by Dr. C.H. Weaver M.D. 6/2020
Results from the Keynote-177 clinical trial demonstrate that initial therapy with the immune checkpoint inhibitor Keytruda doubles progression-free survival compared to chemotherapy in patients with a type of advanced colorectal cancer and microsatellite instability high/mismatch repair deficient (MSI-H/dMMR). The results of the Keynote-177 clinical trial led to Food and Drug Administration approval of Ketruda as initial therapy for MSI-H colon cancer in June of 2020.
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 initially updated in May 2020 at the American Society of Clinical Oncology Annual Meeting. The trial evaluated first-line treatment with Keytruda for patients with MSI-H or dMMR in 307 patients with unresectable or metastatic colorectal cancer.
Patients were randomly assigned to receive first-line Keytruda for up to 2 years or the doctors choice of six different standard chemotherapy regimens: mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin); mFOLFOX6+bevacizumab; mFOLFOX6+cetuximab; FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan); FOLFIRI+bevacizumab; or FOLFIRI+cetuximab and directly compared
Keytruda treated patients survived on average 16 months without cancer progression compared to 8.2 months for those treated with standard chemotherapy. At 24-months follow up, progression-free survival was 55.3% with Keytruda compared to 18.6% with chemotherapy. All patients with colon cancer should undergo genomic biomarker testing to determine whether they have MSI-high or either markers that can help determine optimal treatment.
Learn about other cancer driving mutations that can be targeted: Precision Cancer Medicines and Colon Cancer
- 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
- FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer