- The Food and Drug Administration has begun a new speedy review for Merck & Co.'s drug Keytruda, through which it may approve the immunotherapy for people whose tumors have a specific genetic signature, called high tumor mutational burden, no matter where their cancer originated.
- If approved by the FDA's June 16 deadline, it would be the second so-called tissue agnostic approval for Keytruda. The Merck drug already made history in 2017 when the agency cleared the drug for patients whose tumors have one of two genetic problems, microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). That, in turn, paved the way for other, similar approvals.
- A positive decision from the FDA would also help to establish tumor mutational burden, or TMB, as one of just two validated immunotherapy biomarkers. That could bolster Bristol Myers Squibb, which is leaning on TMB for evidence to support approval of its Opdivo/Yervoy immunotherapy combination in lung cancer.
The past few years have already included a breakthrough for genetic medicine in cancer: three drug approvals, since 2017, based solely on the tumor DNA fingerprints they target. The FDA's coming decision on Keytruda represents another potential step forward for these so-called tissue-agnostic approvals.
An FDA nod would be another notch for Merck's drug. Not only is it the top-selling immunotherapy in the world, with $11.1 billion in sales in 2019, but it won the first-ever tissue agnostic approval in 2017. The nod was for its effectiveness against tumors with genetic defects — MSI-H and dMMR — present in multiple different cancers.
At the time, Richard Pazdur, the acting director of the FDA's Office of Hematology and Oncology products, called it an "important first for the cancer community."
Since then, the FDA has granted two more similar approvals. Loxo Oncology, now owned by Eli Lilly, followed in 2018 with Vitrakvi, which knocks out tumors in which a gene called NTRK is abnormally fused to another gene. Then, in 2019, came the Roche drug Rozlytrek, which works similarly. Others, like Turning Point Therapeutics, are advancing potentially tissue-agnostic cancer medicines.
Keytruda could further add to its lengthy list of approvals this summer. By June 16, the agency will decide whether to approve the drug as a monotherapy for patients whose advanced solid tumors have unusually high levels of genetic mutations and who don't have any other good treatment options.
Merck characterizes the measure, "tissue tumor mutational burden-high," or TMB-H, as tumors with at least 10 mutations per megabase or greater, which would be determined via an FDA-approved test. And Merck, incidentally, is leaning on evidence from the same Keynote-158 study that led to its first tissue-agnostic approval in 2017. Updated evidence from the study last year showed higher response rates to Keytruda for people with TMB-high tumors than others.
A positive decision from the FDA would help to validate TMB as an immunotherapy biomarker, or a measure that helps predict whether someone will respond to treatment. Biomarkers are sorely needed for immunotherapy, which, despite its meteoric rise, still only helps a fraction of people who get it. Thus far the only way to tell if patients might respond to immunotherapy is how much of the protein PD-L1 is on their tumors — an imperfect measure.
TMB has its drawbacks as well. Merck and rival Bristol Myers, for instance, have ultimately come to define it with the same cutoff of 10 mutations per megabase. But that cutoff has been the subject of debate within the scientific community. And Bristol Myers has had to pull approval applications in both the U.S. and Europe in the past two years to accrue more evidence supporting its TMB work.
Thus far TMB hasn't been embraced by regulators, but that's what makes the ongoing reviews of Keytruda — and Bristol's Opdivo/Yervoy combination — worth watching. Bristol Myers' application for the immunotherapy combo is largely based on effects seen in high-TMB patients. The FDA will render a decision next month, setting the table for its call on Keytruda.