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Virginia Kaklamani, MD, discusses data from the ELEVATE study of elacestrant as a combination component in ER+/HER2- breast cancer.
Elacestrant (Orserdu) was effective in combination with both abemaciclib (Verzenio) and everolimus (Afinitor) for the treatment of patients with estrogen receptor (ER)–positive/HER2-negative metastatic breast cancer, paving the way for its use as an endocrine therapy backbone for combination strategies with targeted agents, according to Virginia Kaklamani, MD.
“The ELEVATE trial explored elacestrant in combination with everolimus, capivasertib [Truqap], alpelisib [Piqray], and other targeted agents,” Kaklamani explained in an interview with OncLive®. “This trial has provided valuable information on how we can use elacestrant across different patient scenarios.”
During the
Moreover, patients who received elacestrant plus everolimus (n = 50) had a median PFS of 8.3 months (95% CI, 4.0-10.2). The ORR, DCR, and median DOR were 19.5%, 82.9%, and 8.54 months, respectively.
In the interview, Kaklamani, a professor of medicine in the Division of Hematology-Medical Oncology at The University of Texas Health Science Center San Antonio and the leader of the breast cancer program at the Mays Cancer Center, highlighted the safety and efficacy data from ELEVATE, the potential shifts they could cause in clinical practice, and future directions for this research area.
Kaklamani: The results presented at SABCS this year focused on two arms: the combination of elacestrant with abemaciclib and the combination of elacestrant with everolimus. The results were very impressive. They showed that these combinations are both safe and efficacious.
These findings are important because they help guide how we may use these agents moving forward. We now have many targeted therapies, [such as] CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, and AKT inhibitors, as well as multiple endocrine therapies. We need to decide when to use these agents as single therapies and when to combine them. Depending on the clinical setting, the patient’s mutational profile, and other factors, different combinations may offer the best chance for success.
When we look at currently approved agents and combinations, we have elacestrant and imlunestrant [Inluriyo] approved as single agents for patients whose tumors harbor ESR1 mutations.2,3 We also have approved combinations of everolimus with other endocrine therapies, such as fulvestrant [Faslodex]. In patients with tumors that have PI3K or AKT pathway alterations, we have agents [such as] alpelisib and capivasertib available.
At the moment, things are relatively straightforward: if a patient has an ESR1 mutation, we can use elacestrant or imlunestrant. However, that is likely to change soon. There are multiple ongoing clinical trials evaluating novel combinations that have not yet been approved by the FDA. Over the next year or 2, treatment decision-making will become much more complex.
We are also seeing results from other trials, such as the [phase 3] EMERALD [NCT03778931] and VERITAC-2 [NCT05654623] studies, that are adding additional combination strategies. Trials like ELEVATE will be critical in helping us determine which treatments are most appropriate for specific patient populations.
First, these data reinforce that we should not assume combinations are safe without studying them. Everolimus has been available for a long time, and we know how to use it, but [data from] ELEVATE showed that when everolimus is combined with elacestrant, the standard 10-mg daily dose is not ideal. Instead, a lower dose of 7.5 mg per day should be used. This is exactly the type of information we gain from trials like ELEVATE.
Second, when elacestrant was combined with abemaciclib or everolimus, there was no unexpected additive toxicity. The safety profile reflected what we would expect from the individual agents. Overall, the trial helped define how to use these combinations safely and how to select appropriate dosing for patients.
The future is very promising. We’ve seen strong activity with elacestrant both as a single agent and in combination. There are additional phase 3 trials underway evaluating elacestrant with everolimus, although ELEVATE itself included a relatively small patient population, so we need more data.
Ultimately, we need to determine which combinations will be approved and how we can best use them in practice. Each trial adds another piece to the puzzle and helps us better identify the right treatment for the right patient. Even within ER-positive metastatic breast cancer, tumor characteristics and patient factors can influence whether one therapy is more effective than another. Trials like ELEVATE help clarify where elacestrant fits best in the treatment landscape.
As mentioned, ELEVATE continues to evaluate multiple combinations, including elacestrant with capivasertib and alpelisib. This is particularly important for patients whose tumors harbor co-mutations, such as ESR1 mutations alongside AKT pathway alterations. Understanding how to treat these patients effectively—while also minimizing toxicity—is a key goal.
This is the future direction of ELEVATE. As new combinations emerge, the trial platform allows us to assess them efficiently and refine our understanding of how to optimally sequence and combine therapies.
