- The Food and Drug Administration has approved the Merck & Co. immunotherapy Keytruda for people whose tumors have a certain number of genetic mutations — a measure called high tumor mutational burden — no matter where their cancer originated.
- The decision marks the second so-called tissue agnostic approval for Keytruda, which made history in 2017 when the Food and Drug Administration cleared it for patients whose tumors have one of two genetic problems — microsatellite instability-high or mismatch repair deficiency. Other tissue agnostic approvals for Bayer's Vitrakvi and Roche's Rozlytrek have since followed.
- Tumor mutational burden, or TMB, has been studied in multiple immunotherapy trials, but Merck's approval marks its first validation by a drug regulator. Merck rival Bristol Myers Squibb had focused on TMB in developing its immunotherapy combination for lung cancer, which was approved last month. But the FDA didn't mention the marker in its decision.
Wednesday's FDA decision is another notable notch for Merck's immunotherapy, which has fast become the top-selling drug of its kind and one of the most lucrative medicines in the world.
Keytruda is already used for several tumor types, including skin, lung, bladder and more. And three years ago, it became the first cancer drug ever to win an approval based solely on specific genetic fingerprints of a tumor — microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) — regardless of where in the body that tumor formed.
That approval paved the way for others. The FDA has since cleared Vitrakvi, from Loxo Oncology, and Rozlytrek, from Roche, for tumors with other genetic alterations. And Merck's work in MSI-H and dMMR has illuminated use in colorectal cancer, where new data presented at the American Society of Clinical Oncology's meeting a few weeks ago showed particular benefit for newly diagnosed patients with advanced disease.
Bristol Myers' Opvido, too, has been approved for colorectal cancer patients whose tumors have those genetic defects.
Now Keytruda has validated a second tissue-agnostic target. It's characterized as "tissue tumor mutational burden-high," or TMB-H, meaning tumors with at least 10 mutations per megabase or greater. In the same KEYNOTE-158 study that led to its first tissue-agnostic approval in 2017, Merck found higher response rates to Keytruda for people with TMB-high tumors than others. The FDA has simultaneously cleared a test from Foundation Medicine as a companion diagnostic to help diagnose patients with TMB-high tumors.
With the approval, TMB-high has become just the second immunotherapy biomarker — a measure that helps predict whether someone will respond to treatment — supported by the FDA. Prior to Wednesday, the only immunotherapy biomarker cited in FDA approvals was a measure of how much of the protein PD-L1 is on patients' tumors.
And Merck has beaten its rival to that goal. Bristol Myers had based a review of its immunotherapy combination Yervoy and Opdivo in lung cancer on effects seen in TMB-high patients. But Bristol Myers pulled approval applications in both the U.S. and Europe in the past two years to accrue more evidence supporting its TMB work. The agency recently approved Yervoy and Opdivo for lung cancer, but TMB wasn't mentioned in the FDA's decision.
Still, TMB has to prove its worth in practice. Like PD-L1, it is an imperfect measure. Merck and rival Bristol Myers have come to define it with the same cutoff of 10 mutations per megabase, but that definition has been the subject of debate within the scientific community.
What's more, as an "accelerated" approval decision, Merck has to confirm Keytruda's benefit for TMB-high patients through additional testing. It also doesn't have evidence of an effect on TMB-high patients with central nervous system cancers.
The approval is specifically for TMB-high patients with solid tumors whose disease has progressed and have no good alternative treatment options.