Checkpoint Inhibitor Immunotherapy Delays Colorectal Cancer Progression

MedMaven

by Dr. C.H. Weaver M.D. 4/2/2020

Keytruda was found to significantly delayed cancer progression compared with chemotherapy when used to treat certain patients with advanced colo-rectal cancer. The full results of this trial will be released shortly.

Microsatellite instability (MSI) is the condition of genetic hypermutability or a predisposition to mutations in cells that results from the bodies impaired DNA mismatch repair (MMR) mechanism. DNA MMR is an essential function and the way the body naturally corrects errors that spontaneously occur during cell division associated DNA replication.

Mismatch Repair Genes work like genetic “spell checkers.” When problems occur in these spell-checking MMR genes, it means that areas of DNA start to become unstable and the body is unable to correct the errors that occur during DNA replication and consequently accumulate errors. The accumulation of errors causes the creation of novel microsatellite fragments that can be measured. The presence of MSI represents evidence that the MMR function is not working normally and predisposition to developing cancer exists. It is estimated that approximately 10-15% of colorectal cancers will have either an MSI-H or dMMR when testing is performed.

Checkpoint Inhibitor Medications

Checkpoint inhibitors are a type of precision cancer immunotherapy that helps to restore the body’s immune system to fight the cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight colon cancer cells.

Keytruda (pembrolizumab) and Opdivo (nivolumab) belong to a class of medicines called “checkpoint inhibitors” and both have significant anti-cancer activity in advanced colorectal cancer patients with mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) abnormalities.

Data from the Phase 3 KEYNOTE-177 clinical trial was released April 2, 2020. The trial evaluated first-line treatment with Keytruda for patients with MSI-H or dMMR in 308 patients with unresectable or metastatic colorectal cancer. Patients were treated with either Keytruda alone or with mFOLFOX6 or FOLFIRI, with or without bevacizumab or cetuximab chemotherapy and directly compared.

Reference:

Merck Announces KEYTRUDA® (pembrolizumab) Significantly Improved Progression-Free Survival as First-Line Treatment for Advanced Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Colorectal Cancer

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