ELEVATE Trial Shows Promise of Elacestrant Combinations in ER+/HER2– mBC

Early results from the ELEVATE trial (NCT05563220), a phase 1b/2 study of elacestrant (Orserdu) given in combination with various targeted therapies, showed promise when used for the treatment of patients with estrogen receptor-positive (ER+)/HER2-negative (HER2–) metastatic breast cancer (mBC) who have received prior endocrine therapy and CDK4/6 inhibitors.¹

While endocrine therapy plus CDK4/6 inhibitors is the standard first-line treatment for ER+/HER2– mBC, resistance to endocrine therapy eventually develops, which limits treatment options. Now, ELEVATE is investigating the safety and efficacy of elacestrant when given with 6 different targeted therapies: abemaciclib (Verzenio), capivasertib (Truqap), everolimus, alpelisib (Vijoice, Piqray), ribociclib (Kisqali), and palbociclib (Ibrance). The initial phase aims to determine the most safe and effective dose for each combination.

Findings showed that all combinations were well tolerated and the adverse events (AEs) observed were consistent with the known safety profiles of the individual drugs. The most common AEs included decreased neutrophils, nausea, fatigue, diarrhea, and rash. Additionally, there were no unexpected safety concerns.

The trial is ongoing, and further data on safety, efficacy, and long-term outcomes will be reported.

In an interview with Targeted Oncology^TM, Hope S. Rugo, MD, FASCO, professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco Comprehensive Cancer Center, further discussed the rationale behind this study and most recent findings.

Targeted Oncology: What are the unmet needs in this patient population?

Rugo: Hormone receptor-positive breast cancer is the most common subset of breast cancer, and breast cancer is the most common malignancy in women worldwide. This represents a huge population of patients, and as you treat with hormone therapy in the metastatic setting, the tumors can expand to resistant clones. One identified area of resistance is mutations in the estrogen receptor, referred to as ESR1. There are several different kinds of these mutations, and early trials that had compared whether, after cancer progressed on an aromatase inhibitor, you would be better off giving examestane [Aromasin], the steroidal aromatase inhibitor, or fulvestrant. [Research] showed that they were relatively similar, except for when the investigators went back and looked for ESR1 mutations, and what they found was that exemestane did not do well at all. Aromatase inhibitors basically do not work in patients who have ESR1 mutations, but fulvestrant worked better. But still, what we see now in current clinical trials is that the progression-free survival to second-line endocrine therapy with fulvestrant alone is generally fairly short. There is variability in different studies, but the progression-free survival is quite short. So that has been a little discouraging, and certainly part of that cause is due to ESR1 mutations.

There are other mutations that are associated with poorer responses, like mutations in the PIK3CA pathway, but ESR1 mutations start out quite rare, around 4% at the beginning of metastatic disease that occurs not on an aromatase inhibitor, but then by the time a patient gets to the second-line or third-line setting, it could be 40%. This is a big unmet need in terms of understanding how we can improve the treatment of hormone receptor-positive disease with understanding of the mechanisms of resistance. I will say this also translates into early-stage disease, because we do not really understand why patients who are treated appropriately develop metastatic hormone receptor-positive disease. What we know is that there is expansion of a resistant clone, and some of that is likely to be due in the early relapsing patients to the development of ESR1 mutations. Understanding the right drugs for that mutation and mechanism of resistance or mechanism of escape could lead us to more effective therapies in the early-stage setting.

Now, the last unmet need is we need more oral therapies for breast cancer, both early- and late-stage disease, but I think most importantly in the metastatic setting now, patients do not want to be tied to the infusion center when they know that they have a disease that is not curable. The more we could give oral therapies that would be tolerable and effective, the better off we are.

3D rendering of breast cancer: © Giovanni Cancemi- stock.adobe.com

What is the ELEVATE study evaluating? What are the end points and goals of the study?

The first and now only oral selective estrogen receptor down regulator with regulatory approval is elacestrant. Elacestrant, in the EMERALD trial [NCT03778931] showed, particularly in patients with endocrine-sensitive disease, improved progression-free survival compared to fulvestrant. When that subset was looked at, some patients who had had previous fulvestrant could have received exemestane. This result led to approval of elacestrant. When [researchers] looked at the patient population with ESR1 mutations, improvement appeared to be much greater. The approval for elacestrant is in the ESR1-mutant population as in patients whose cancers progressed on aromatase inhibitors, and importantly in EMERALD, all patients had to have received a CDK4/6 inhibitor. This understanding of what to do in patients whose cancers have progressed on an aromatase and CDK4/6 inhibitor is very important. That is what the current approval is for patients with ESR1 mutations.

But then we go to the present day where we do not want to give single-agent endocrine therapy even in the second-line setting. We are really interested in combinations with targeted agents. The ELEVATE trial is really trying to look at both: first the safety of combining elacestrant with any number of targeted agents, essentially the ones that we have to use, and then in the phase 2 expansion, looking at the efficacy of these combinations, and of course, additional safety with larger numbers of patients.

We are now able to look at all the CDK4/6 inhibitors. We started out with alpelisib. But now we switch gears to look at capivasertib, the AKT inhibitor, as we expect that most patients who are treated with capivasertib have PIK3CA pathway alterations, rather than alpelisib due to an improved safety profile. The ELECTRA study [NCT05386108] actually has already shown in phase 1b testing that the combination of elacestrant and abemaciclib at full dose is safe and is moving on to test that combination in patients with brain metastases. But now we have the phase 2 expansion cohort in ELEVATE looking at the combination, not in patients with brain metastases, with elacestrant, alpelisib, and abemaciclib.

In fact, for ELEVATE, [patients] do not need to have an ESR1 mutation. It is really looking at all [patients], which will expand our data in patients who do not have ESR1 mutations, looking at the oral agent elacestrant. We are still looking at ribociclib in the phase 1b portion. We know that it is safe in combination with 400 mg, and we are just doing 1 additional cohort of 600 mg. Then in combination with everolimus, we looked at 5 mg, and then 10 and 7.5. We decided that it was easiest to give 7.5 mg, not because there was any pharmacokinetic interaction, but because just patients tolerate 7.5 mg better. We are now looking at our expansion study with elacestrant and everolimus, which we are excited about.

The combination of these agents, I think, is an important pathway forward. It does meet an unmet need for our patients. The ELEVATE trial is already moving forward with the dose expansion in certain cohorts and should be expanding other cohorts later this year. We will be studying capivasertib and elacestrant in the phase 1b portion, and then we will expand to phase 2 over time.

What are some findings you can discuss?

It is important to keep in mind that these are cohorts with escalating doses. ELEVATE looked at a lower dose of elacestrant and then the full dose. Cohort 1 was the lower dose, and cohorts 2 and 3 were full doses. The combined agent started out lower and then went up to our full dose by cohort 3, or our appropriate dose, like 7.5 mg of everolimus. These are tiny cohorts, and we combine them all to just get an initial look at efficacy.

First of all, safety. Absolutely no additional safety signals, which was exciting with all of these combinations: nothing unexpected, nothing new, and nothing increased over what we would expect from the generally targeted agent itself. In terms of efficacy, we saw nice responses [like] complete shrinkage of a target lesion in both the ribociclib and everolimus cohorts. [It might look] like everolimus was better than ribociclib, but it just has to do with not having enough patients in the [ribociclib] cohort. But we saw responses in both, and these are patients who were relatively heavily pretreated. The patients in the phase 2 expansion cannot receive chemotherapy or multiple lines of endocrine therapy. They have to receive their first line and then no more than 2 lines. But I think that in phase 1b, we already saw nice responses and quite durable responses in some patients, so that data will be reported in more detail in the near future.

Are there any next steps that you anticipate moving forward?

We are interested in moving oral selective estrogen receptor degraders [SERDs] into the early-stage setting, in particular, to try and avoid this development of resistance we were talking about earlier. Elacestrant will join numerous oral SERDs that are in the early-stage setting soon. That is exciting as well. We have imlunestrant and camizestrant in the early-stage setting, as well as some trials with giredestrant. These oral SERDs are now being studied in multiple different areas and in combination with different targeted agents. I think the other thing is to move them into the first-line setting, in certain situations, in combination, so that we can see in patients who have relapsed on aromatase inhibitors or who have ESR1 mutations, for example, maybe this will be an appropriate first step in treatment. That is going to be an interesting area for exploration that we are moving towards. I think these oral SERDs are so much better tolerated than the earlier generations of agents that we saw, without as much gastrointestinal toxicities or other issues.

REFERENCE:

Rugo HS, O'Shaughnessy J, Cortes J, et al. Elacestrant in various combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (adv/mBC): Preliminary data from ELEVATE, a phase 1b/2, open-label, umbrella study. J Clin Oncol. 2024;42(Suppl 16):1069. doi:10.1200/JCO.2024.42.16_suppl.1069