Hope Rugo, MD
The next wave of progress in hormone receptor (HR)-positive breast cancer treatment is likely to center around earlier introduction of CDK4/6 inhibitors, uncovering mechanisms of resistance through cell-free DNA (cfDNA), and developing novel pathway blockades like PI3K inhibitors, explained Hope S. Rugo, MD.
“The field of treating HR-positive advanced breast cancer has changed tremendously over the last 10 to 12 years,” said Rugo. “Having the CDK4/6 inhibitors [arrive] based on really robust clinical data has been really exciting,” she added.
All 3 CDK4/6 inhibitors—palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)—are approved by the FDA in combination with an aromatase inhibitor for the treatment of patients with HR-positive, HER2-negative breast cancer. In 2018, abemaciclib and ribociclib received expanded approvals based on data from the phase III MONARCH 3 and MONALEESA-3 and -7 trials, respectively.
Although research has yet to pinpoint the origin of CDK4/6 inhibitor resistance, Rugo cited cyclin E expression and FGFR
overexpression as potential mechanisms.
In an interview during the 2018 OncLive®
State of the Science Summit™ on Breast Cancer, Rugo, a professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed CDK4/6 inhibition in HR-positive breast cancer, mechanisms of resistance to these drugs, and other potential pathway blockades.
OncLive: What do we know about CDK4/6 inhibitors in HR-positive metastatic breast cancer?
We now have 3 CDK4/6 inhibitors: palbociclib, ribociclib, and abemaciclib that are approved in the first-, second-, or greaterline settings in combination with endocrine therapy. Abemaciclib is approved in later-line treatment after chemotherapy as a single agent.
We understand a lot more about the toxicities of these agents, [such as] neutropenia and other less serious toxicities. We know that a small number of patients on ribociclib may have QT prolongation. Abemaciclib is given continuously and is associated with more diarrhea, although that can be managed with dose delays, dose reductions, and patient education. We also understand that fatigue is an issue with these medications as well as some degree of alopecia. Occasionally, we see abnormal liver enzymes with some of the agents.
We know that we can partner these drugs in postmenopausal patients and in premenopausal women on ovarian suppression. We know that it doesn’t appear to be safe to combine tamoxifen with ribociclib in the premenopausal population because you may enhance the QT effect of that drug. On the other hand, we know that fulvestrant (Faslodex) can be given safely with all 3 CDK4/6 inhibitors, even in the first-line setting based on the MONALEESA-3 trial.
Where is the field headed?
We know that progression-free survival (PFS) is essentially doubled with the addition of a CDK4/6 inhibitor. We will see the data from PALOMA-3 in terms of [overall] survival at the 2018 ESMO Congress. It will be really fascinating to understand the impact on survival and to learn if there’s a subpopulation of patients who benefit.
We have been really interested in trying to understand resistance to these drugs, both in upfront and acquired subpopulations who do benefit from them. In the PALOMA studies, it’s been impossible to identify a subpopulation that doesn’t benefit from CDK4/6 inhibitors, except maybe those who have upfront mutations in the Rb gene. That, thankfully, is a very small percentage of patients.
Looking at acquired or even in some patients with upfront mechanisms of resistance, mutated cyclin E has emerged as a very interesting biomarker of resistance. More cyclin E may [be a reason for which the tumor can] overcome the effect of the CDK4/6 inhibitors. Other mechanisms have been studied, showing really elegant data with FGFR
overexpression. A number of trials are looking at ways to overcome those mechanisms of resistance, also looking at cfDNA as one way to try to identify those mechanisms.
We’re moving the CDK4/6 inhibitors into the early-stage breast cancer setting. That is critical to understand the impact both in post-neoadjuvant trials and adjuvant trials that are focusing on a very high-risk estrogen receptor (ER)–positive population. There will be more than 15,000 women treated in early-stage CDK4/6 inhibitor trials. Hopefully, we’ll have data in the next few years about whether or not we can cure more women with ER-positive breast cancer.