CDK4/6 Inhibitors: The Future of Metastatic HR-Positive Breast Cancer

Most discussion in hormone receptor (HR)—positive metastatic breast cancer are now focused on CDK4/6 inhibition, according to Denise A. Yardley, MD, who added that, after demonstrating significant survival benefits, these agents have transformed the standard of care.

“There are 3 key agents: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). Several phase 3 trials incorporating these agents showed a resounding, reinforcing message of improvement in median progression-free survival (PFS). In earlier lines of therapy, this translated to a doubling in PFS,” said Yardley. “Ultimately, these data put these agents on our radar, which later resulted in approvals.

We now have 1 of the gold standards in terms of selecting agents and making treatment algorithm recommendations for our patients because there are finally data to support an overall survival (OS) advantage.”

In an interview with Oncology Nursing News' sister publication, OncLive, during the 2020 International Perspectives in Cancer webinar on Breast Cancer, Yardley, a senior investigator in the Breast Cancer Program at Sarah Cannon Research Institute, highlighted the evolving role of adjuvant CDK4/6 inhibition in HR-positive metastatic breast cancer.

OncLive: Could you expand on the HR-positive metastatic breast cancer treatment landscape?

Yardley: All discussions of HR-positive metastatic breast cancer now involve CDK4/6 inhibitors, as these agents have really evolved and changed our standard of care. Three trials have shown an OS advantage [with this approach], which is a resonating message of a good surrogate for having benefit. We are seeing the median PFS benefit translate into an OS advantage.

On the heels of that, an important question with patients who have HR-positive disease is determining how to incorporate [what we have learned] into our day-to-day practice. One of the groups that we've always had some hesitation in approaching with endocrine-based therapy is the group with visceral metastasis.

During the 2020 ASCO Virtual Scientific Program, data presented from the MONALEESA-3 and the MONALEESA-7 trials, which examined ribociclib. Results showed that about 60% of the population had visceral metastasis on both of trials. I would say benefits mirrored what we saw with the overall MONALEESA-3 and the MONALEESA-7 study populations. We saw a 20% reduction in the risk of death in patients with visceral metastasis in MONALEESA-3 who received treatment with ribociclib and approximately 30% for those [with metastasis] in MONALEESA-7. We carved out just those with liver metastasis, which is a life-threatening organ to be involved with metastatic disease, and we saw similar benefit in both PFS and OS.

That may have been a group of patients that practitioners have concern about in terms of using endocrine therapy or endocrine therapy with CDK4/6 inhibition, which is cytostatic. Now, we have great data showing that these patients do just as well [with this treatment] as the study population as a whole. The benefit of that doublet therapy didn’t translate into more adverse effects for that population; it reinforces the efficacy of taking the approach in a more challenging group of patients with visceral metastasis, whether it's liver or lung.

I believe that provides comfort and shows the importance of not pulling the trigger for chemotherapy or even the consideration of oral chemotherapy. We can now feel comfortable moving forward with making that recommendation of endocrine therapy in combination with CDK4/6 inhibition based on these studies.

What challenges have been faced in terms of research?

I believe we can widen the audience of patients with HR-positive metastatic breast cancer who are going to benefit from the CDK4/6 inhibitors; however, a challenge is that resistance does develop. Now we must determine if we can categorize and predict that resistance.

Many studies have examined potential biomarkers of sensitivity or resistance. Right now, we still say ER positivity is the only biomarker for benefit. Many markers have been examined, but none have been consistently validated. That research avenue continues to be explored.

We are now wondering whether we could identify a patient who might derive less benefit from this approach due to intrinsic resistance or patients who stop deriving benefit beyond 6 months due to acquired resistance. Although a lot of emphasis has been placed on that, I believe we are challenged by many different signals, in addition to learning how to incorporate them. Mutations in the RBG, PI3K, and cyclin E, all seem to resonate but are not ready to be used for real-time assessment and decision making.

How do ESR1 mutations play a role in decision making? What are some of the data that we have seen with regard to treating this patient subset?

The ESR1 mutations are also emerging as having a role in making treatment decisions in patients with HR-positive metastatic breast cancer. For patients who develop the ESR1 mutation either at baseline, which is 1% to 5%, or after exposure to an aromatase inhibitor (AI), which increases to 30% to 40%, what do we do? Many of these patients have gone onto fulvestrant (Faslodex), which clearly has a role in those who demonstrate ESR1 mutations.

Interesting data from the PADA-1 trial, which were presented during the ASCO 2020 Virtual Scientific Program, examined patients at baseline and measured the ESR1 mutation. We know if patient was treated with an AI and palbociclib and they had [the ESR1] mutation [at baseline], the [prevalence] rate [of the mutation] was approximately 3%; if they had received a prior AI in the adjuvant setting, that rate goes up to about 7%. Those patients did poor versus the group who had no mutation, with a median PFS of about [7] months versus about 26 months, respectively.

Interestingly, when the group that had the ESR1 mutations who were treated with an AI and palbociclib were remeasured 1 month later, those who cleared their ESR1 mutation with treatment with a CDK4/6 inhibitor and an AI did just as well as those who didn't have [the mutation] at baseline. How do we adopt this to our practice? Before I saw these data, I would be hesitant to give AI after measuring an ESR1 mutation. However, now I have some comfort level, particularly in those patients who have already received fulvestrant or may not be a candidate, to challenge with an AI and a CDK4/6 inhibitor.

Maybe I would remeasure it in a month to determine if I have cleared it and feel confident that the patient has every reason to hopefully benefit and continue monitoring them.

We’re still trying to figure out all the different permutations of how to get around ESR1 mutations. I think the oral selective estrogen receptor downregulators are certainly very prevalent in the clinical trials and may be vastly easier than fulvestrant in a group of patients. We will hopefully see an approval of 1 of these therapies in the near future so that we can get them into the clinics and in commercial use.

Shifting to those with PI3K mutations, could you shed light on the BELIEVE trial?

Another challenge is understanding what to do after CDK4/6 inhibition. This has [shifted] our standard of care as a first-line therapy and second-line therapy for patients who didn't receive it in the first line. We’re working on becoming savvy with continuing to screen those patients now for other actionable mutations. PI3K mutations really come up in that particular setting.

In the BYLieve trial, investigators assessed patients with a PI3K3CA mutation who had received a prior CDK4/6 inhibitor plus an endocrine agent, endocrine therapy, or systemic chemotherapy. In the trial, they either received [a CDK4/6 inhibitor plus an AI,] alpelisib (Piqray) with fulvestrant, [or chemotherapy or endocrine therapy following progression on an AI].

Those patients did remarkably better than the group who were just treated with standard-of-care agents from a FLATIRON database. Looking at post CDK4/6 failures just treated with either fulvestrant, CDK4/6 inhibitor, or chemotherapy, compared with those tested in the BYLieve trial who were offered an alpha-specific PI3K alpelisib with fulvestrant, results showed that this [approach] doubled the [benefit] for these patients in a matched analysis. As such, if you find that population, it’s certainly worth testing because they fare better [with this approach] as compared with standard therapy.

The ways in which we think about treating our patients with HR-positive metastatic breast cancer is constantly broadening. We’re also embracing doublet therapy over monotherapy endocrine therapy. There is a clear rationale and basis for scrutinizing these tumors, in addition to continuing to look for these alterations that we can target very effectively; by doing this, we continue to improve outcomes.

Several other PI3K [inhibitors are being examined] in clinical trials. We're now examining triplets comprised of PI3K inhibitor, a CDK4/6 inhibitor, and endocrine therapy in the first-line setting for patients with PI3K-mutated disease. We're going to see if we can build on the data, we already have with the doublet CDK4/6/endocrine therapy. That may be quite a challenge, but it will be interesting to see how that triplet therapy may fare in comparison with doublet therapy.

What is some of the research that is being done with AKT inhibitors?

Some trials are examining AKT inhibitors and their role in combination with endocrine therapy. We have capivasertib (AZD5363), which is being evaluated in a post-CDK4/6 pathway and investigators assessed whether the patient had PI3K mutation or not. [The presence of the mutation] did not appear to affect the benefit and the outcome of the doublet comprised of the AKT inhibitor and endocrine therapy. That's likely going to be another targetable agent that's not going to be mutation dependent as a PI3K to achieve that efficacy.

I believe we're starting to see this algorithm of an endocrine backbone partnered with a targeted agent. What we see is really manipulation of what we know in the HR-positive metastatic breast cancer space in terms of that estrogen signaling pathway and where we see alterations that result in shortened duration of benefit or resistance that we're able to target and provide more longevity to an endocrine therapy-based approach for these patients.

We need to keep chemotherapy on the back burner as we learn how to sequence these agents. I believe the trials are going to continue and we're going to have a continued altering standard of care and algorithm of standard-of-care options for these patients. It’s very exciting to be a part of some of these trials and see these drugs make it to the clinic where they can benefit so many more patients.

This article was originally published on OncLive as, "CDK4/6 Inhibitors Shift Standards in HR+ Metastatic Breast Cancer."