Hope S. Rugo, MD, discusses CDK4/6 inhibition in HR-positive breast cancer, mechanisms of resistance to these drugs, and other potential pathway blockades.
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.Rugo: 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.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.
One of the important things in these studies is the need for very long-term follow-up. Even with stage I breast cancer, we’re seeing 14% of patients with recurrent disease after 5 years of adjuvant endocrine therapy and [risk of recurrence] up to 20 years. That can rise to 50% in patients who have higher-risk multi-node breast cancer. Could we use CDK4/6 inhibitors to “nip the disease in the bud,” so you don’t have dormancy and late recurrences? That will be fascinating to see as we look at these trials over time. It’s also going to be important to evaluate quality of life and make sure that we’re not making everybody exhausted for all those years. Identifying the patients who are most likely to benefit will be critical.
The NATALEE trial, which is supposed to open later this year, will use 3 years of a CDK4/6 inhibitor; this is the adjuvant trial with ribociclib. Three years is a long time, so it will be interesting to see what the compliance is with longer durations. We’ve found that even 2 years is a long time in the adjuvant setting, although many people with high-risk disease will stick with it.Along with CDK4/6 inhibitors, there’s a great desire to look at other pathways to block. There are many different studies ongoing looking at HDAC inhibitors, early-phase trials of FGFR inhibitors, and other agents of great interest. IPATunity 130 is a trial with the AKT inhibitor ipatasertib in both ER-positive and triple-negative breast cancer. The trial is targeting patients whose tumors have disordered AKT-PI3K or PTEN tumor suppressor gene.
Next on the block is PI3K. We know up to 50% of our patients with ER-positive breast cancer will, at some point, have mutations in PI3K. An alpha-specific inhibitor, alpelisib (BYL719), has the greatest promise of any of the PI3K inhibitors that we’ve studied so far, including the pan-PI3K inhibitors. The beta-sparing PI3K inhibitor taselisib (GDC-0032) had very minimal activity and a lot of toxicity. Alpelisib [is associated with] skin rash and hyperglycemia, as well as weight loss that we have seen with the more focused PI3K inhibitors. However, it doesn’t have some of the other toxicities that make [those more focused PI3K inhibitors] tough, like colitis, psychiatric issues and liver function test abnormalities.
A news release suggested that the primary endpoint of improved PFS was met in the SOLAR-1 trial, which randomized patients in the second-line setting to fulvestrant and placebo or alpelisib. We need to see those data presented at the 2018 ESMO Congress, but I’m very excited that these data will lead to the first approved PI3K inhibitor in treating PI3K-mutant metastatic breast cancer.*
That may lead us to understand how we’re going to use targeted agents. If the cancer has a PI3K mutation, maybe the patient should get that drug before a CDK4/6 inhibitor. Maybe we’ll learn that in the setting of further studies with oral selective ER down regulators, where there are many drugs in clinical trials.
*This interview was conducted prior to the 2018 ESMO Congress, where data from the SOLAR-1 trial were released.