Navigating Frontline Treatment With CDK4/6 Inhibitors in HR+ Metastatic Breast Cancer

Denise A. Yardley, MD

With the approval of 3 CDK4/6 inhibitors, the frontline treatment landscape of hormone receptor (HR)—positive, HER2-negative metastatic breast cancer has evolved with chemotherapy no longer being the go-to approach, said Denise A. Yardley, MD. 

In March 2017, the FDA granted a full approval to palbociclib (Ibrance) in combination with letrozole as a frontline treatment for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, based on data from the confirmatory phase III PALOMA-2 trial (NCT01740427). Palbociclib is also indicated for use in combination with other aromatase inhibitors (AIs) in this setting.

In April 2019, the FDA expanded the indication for palbociclib plus an AI to include men with HR-positive, HER2-negative advanced or metastatic breast cancer.

Also in the frontline setting, ribociclib (Kisqali) received approval in March 2017 for use in combination with an AI in the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, based on results of the phase III MONALEESA-2 trial (NCT01958021). In July 2018, the FDA expanded the indication to include pre/perimenopausal women. The agency had simultaneously approved the CDK4/6 inhibitor in combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, either in the frontline setting or after disease progression on endocrine therapy.

Finally, in February 2018, results from the phase III MONARCH 3 trial (NCT02246621) led to the FDA approval of abemaciclib (Verzenio) in combination with an AI for the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

"Right now, we are looking at the data [to choose among the available CDK4/6 inhibitors]," said Yardley. "Abemaciclib showed penetration into the brain, which is exciting. It is always challenging when we look at HR-positive patients, because many of them are excluded from clinical trials because of brain metastases."

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Breast Cancer, Yardley, a senior investigator in the Breast Cancer Research Program, Sarah Cannon Research Institute, discussed the implications of CDK4/6 inhibitors in HR-positive/HER2-negative breast cancer. 

OncLive:  How has the role of chemotherapy evolved with the introduction of CDK4/6 inhibitors?

Yardley: We used to limit chemotherapy to patients with HR-positive breast cancer who had evidence of disease in the viscera, lung, or liver—or who had a high tumor burden. 

Now we are trying to understand how to continue with chemotherapy as a backbone for these patients, particularly when the disease becomes resistant. We want to make [chemotherapy]-based strategies more patient friendly, perhaps through oral agents that may have lesser toxicities. 

Our hallmark was capecitabine (Xeloda), which came into the treatment of HR-positive disease as an oral agent and was not much different from our oral endocrine therapies. Now we are seeing data that will continue to build upon oral chemotherapeutics for HR-positive metastatic breast cancer. 

How have CDK4/6 inhibitors been used in clinical practice?

At this point, CDK4/6 inhibitors have been widely embraced and are a standard of care in the first- and second-line settings for patients with metastatic HR-positive breast cancer. Initially, there was a bit of a curve [in using] CDK4/6 inhibitors, particularly for patients with high tumor burden or disease in the liver or lung. 

Now our modern studies with CDK4/6 inhibitors demonstrate advantages in overall response rate, progression-free survival, and overall survival compared with chemotherapy. 

Now the questions become: What happens post-CDK4/6 inhibitor? What are the mechanisms of resistance? Can we select patients who are most likely to benefit from CDK4/6 inhibitors and give chemotherapy to those unlikely to benefit? We are seeing that horizon broaden. 

How are CDK4/6 inhibitors used in the real-world setting compared with the clinical trial setting?

In the community setting, we are seeing some adaptation to different schedules beyond the 21-day schedule, with 1 week off that we see with palbociclib and ribociclib. That schedule can still be challenging for some patients. For example, I have seen a 14-day schedule with 1 week on and 1 week off. 

We are still trying to [derive the most] benefit from these agents, although we don't have a clinical trial yet to tell us how efficacious [alternative scheduling is]. For patients who may struggle with the hematopoietic blood count element of HR-positive breast cancer, alternative schedules [may be helpful]. 

We are also learning how to select among palbociclib, ribociclib, and abemaciclib because there are differences. Perhaps one agent may benefit a particular subtype of HR-positive disease [more than another]. 

Could you elaborate on research focusing on other targets in breast cancer?

We have seen some exciting data exploring combination endocrine therapy. We first saw it in 2012 with the addition of everolimus (Afinitor), an mTOR inhibitor. Then we saw the CDK4/6 inhibitors combined with AIs in fulvestrant (Faslodex). Now, we look at PI3K inhibitors that have demonstrated activity post CDK4/6 inhibition in combination with endocrine therapy. 

We are also looking at the AKT pathway from the FAKTION trial, as [fulvestrant combined with AKT inhibition] also demonstrated benefit. Many of these trials started as the CDK4/6 inhibitors became standard of care, so they have a mixed population [of patients exposed or not exposed to CDK4/6 inhibitors]. We are going to continue with combination endocrine therapy but perhaps change the partner based on mutations [these patients may harbor]. 

We have also learned that PIK3CA-mutated tumors appear to derive the greatest benefit. It is important to identify the 40% of endocrine-positive tumors that harbor a PIK3CA mutation. It strongly signals us to continue genomic profiling and enroll patients on clinical trials.