Standardized Frontline CDK4/6 Inhibition Sets the Stage for Further Research in HR+/HER2- Breast Cancer

Katherine K. Clifton, MD

CDK4/6 inhibition has transformed the treatment paradigm of metastatic hormone receptor (HR)–positive, HER2-negative breast cancer, said Katherine K. Clifton, MD, who added that the survival advantage observed with these agents has solidified their role in the frontline setting.  

“Overall, because [CDK4/6 inhibitors] have shown such great improvements in progression-free survival [PFS] and, in some cases, overall survival [OS], and they are generally well tolerated, they have really become our first-line standard of care for patients with HR-positive breast cancer,” said Clifton.

Currently, 3 agents, ribociclib (Kisqali), abemaciclib (Verzenio), and palbociclib (Ibrance) are approved in combination with fulvestrant (Faslodex) for the first- or second-line treatment of patients with HR-positive, HER2-negative disease. 

Now, research efforts are focused on adapting CDK4/6 inhibitors to other therapeutic settings, such as the neoadjuvant setting, optimizing the endocrine backbone used with these agents, and further exploring the role of CDK4/6 inhibition after progression on another CDK4/6 inhibitor. 

Additionally, with PI3K inhibitors, such as alpelisib (Piqray) gaining a more significant role in the advanced HR-positive/HER2-negative space, determining how to best utilize these agents with CDK4/6 inhibitors remains an area of clinical interest, said Clifton. 

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on breast cancer, Clifton, an assistant professor in the Department of Medicine within the Oncology Division of Washington University School of Medicine in St. Louis, discussed the utility of CDK4/6 inhibitors as frontline treatment for patients with HR-positive/HER2-negative breast cancer, the growing role of PI3K inhibitors in this space, and potential future research directions with these treatments.

OncLive^®: How has the field adopted CDK4/6 inhibitors into clinical practice? How do these agents distinguish themselves with regard to toxicity? 

Clifton: Three CDK4/6 inhibitors: palbociclib, ribociclib, and abemaciclib, [are approved in HR-positive/HER2-negative breast cancer based on] phase 3 trials. All [3 agents are approved] in the first- and second-line settings and showed significant improvement in PFS in patients with advanced breast cancer. We’ve also seen OS benefits with ribociclib and abemaciclib, as well as in a subgroup of patients with palbociclib in the PALOMA-3 trial. [These agents] are well tolerated. They all have high rates of neutropenia, but the rates of febrile neutropenia are fairly low. Some CDK4/6 inhibitors, such as ribociclib, have low but significant rates of [QT] prolongation [on electrocardiograms]. However, we [know] how to monitor for that. Additionally, abemaciclib is associated with higher rates of diarrhea. 

The PFS benefits observed with ribociclib, abemaciclib, and palbociclib were comparable. Now that we have OS data with ribociclib and abemaciclib, does palbociclib still have a role in treatment?

There are definitely still situations where palbociclib is useful. Some survival benefit was seen in the subgroup of patients in the PALOMA-3 trial who were endocrine sensitive. It is hard to compare different CDK4/6 inhibitors across trials because, of course, the patient populations might have been different. So, although palbociclib does have a role, [it is important] to keep the toxicity profile in mind, [particularly] the small but significant rate of [QT] prolongation and higher rates of diarrhea with abemaciclib. [Those adverse effects] may help with the decision-making process.

Have you found it frustrating or valuable to use different endocrine therapy backbones with the CDK4/6 inhibitors?

Trying to decide which [backbone] is the ideal partner to [pair with a] CDK4/6 inhibitor [is a common question we face]. The PARSIFAL trial, which was presented at the 2020 ASCO Virtual Scientific Meeting helped us answer that question. [PARSIFAL] was a phase 2 trial in the first-line setting looking at palbociclib with fulvestrant or letrozole. [The data] showed no PFS difference between the 2 endocrine backbones.

Generally, in the first-line setting, if the patient has not recently been on or progressed on an aromatase inhibitor [AI], we will usually start [an AI] and then start fulvestrant in the second-line setting.

Now that CDK4/6 inhibitors have been heralded as the new standard of care in the front-line setting, are trials like MONARCH 2 becoming less relevant? 

Definitely, because it seems like the majority of these patients are receiving CDK4/6 inhibitors in the first-line setting. Some unique situations [may exist] of patients who don’t tolerate CDK4/6 inhibitors initially or older patients who want to start with endocrine therapy alone where those older studies are still relevant. 

What other questions with CDK4/6 inhibitors are outstanding that you would like to see addressed with future research?

The big questions now are in the high-risk adjuvant setting. At the 2020 ESMO Virtual Congress, we saw the recent updates to the monarchE and PALLAS trials. [These trials explored] the use of CDK4/6 inhibitors in the adjuvant setting in high-risk patients and were very interesting. The PALLAS trial was stopped early, whereas the monarchE trial showed some benefit. Long-term follow up from the monarchE trial will be really interesting.

Also, the results from the NATALEE trial looking at ribociclib in the high-risk adjuvant setting [could] help [us] see where we should use CDK4/6 inhibitors in the adjuvant setting. 

Then comes the question of: If a patient receives a CDK4/6 inhibitor in the adjuvant setting but progresses on it or develops metastatic disease, what is therapy we should start with in the metastatic setting?

If the patient does progress on a CDK4/6 inhibitor in the metastatic setting, will treatment selection be based on mechanisms of resistance? 

A lot of questions are unanswered [regarding treatment selection for those patients who progress on CDK4/6 inhibitors]. Some of [the decision] will depend on whether the patient develops metastatic disease while on the CDK4/6 inhibitor vs if there has been somewhat of a gap between finishing adjuvant CDK4/6 inhibitor therapy and developing metastatic disease. 

We have some data on switching to a different CDK4/6 inhibitor upon progression, but a lot of those data are from retrospective or from phase 1/2 trials. However, there are larger trials ongoing that will help answer the question of what to do if a patient progresses on a CDK4/6 inhibitor. Will they derive any benefit from switching to a different CDK4/6 inhibitor?

PI3K inhibitors, particularly alpelisib, are also exciting in this space. How is that agent being incorporated into practice?

Alpelisib is a PIK3CA inhibitor and has really been used in the second-line setting. The agent was approved based on findings from the SOLAR-1 trial. Patients [in SOLAR-1] had already received endocrine therapy and received alpelisib in combination with fulvestrant. [The combination] showed significant improvements in PFS; the OS data are not mature yet. Alpelisib does have some pretty important toxicities to point out, including a high rate of grade 3 hyperglycemia. It is important to note that there are specific recommendations in the package insert about how to carefully monitor and manage hyperglycemia. 

Is there any rationale to combine CDK4/6 inhibitors with PI3K inhibitors, or would that result in too much toxicity?

I’m not sure if that [strategy] has been studied yet, but I could see why that would [result in] a great deal of toxicity. Although CDK4/6 inhibitors and PI3K inhibitors are different and don’t necessarily have overlapping toxicities, each together may harbor toxicity.

What could be learned from the ongoing BYLieve trial with alpelisib?

When SOLAR-1 was conducted, about 6% of patients received CDK4/6 inhibitors. Obviously, the landscape when that trial was conducted is very different from our current practice today. The BYLieve trial is helping us determine the efficacy of alpelisib in patients who previously received CDK4/6 inhibitors. Cohort A [of the BYLieve] trial was presented at the 2020 ASCO meeting. Those patients who had received a CDK4/6 inhibitor and an AI and progressed went on to receive alpelisib and fulvestrant. The median PFS was about 7 months, which is similar to [what was seen in] the SOLAR-1 trial. That is reassuring us to use alpelisib in patients who have received a CDK4/6 inhibitor. 

Cohort B, which hasn’t been reported yet, will probably be the most interesting [cohort]. [In cohort B], patients who have received fulvestrant [with or without] a CDK4/6 inhibitor and progressed, went on to receive alpelisib and an AI. We commonly encounter that scenario in clinical practice. Since [we only have] data for alpelisib and fulvestrant, it will be interesting to see data with alpelisib and an AI. We are eagerly awaiting those results. 

Is there any other research being done at your institution that you want to spotlight?

We do have a clinical trial looking at CDK4/6 inhibitors in the neoadjuvant setting. Patients who are eligible to receive neoadjuvant endocrine therapy are started on a new regimen [consisting of] endocrine therapy for at least 2 weeks. Then patients undergo a repeat biopsy to examine Ki-67. If patients’ Ki-67 is still elevated, they are eligible for this trial, where they will receive a CDK4/6 inhibitor in the neoadjuvant setting.