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Following Pivotal FDA Approval for Keytruda, Promega to Seek Clearance for Mismatch Repair Deficiency Assay


NEW YORK (GenomeWeb) – Less than two months after Merck received fast-track approval for the biomarker-guided use of its Keytruda cancer drug, Promega said it plans to seek US Food and Drug Administration clearance for an assay based on microsatellite instability technology for the detection of colorectal cancer.

The FDA's accelerated approval for the treatment of patients whose cancers have a specific biomarker — called microsatellite instability-high (MSI-H), or mismatch repair deficient (dMMR) — marked the first time it approved a drug to be given based on the genomic features in cancer patients' tumors, instead of where the tumor occurs in their bodies.

While the new FDA drug indication didn't come with an FDA-approved companion test, it places a spotlight on the need for well-validated diagnostics.

Last week, Promega said that it would seek FDA clearance for its own MSI assay to help oncologists and pathologists make treatment decisions for colorectal cancer patients. The firm's current research-use-only MSI assay has been available and used in the market as part of lab-developed tests since 2004. 

"The recent announcement from the FDA on the approval of a cancer drug based on microsatellite instability status rather than the site of origin of the tumor is really seminal in the way it relates to matching patients to the best outcome," Heather Tomlinson, the business unit leader for molecular diagnostics at Promega, said in an interview.

"The fact that Promega has an assay that measures microsatellite instability and that has been available to researchers for a number of years led us down the path of considering it as an in vitro diagnostic," she said, adding that people at the company felt "an obligation" to investigate how microsatellite instability "and our assay, in particular, could have an impact in immunotherapy and in predicting [a patient's] response."

Merck's Keytruda (pembrolizumab) is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors. The indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs.

Tumor cells with MSI-H and dMMR have impaired DNA repair capabilities that drive cancer progression, and these features are common in colorectal, endometrial, and gastrointestinal cancers. They also occur in cancers of the breast, prostate, bladder, thyroid gland, and other areas, though less frequently. Around 5 percent of colorectal cancer patients have MSI-H or dMMR tumors.

Achieving clearance for a colorectal cancer diagnostic is the top priority for Promega, but the firm is also "exploring through clinical research the potential to expand that to an immunotherapy application for all solid tumors," Tomlinson said.

"We are investigating the potential of applications in immunotherapy mainly through working with a network of collaborators and by doing more extensive clinical research in this area," she said, adding that "Based on the result of that clinical research, [the firm could] potentially move to a pan-tumor in vitro diagnostic application with the FDA."

Promega expects to have clearance for its MSI test for colorectal cancer detection by the second quarter of 2019, and it is currently working toward completing the FDA presubmission process. The firm will seek CE marking in parallel with FDA clearance.

One possible outcome of the FDA decision to fast track approval for use of an MSI assay with Keytruda and its recognition for the first time of a molecular marker for all solid tumors is that it may speed drug-related clinical trials processes, Tomlinson said.

Currently, pharma companies conduct their drug-related clinical studies for cancers based on the origin of the condition in the body, such as the lung, pancreas, or colon. Over time, some companies decide to expand the indication to new types of tumors, based on another part of the body, but doing so requires additional clinical trials, more time, and a different set of patients, Tomlinson said.  

"By looking at the microsatellite instability status of a marker in all solid tumors, pharma companies would manage trials differently, and time savings would be one very likely outcome because they would be able to conduct trails for multiple types of tumors at one time," Tomlinson noted.

Should Promega receive clearance for use of its assay as an in vitro diagnostic, labs will be able to speed adoption "and reduce their validation burden," Tomlinson said. 

Labs that are CLIA and CAP certified can conduct detailed validation studies using research-use-only tests, and then use the product in clinical diagnostic applications. With an in vitro diagnostic version, laboratories wouldn't have to endure the time and expense associated with setting up and certifying an assay.

Tomlinson said that she believes the company is well positioned to obtain FDA clearance and broader adoption for its assay because of its patent-protected technology, manufacturing capabilities, and its experience in providing fragment-based assays to the forensics industry for human identification, including at crime scene investigations and to solve uncertainties related to paternity.

On Tuesday, Promega said it had become the first major forensic manufacturer to achieve third-party certification of the published ISO 18385 standard to minimize the risk of human DNA contamination in products used to collect, store, and analyze biological material for forensic purposes.

The firm said that its technology is considered the gold standard molecular assay for detecting microsatellite instability.

Microsatellites are repeats in DNA sequences, and a person's number of repeats is usually inherited. As cells become tumorous, the number of repeating sequences of DNA may be altered. "The cause may be a defect in the ability of cells to repair mistakes when DNA is copied," Tomlinson said, adding, "That's called microsatellite instability, and it's why we can measure a mismatch-repair deficiency."

Promega's MSI test is a functional assay that uses fluorescent multiplex PCR to co-amplify seven markers for analysis of the MSI-high phenotype, including five nearly monomorphic mononucleotide repeat markers and two highly polymorphic pentanucleotide repeat markers.

Clinical studies have demonstrated that mononucleotide repeats are the most sensitive and most specific markers for detection of tumors with defects in MMR, Tomlinson said.  "Promega’s MSI system of five mononucleotide repeats represents an optimal panel of markers," she said, adding that the panel also includes two pentanucleotide markers to identify sample mix-ups or contamination, or both.

Antibody-based tests on the market also have the ability to look for mismatch repair proteins, but in looking for the presence or absence of proteins, they don't reveal a cell's functionality, Tomlinson said, and added that "We believe that a functional assay is a better representation of what's happening in a patient's tumor."

Several companies are looking at using next-generation sequencing as a mechanism for measuring mismatch repair deficiencies, she said, by analyzing DNA sequences. They are also seeking to measure the tumor mutation burden, or mutational frequency over a sequence of genes. It's a relatively new test methodology for looking at mismatch-repair deficiency that, similar to antibody testing, identifies the presence or absence of mutations, but is also not a functional assay, Tomlinson said.

She noted that their research showed that large marker panels and tumor mutation burden testing that employ next-generation sequencing are excellent tools for research, but the impact of the information they provide is unclear, the assays are expensive, and the turnaround time is too long for routine near-term use in a diagnostic setting.

By contrast, the MSI assay is being applied clinically, is reimbursable, and has a fast turnaround time, Promega said, and it has a large body of evidence supporting its use in colorectal cancer decisions.

Tomlinson noted that the length and number of repeats impacts the assay's sensitivity. In a research program, the firm is investigating the development of new repeats that it has described in research publications.

In 2015, Promega's Jeff Bacher and colleagues reported in a study published in the journal PLOS One that they had achieved increased sensitivity for detection of the MSI-High phenotype in early colorectal lesions with new long mononucleotide repeat markers. They said that the finding indicates that MSI screening for the early detection of Lynch syndrome, an inherited condition that increases the risk of getting colon and other cancers, might be feasible.

"Over time, we will demonstrate the impact of those new repeats in different situations," Tomlinson said.