Elacestrant + Targeted Therapy for ER+/HER2– Metastatic Breast Cancer: Early Phase Trial Findings

The ELEVATE trial (NCT05563220) is an ongoing phase 1b/2 study investigating elacestrant (Orserdu) combined with various targeted therapies for patients with endocrine receptor-positive (ER+)/HER2-negative (HER2–) metastatic breast cancer (mBC) who have already received endocrine therapy and CDK4/6 inhibitors.

Endocrine therapy combined with CDK4/6 inhibitors is the standard first-line treatment for ER+/HER2- mBC. However, resistance to endocrine therapy eventually develops, limiting treatment options. Elacestrant, a new type of drug, has shown promising results in patients with acquired resistance due to ESR1 mutations.

The ELEVATE trial is evaluating the safety and efficacy of elacestrant combined 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 safest and most effective dose for each combination.

The trial enrolled patients in cohorts for each elacestrant and targeted therapy combination. All combinations were well-tolerated with adverse effects consistent with the known safety profiles of the individual drugs. The most common side effects included decreased neutrophils, nausea, fatigue, diarrhea, and rash. No unexpected safety concerns were observed.

These early findings suggest that elacestrant combined with targeted therapies may be a promising treatment option for patients with ER+/HER2– mBC who have become resistant to standard therapies. The trial is ongoing, and further data on safety, efficacy, and long-term outcomes will be reported.

Transcription:

0:05 | Well, 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. And when that subset was looked at, some patients who had had previous fulvestrant could have received exemestane. So this result led to approval of elacestrant. But when the whole analysis in the intent-to-treat population showed an improvement, when they looked at the patient population with ESR1 mutations, improvement appear to be much greater. So 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. And this understanding of what to do in patients whose cancers have progressed on an aromatase and CDK4/6 inhibitor is very important. So that's what the current approval is for patients with ESR1 mutations.

1:07 | But then we go to the present day where we really don't want to give single-agent endocrine therapy even in the second-line setting. We're really interested in combinations with targeted agents. So 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, so that's the phase 1b part, looking at the efficacy of these combinations, and of course, additional safety with larger numbers of patients. So we're able to now look at all the CDK4/6 inhibitors. And we started out with alpelisib. But now we switch gears to look at capivasertib [Truqap], the AKT inhibitor, as we really expect that most patients will be 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 alpelisib 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 [Verzenio]. So that's actually a really nice combination that's being evaluated now, in the phase 2 expansion.

2:32 | In fact, for ELEVATE, you don't need to have an ESR1 mutation. So it's really looking at all comers, which will expand our data in patients who don't have ESR1 mutations, looking at the oral agent elacestrant. We are still looking at ribociclib. And the phase 1b portion, we know that it's safe in combination with 400 milligrams, and we're just doing 1 additional cohort was 600 milligrams. And then in combination with everolimus, we looked at 5 milligrams, and then 10 and 7.5. And we decided that it was easiest to give 7.5 milligrams, not because there was any pharmacokinetic interaction, but because just patients tolerate 7.5 milligrams better. So we're now looking at our expansion study with elacestrant and everolimus, which we're really excited about. So the combinations of these agents, I think are is a really important pathway forward. It does meet an unmet need for our patients. And the ELEVATE trial is already moving forward with the dose expansion in certain cohorts and should be expanding other cohorts later this year. We're very excited, we'll be studying capivasertib and elacestrant in the phase 1b portion, and then we'll expand to phase 2 over time.

Transcription created with AI and edited for clarity.