Inhibitors CDK4 and CDK6 For Metastatic Breast Cancer
In October 2015, the FDA stated that CDK4 and CDK6 inhibitors were breakthrough therapy for metastatic breast cancer ER positive HER2 negative.
CDK4 is required for mammary production of tumors; CDK6 levels are decreased in many breast tumors. CDK's (cyclin dependent kinases) are key enzymes that regulate the cell cycle causing proliferation of cancer cells. This pathway is implicated in several types of cancer, including the three most common breast, colon and lung.
CDK4 also increases steroid hormone production in breast cancer.
Pablociclib was the first CDK4/CDK6 inhibitor FDA approved for metastatic breast cancer in 2015. It is an oral drug used in combination with letrozole, an aromatase inhibitor that stops production of estrogen by the ovaries and adrenal glands. The studies resulted in improved response rate and disease-free survival.
The combination of fulvestrant (an antiestrogen that binds to the estrogen receptor) and pablociclib also prolonged disease-free survival as well as overall survival. The most common side effects were neutropenia, anemia, and thrombocytopenia, treatable with growth factor injections.
Ribociclib is the second CDK4/CDK6 inhibitor FDA approved in 2017. Ribociclib with letrozole revealed progression free survival of 26 months versus 16 months with letrozole alone. The major side effects were low white blood cell count, diarrhea, and elevated liver function test, and QT prolongation on EKG.
Abemaciclib was the latest CDK4 CDK6 inhibitor FDA approved for metastatic breast cancer. The monarch-3 trial results revealed that by adding abemaciclib to letrozole or anastrozole (aromatase inhibitors) there was improved disease-free survival. The median overall survival was 17.7 months. The most common side effects were diarrhea, neutropenia, fatigue and nausea.
This class of drugs has been innovative, effective and well tolerated giving additional options for ER positive metastatic breast cancer.