CDK4/6 Inhibitors, Targeted Therapies May Expand Their Reach in HR+ Metastatic Breast Cancer

Hope S. Rugo, MD

CDK4/6 inhibitors, currently recognized as the frontline standard of care for patients with hormone receptor (HR)–positive, HER2-negative advanced or metastatic breast cancer, may also be effective and tolerable in a broader spectrum of patient subgroups, including those with metastatic disease, prior exposure to endocrine therapy, and cardiovascular comorbidities, according to Hope S. Rugo, MD. However, several drivers of CDK4/6 inhibitor resistance remain to be identified, which will further clarify the optimal patient populations for these agents.

“Over time, there are going to be expanded treatment options with drugs that target the PI3K pathway, as well as new endocrine therapies,” Rugo said in an interview with OncLive^®.

In the interview, Rugo discussed unresolved questions regarding the efficacy of adjuvant CDK4/6 inhibitors in patients with HR-positive, HER2-negative advanced or metastatic breast cancer; potential treatment options for patients who progress on CDK4/6 inhibitors; the role of targeted therapies and how they could expand for this patient population; and how her current approach to treatment sequencing may evolve based on the presence or absence of actionable mutations and the emergence of new data.

Rugo is the Winterhof Family Endowed Professorship in Breast Cancer, a professor in the Department of Medicine (Hematology/Oncology), director of Breast Oncology and Clinical Trials Education, and medical director of Cancer Infusion Services at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

OncLive: How have data for the 3 CDK4/6 inhibitors approved by the FDA for patients with metastatic HR-positive, HER2-negative breast cancer influenced treatment selection? What questions remain unanswered that future research should address?

Rugo: We have a lot of questions [left] to answer, and we’re going to have more questions to answer. First, we don’t yet understand the effects of the use of adjuvant CDK4/6 inhibitors on patients in the metastatic setting. No trial has addressed that because we don’t have the patient population.

In the phase 3 trials that have been presented so far, only a small percentage—under 5% of patients—have received CDK4/6 inhibitors in the early-stage setting. If [a patient receives] an adjuvant CDK4/6 inhibitor, will they have resistance in the metastatic setting? That’s assumed. However, what if they relapse at 10 years or have a new cancer with recurrence? We don’t know.

The second question is about the effect of mutations. We have seen fascinating data from the phase 3 INAVO120 trial [(NCT04191499), which investigated a] now-approved combination of the alpha-specific PI3K inhibitor inavolisib [Itovebi] plus palbociclib [Ibrance] and fulvestrant [Faslodex]. However, this trial [enrolled] a specific population of patients. These were patients who had developed metastatic disease in either the primary or secondary endocrine-resistant settings from the early stage. A percentage of patients had relapsed within 2 years of starting adjuvant endocrine therapy. Every patient had to have either relapsed during adjuvant endocrine therapy or within 1 year of completing that therapy, and they had to have an activating PIK3CA mutation.

PIK3CA mutations are seen in approximately 30% to 40% of patients with advanced breast cancer. In the phase 3 CAPItello-291 trial [NCT04305496], approximately 30% [of patients had these mutations]. [Therefore, drugs targeting these mutations] could affect a significant percentage of patients who have early relapse.

However, most of the patients we see don’t have early relapse. That’s a whole other question. What about patients [who don’t have early relapse] and have mutations? Should they be treated differently? Does sequencing therapies work as well as giving a triplet therapy up-front, which is associated with more toxicity and higher cost? If we can markedly improve outcomes, we can work on making the tolerance as good as possible. It appeared that in the population selected for INAVO120, the tolerance [of the investigational regimen] was good.

We’re also trying to understand which patients [are more likely to have] a poor response to up-front therapy. For example, if we give an aromatase inhibitor [AI] plus ribociclib [Kisqali], who are the patients whose best response is progression? They have estrogen receptor [ER]–positive disease, but they don’t all have PIK3CA mutations. We don’t know what is driving resistance in those patients or how we should treat those patients in a different and better way. A lot of [agents] are being evaluated now for [this subgroup]. A new CDK4 inhibitor will be in 2 phase 3 trials by the end of 2024, both in the second- and first-line settings.

[Are] triplets a better approach for all patients, even if they have a late recurrence? We don’t know the answer to that either. [We also need to] understand the right sequencing. A trial indicated that we could give CDK4/6 inhibitors in the second-line setting and [those patients would respond] as well [as those who receive these agents in the frontline setting]. Is that true for all patients? We don’t believe it, and we want to keep giving patients CDK4/6 inhibitors in the first-line setting because we have more options for them in the second-line setting, where the idea is that an overall approach improves outcomes. There’s also the whole other question of changing therapy based on the emergence of an ESR1 or ER mutation. Could we change outcomes [by switching early] vs waiting to change treatment later?

Lastly, does giving endocrine therapy in the adjuvant setting affect [outcomes]? In INAVO120, just under half of patients received tamoxifen as their only adjuvant endocrine therapy. Is that what also affected the marked improvement in outcomes [with inavolisib/palbociclib/fulvestrant vs placebo/palbociclib/fulvestrant]? It seems unlikely because those patients were getting the addition of inavolisib vs placebo to a palbociclib/fulvestrant backbone. It doesn’t seem like the endocrine therapy they received before would be the key determinant [of their outcomes]; however, that is a question [we need to answer].

In pivotal trials with CDK4/6 inhibitors and other agents, comorbidities are often exclusion criteria for enrollment. In October 2024, you coauthored a study evaluating the efficacy of palbociclib plus AIs in patients with metastatic breast cancer with cardiovascular diseases. What did this study find?

Palbociclib doesn’t prolong the QT interval. It [is not associated with] cardiovascular issues. It’s always hard to categorize what’s an important cardiovascular effect, but one of our main considerations is [whether the agent] affects the QT interval. We don’t want to cause that problem. There could be drug-drug interactions there. The most common drug-drug interaction we deal with is with drugs that are given for cardiovascular comorbidities.

The second question is: Is there a difference in tolerance [to the breast cancer drugs in patients who] have a comorbidity related to the heart, [such as] atrial fibrillation, cardiovascular disease, etc.? Interestingly, palbociclib can be given to patients who have heart failure. We are not going to be aggressively treating a patient who has an expected survival of 1 or 2 years because then we’re not helping them; [the treatment will make] them feel more tired and [expose them to the adverse effects (AEs)] we see with these drugs. However, in general, for patients with cardiovascular morbidities, [palbociclib] is well tolerated and resulted in [outcomes] we would have expected to see regarding efficacy.

Upon disease progression, patients harboring PIK3CA mutations could be eligible to receive alpelisib (Vijoice), which is associated with hyperglycemia, rash, and diarrhea. What strategies do you employ to manage and monitor these AEs?

Alpelisib has been a tough drug. In clinical trials, we managed the [associated] toxicities in most patients. However, approximately one-quarter of patients in both the phase 3 SOLAR-1 trial [NCT02437318] and in the phase 2 BYLieve trial [(NCT03056755] discontinued [alpelisib] early. That’s tough.

[Alpelisib is still] a potent and active drug; despite [the toxicities], we saw marked improvements in progression-free survival [PFS], even in patients who had received [prior] CDK4/6 inhibitors. In BYLieve, we saw nice PFS [outcomes with alpelisib plus fulvestrant] compared with endocrine therapy alone, even in patients who had received fulvestrant and a CDK4/6 inhibitor and went on to receive an AI. Almost all those patients had received prior AIs, and they still had a benefit.

[Alpelisib] is a potent drug. However, with its potency comes pathway-specific toxicities that we’re hoping new generations [of agents] may overcome, including a lot of hyperglycemia—even in patients with normal hemoglobin A1C levels, where we don’t expect to see problems. We see that across the board with [many] drugs. However, with alpelisib, it was unexpected, and it seems more [common]. There are no comparisons between all the different agents that target the PI3K pathway, [including] alpha-specific PI3K inhibitors or drugs that block the AKT pathway.

However, there are variances in the incidence of hyperglycemia [between these agents]. For example, regarding inavolisib, patients enrolled in INAVO120 had to have close-to-normal hemoglobin A1C levels, whereas [in the CAPItello-291 trial investigating] the AKT inhibitor capivasertib [Truqap], patients could have hemoglobin A1C levels [below 8.0%]. It’s hard to do cross-trial comparisons, but what we’re interested in with alpelisib, which is still an active drug, is helping oncologists understand how best to monitor and manage the toxicities.

The key toxicities patients [have] with [alpelisib are] hyperglycemia and rash. For rash, we recommend all patients receive a double dose of a non-sedating antihistamine. I try to start [patients on this antihistamine] the day before they start [alpelisib], or at least the day of. They take [this] drug twice a day, for example. Even though the over-the-counter label says [to take the antihistamine] once a day, we can give it up to 4 times a day for many patients, with the only AEs being dry mouth and dry eyes. Giving that preventively is helpful because once the patient’s immune system is activated, it’s hard to overcome a bad rash. We want to try to prevent the initial recognition and activation.

Hyperglycemia is a little more challenging [to manage]. The phase 2 METALLICA study [NCT04300790] investigated premedicating patients with metformin [Glucophage] to see whether that could reduce hyperglycemia, and it did, which was interesting. A lot of oncologists have adopted that when they use alpelisib.

We are still running into challenges with patients with glucose intolerance. We want to monitor those situations closely because this is an early effect like rash. It occurs early in the first 8 weeks; mostly we see hyperglycemia in the first few weeks after [the patient starts therapy], so we want to monitor it. We can’t start the patient on alpelisib and have them come back in a month. We need to monitor whether a patient has risk factors—once per week for the first month and then every 2 weeks in the second month. Metformin for prevention is a nice idea. We can always taper off and see [whether the patient] needs it, but starting [with this agent] may make it easier to keep a patient on [alpelisib].

Lastly, we need to partner with [physicians] who manage hyperglycemia because we’re been able to keep patients with hyperglycemia on [alpelisib] with some of the new GLP-1 agonists, and [this AE has] been managed much better than in the past. As oncologists, if we can avoid all that, it’s nice. If we can find drugs that are active against [the PI3K] pathway, clearly an important area to target, that [are not associated with] severe hyperglycemia or [only induce] it in a small percentage of patients, it will be a big win.

What data have been seen for patients who progress on CDK4/6 inhibitors? How might novel endocrine therapies fit into this treatment paradigm?

There are 2 main areas we’re evaluating for patients whose cancers are progressing on initial endocrine therapy plus a CDK4/6 inhibitor. One is to investigate new targeted agents that might target the biology of the cancer more effectively. The second is to examine new endocrine therapies that may overcome mechanisms of resistance that we understand right now: ESR1 mutations.

Lots of drugs that are important in degrading the ER and are oral as opposed to the injection of fulvestrant—[such as] the oral selective ER degraders [SERDs], proteolysis targeting chimeras [PROTACs], and complete ER agonists—seem to be active in patients with ESR1 mutations. This is a big difference from PI3K inhibitors and PIK3CA mutations. PIK3CA mutations are conserved. They’re clonal. We can see them in the early-stage and metastatic settings. In the metastatic setting, we see a small acquisition of PIK3CA mutations over the course of treatment, probably in the under 10% range.

However, ESR1 mutations found in untreated cancer are rare. We see the acquisition of mutations over time under the pressure of treatment. It’ll go from 9% to 20%, 30%, and up to 40% over the course of treatment. These are different types of areas to target.

The oral SERD area is exploding. There are trials in the first- and second-line settings. There are trials in the early-stage setting, both up-front and after an initial 2 to 5 years of standard endocrine therapy, where patients are randomly assigned to receive oral SERDs or not. There are combination studies. There’s a study investigating giving an oral SERD to patients who acquire an ESR1 mutation before they have evidence of progressive disease by imaging or exam. There are also new classes of drugs, [including the] PROTAC vepdegestrant [ARV-471].

[Research is] trying to see differences between these agents, such as whether they’re all better than fulvestrant in only patients who have ESR1 mutations or [an all-comers population], [as well as] whether we could have a better treatment plan that wouldn’t be dependent on ESR1 mutations if we combine these drugs with a targeted agent.

We don’t want to give fulvestrant alone because, in general, the PFS lengths have been short. [Patients are] stable on the first scan and then progress, or even progress at the first scan. Some studies have shown longer PFS outcomes with fulvestrant. If we carefully select patients for endocrine sensitivity, [including those who spent a] long time on first-line therapy, [those with] bone-only disease, [those with] soft-tissue disease, [or those with] limited disease, [those patients achieve] a longer PFS with fulvestrant alone

However, that’s not the patient population we see all the time. [Researchers] don’t want to do trials anymore with fulvestrant as a single agent. We want to investigate combinations. That’s translated into an explosion of trials evaluating oral SERD–like drugs in combination with targeted therapies.

Regarding the advances we’re making in targeted therapies, we have a newly approved AKT inhibitor, capivasertib, that’s highly active. Patients are eligible [to receive this agent] if they have activating mutations in PIK3CA, but also in the AKT pathway, as well as PTEN loss.

Capivasertib is now being evaluated in a phase 1b/3 triplet [trial, CAPItello-292 (NCT04862663), which is] like INAVO120, but [it is enrolling patients] regardless of mutation status. In the first-line setting, [patients are receiving] either provider’s choice of palbociclib or ribociclib plus fulvestrant and capivasertib, or fulvestrant plus a CDK4/6 inhibitor alone. That is an interesting area of investigation.

We also have other drugs. There is a host of new PI3K inhibitors. Inavolisib is being compared head-to-head with alpelisib; [those data are] going to be fascinating. There are new CDK4/6 inhibitors, [such as those being investigated in the] phase 3 CDK4 inhibitor trials, which will be fascinating to see. Combination trials with CDK4 inhibitors [are also planned] because [these agents] are well tolerated. They do not cause the cytopenias or diarrhea we see with the currently approved CDK4/6 inhibitors. CDK2 inhibitors, which seem to [be associated with] more toxicity, are also being evaluated, but they are not yet in registrational approaches.

Along with that, there’s interest in determining which patients are not going to benefit from second-line endocrine therapy and should go on to receive chemotherapy or an antibody-drug conjugate. We’re still trying to figure that out. In patients with a short PFS and those who lose ER, we’re going to need to biopsy the liver metastases when they happen because there’s now a growing subset of patients who lose ER when their cancers progress more rapidly.

How do you currently approach treatment for patients with HR-positive, HER2-negative metastatic breast cancer, both with and without actionable mutations? How do you aticipate those current treatment pathways changing in the coming years, based on emerging data?

We have to wait and see. We’re going to be using oral SERDs more. Another area that is being explored is in patients who don’t have actionable mutations. Right now, we have data with using CDK4/6 inhibitors after [progression on a] CDK4/6 inhibitor [to see] how changing the CDK4/6 inhibitor affects outcomes. We’re going to see more of those data at [the 2024 San Antonio Breast Cancer Symposium] with results from the phase 3 EMBER-3 trial [NCT04975308], which investigated the oral SERD imlunestrant [LY3484356] alone vs fulvestrant vs imlunestrant plus abemaciclib [Verzenio]. These are all going to be interesting data, and they have already affected treatment decisions in patients who don’t have targetable mutations and have limited progression.

[Patients who] have a little progression in 1 bone lesion or an extra bone lesion are those in whom we might use a CDK4/6 inhibitor after a CDK4/6 inhibitor and change the endocrine therapy partner to try to avoid some of the toxicities [associated with] the targeted agents. Will we be replacing CDK4/6 inhibitors in that sequential format with a CDK4 inhibitor? How do we assess the targetable mutations, and what’s the best way?

For example, we use a combination of tissue and plasma circulating tumor DNA [assays], but there is an ongoing discussion about when we do which test. We want to do tissue biopsies at some point because we need to look at ER and HER2 status. We need to document metastatic disease from the breast primary. That’s important. Then, if the patient is not having the response we expect, we need to make sure ER is being retained.

If you’re considering sequential therapies, sometimes biopsies are done to look for HER2 expression, for example, with a new HER2-low approach. Regarding other mutations, we can best look at PIK3CA and ESR1 in plasma because ESR1 mutations are acquired. You’re not going to continue to biopsy [tissue] over time. You might do 2 [tissue biopsies], but you’re not going to do it at every progression.

We can see AKT mutations [in the plasma]. PTEN deletions are not seen in blood. Importantly, large deletions of BRCA are not seen in blood either. We want to do next-generation sequencing in tissue at least once, just to look for those [mutations].

Ultimately, we will move these drugs—if they’re more effective—earlier in the course of treatment to both help patients stay in the first-line setting for as long as possible and help them avoid developing metastatic disease.