. Its label explains the mechanism. T cells carry a receptor called PD-1. When PD-L1 or PD-L2 binds to it, the T cell stops multiplying. Some tumors carry those ligands and use the switch. Pembrolizumab blocks PD-1 so the switch cannot be thrown. Our page on immunotherapy covers this drug class.

Where these tumors turn up

dMMR and MSI-H tumors are found most often in colorectal, endometrial, and gastrointestinal cancers. They also occur in people with Lynch syndrome, an inherited condition affecting the mismatch repair genes. And they arise on their own.

Researchers behind the approval tested mismatch repair status in more than 12,000 tumors across 32 cancer types. About 5 percent were dMMR. They estimated that translates to roughly 60,000 cases a year in the United States.

What the trials found

The 2017 accelerated approval rested on five single-arm trials. Investigators found 149 people with 15 different cancer types whose tumors were MSI-H or dMMR. About 40 percent had measurable tumor shrinkage. Of those who responded, 78 percent held that gain for six months or more.

One trial made the comparison starkly. Among people with colorectal cancer, 40 percent of those with dMMR tumors responded. None of those with working mismatch repair did.

The label now reports a larger pooled analysis. It covered 504 people in KEYNOTE-164, KEYNOTE-158, and KEYNOTE-051. The objective response rate was 33.3 percent. Complete responses made up 10.3 percent. Among those who responded, the median duration was 63.2 months. Thirty-nine percent lasted three years or more.

Response varied a lot by tumor type. It was 59 percent in small intestinal cancer and 50 percent in endometrial cancer. It was 39 percent in gastric and gastroesophageal junction cancer, and 34 percent in colorectal cancer. It was 18 percent in pancreatic cancer and 4 percent in brain cancer.

In 2020 FDA approved pembrolizumab as first-line treatment for MSI-H or dMMR colorectal cancer. KEYNOTE-177 randomized 307 previously untreated people to pembrolizumab or chemotherapy. Median progression-free survival was 16.5 months against 8.2 months, with a hazard ratio of 0.60.

The test is the gatekeeper

None of this works without knowing a tumor's status, and the label requires an FDA-authorized test. MSI is measured by polymerase chain reaction, a method that amplifies DNA. Mismatch repair proteins are measured by immunohistochemistry, which stains tissue for specific proteins.

The label records something important here. In one group within KEYNOTE-158, local and central tests often disagreed. Of 104 samples called MSI-H or dMMR by a local lab, only 56.7 percent came back MSI-H on one approved test. With a different panel, 62.1 percent of 169 samples came back dMMR.

That is a real-world caution about which laboratory ran which test. Our page on biomarker testing and precision medicine explains how these results are produced and read.

When to call the team during treatment

The label's central warning is immune-mediated adverse reactions. Releasing the brakes on the immune system can let it attack healthy tissue. These reactions may be severe or fatal. They can hit any organ, and several at once. They can start at any point, including after treatment stops.

Liver enzymes, creatinine, and thyroid function are checked before treatment and periodically during it. Anyone on this drug should report promptly:

• New or worsening cough, breathlessness, or chest tightness
• Diarrhea more than a couple of times above normal, or blood in the stool
• Yellowing of the skin or eyes, or dark urine
• New severe fatigue, dizziness, or unusual thirst and urination
• Any new rash, especially one that blisters or peels

The point of the list is timing. Early treatment of these reactions, usually with steroids, is what keeps them manageable.

What this does not mean

A tissue-agnostic approval is not a universal treatment. It applies to tumors with a specific, testable feature. The person's disease must have progressed, with no satisfactory alternative left. And roughly one in three responded, which means most did not.

Accelerated approval is also a provisional standard. It rests on response rate, which measures tumor shrinkage rather than length of life. Here the follow-up data were strong enough for FDA to convert the indication to full approval. That decision drew on three larger trials. They covered more than 500 adults and children across more than 30 cancer types. This does not happen with every accelerated approval.

Finally, the response figures per tumor type come from small groups. Eight people with prostate cancer and 11 with cervical cancer cannot support a confident number. Our page on what is cancer sets out why tumor biology varies so much between sites.

Sources

• NCI, Pembrolizumab Approved for Tumors with Specific Genetic Features — https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-pembrolizumab-genetic-features
• NCI, Pembrolizumab — https://www.cancer.gov/about-cancer/treatment/drugs/pembrolizumab
• DailyMed, KEYTRUDA (pembrolizumab) prescribing information — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287
• FDA, FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer — https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-first-line-treatment-msi-hdmmr-colorectal-cancer

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

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