Dynamic combo

MADISON, Wis.—A genetic test could help doctors decide which patients get a widely used cancer drug. The test, which determines how well tumor cells correct DNA errors, can guide decisions about whether patients are likely to benefit from an immunotherapy drug.

Promega Corp. has entered into a global collaboration with Merck and Co., known as MSD outside the United States and Canada, to develop Promega’s microsatellite instability (MSI) technology as an on-label, solid tumor companion diagnostic (CDx) for use with Merck’s anti-PD-1 therapy, Keytruda (pembrolizumab). Keytruda is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. While the global collaboration will first seek regulatory approval for the Promega MSI CDx in the United States and China, there may be plans to seek approvals in additional parts of the world as well.

The National Cancer Institute (NCI) defines MSI as “a change that occurs in certain cells (such as cancer cells) in which the number of repeated DNA bases in a microsatellite (a short, repeated sequence of DNA) is different from what it was when the microsatellite was inherited.” MSI may be caused by mistakes that go uncorrected when DNA is copied in a cell. Found most often in colorectal, gastric and endometrial cancer, it may manifest itself in other types of cancer as well.

Promega's MSI technology, which has been validated in labs around the world to characterize solid tumor MSI status, measures the genomic accumulation of insertion or deletion (INDEL) errors caused by a deficient mismatch-repair system (dMMR) that occurs in certain types of solid tumors. The PCR-based method detects MSI, which is a form of genomic instability caused by insertion or deletion of additional bases into DNA microsatellites.

During DNA replication, failure of the mismatch repair system to correct these errors causes MSI. MSI status is a measure of dMMR found in certain solid tumors, providing oncologists, pathologists and patients with information that characterizes tumors. This screening may be used to better characterize tumors and guide therapy choices.

Tumors with MSI-High status have been shown to respond to immune checkpoint inhibitor therapies. This outcome may be explained by MSI-driven tumor expression of mutation-associated neoantigens that are believed to cause immune cell infiltration into the tumor microenvironment. Tumor-induced inhibition of immune cell activity can be overcome with immune checkpoint inhibitor therapies, enabling tumor cell destruction by the immune cells.

According to Bill Linton, president and CEO of Promega, “It is gratifying to see our MSI technology have such meaning within the oncology community. Promega developed this technology well over a decade ago, and our long-term commitment to R&D helped evolve its use.”

Dr. Jeff Bacher, senior research scientist at Promega, added, “Unlike other DNA-based molecular screening options, Promega MSI technology uses five monomorphic mononucleotides, which is recommended by the National Cancer Institute. Our test uses a sensitive and specific panel of markers for detection of MSI status and offers valuable insight to help inform physicians on how best to treat patients with cancer, including those likely to benefit from immune checkpoint inhibitor treatment.”

The current Promega Research Use Only MSI assay has been available since 2004, has been used extensively in clinical research and is supported by more than 140 peer-reviewed publications. Promega MSI technology, one of the leading standard tests for MSI status detection in research laboratories, recently achieved innovation status and priority review by the National Medical Products Administration (NMPA) in China.