CDK4/6 inhibitors are a new class of drugs that have shown promise in the treatment of advanced ER- positive breast cancer. Cyclin dependent kinases (CDK) regulate the process of cell division, required for growth. The thought is that if we can block CDKs, then cells won’t multiply and cancer can be slowed or stopped. This approach is not new. CDK inhibitors have been tested in over 60 clinical trials since 1998 but with limited success until recently. Previous attempts used inhibitors that blocked all different types of CDKs. New drugs are more specific for blocking only CDK4 and CDK6, making them more effective with fewer side effects.
CDK4/6 Inhibitors in Hormone Receptor Positive Metastatic Breast Cancer
At the AACR Annual Meeting on April 1, BCRF Investigator, Hope Rugo, discussed the clinical trials that led to the approval of two CDK4/6 inhibitors in breast cancer: palbociclib (Ibrance®) which was approved in 2016 and ribociclib (Kisqali®) which was approved this year. A third drug, abemaciclib, is showing promising results in clinical trials and may see approval later this year or in 2018. All three drugs have similar side effects, including causing low blood counts and hair loss. However, only ribociclib causes some heart toxicity that may require additional monitoring. Each shows similar results in improving progression free survival (the period of time a patient lives with a disease but it does not get worse) in patients with hormone receptor positive metastatic breast cancer.
Challenges That Lie Ahead
Although CDK4/6 inhibitors consistently delay the need for chemotherapy, challenges still remain. Fabrice Andre, another BCRF Investigator, discussed the difficulty in finding biomarkers, or ways of predicting response to drugs. Initial thoughts were that if a patient had alterations in their CDK4/6, or the other proteins involved in the pathway, they may respond better or worse. But, the data from clinical trials does not suggest that alterations in the CDK4/6 pathway are predictive of response. The same is true for the amount of estrogen receptor expressed by the cancer.
Drug resistance toward CDK4/6 inhibitors is another struggle. Questions remain on whether other CDKs, like CDK2, can fulfill the role of CDK4 and CDK6 which are blocked by CDK4/6 inhibitors. Another theory posits that Rb, the protein that CDK4/6 acts on, becomes able to cause proliferation without CDK4/6 activity.
While more studies need to be done on the use of CDK4/6 inhibitors, scientists agree they present an exciting new potential for breast cancer patients. More results on clinical trials for abemaciclib and ribociclib will be presented at the AACR meeting. We expect to hear more about these drugs throughout the year.