Elacestrant/Abemaciclib for ER+, HER2- Breast Cancer: Promising Early Results

While endocrine therapy plus CDK4/6 inhibitors are a mainstay for the treatment of endocrine receptor-positive (ER+), HER2-negative (HER2–) metastatic breast cancer, endocrine therapy resistance can emerge.

The phase 1b/2 ELECTRA study (NCT05386108) sought to investigate a new all-oral combination of elacestrant (Orserdu) plus abemaciclib (Verzenio) to overcome this resistance.

Phase 1b is determining the safest and most effective dose of the combination. Phase 2 will look at the efficacy and safety, specifically in patients with brain metastases.

Preliminary results were presented at the 2024 American Society of Clinical Oncology Annual Meeting and showed a clinical benefit rate of 73%, with 1 complete response (CR), 4 had partial responses (PR), and 14 cases of stable disease. The combination also appeared tolerable, with no grade 4 adverse events or cases of grade 3 diarrhea.

In an interview with Targeted Oncology^TM, Erika Hamilton, MD, director of the Breast Cancer Research Program at Sarah Cannon Research Institute, discussed the findings, implications, and next steps of this research into a new potential cornerstone of hormonal therapy for this subset of patients.

Targeted Oncology: What are some of the unmet needs in the patient population this study focused on?

Hamilton: For endocrine therapy plus CDK4/6 inhibitors, there are 3 different ones that are our standard of care in the first-line treatment for patients that have ER+ metastatic breast cancer. However, inevitably, resistance develops, and our patients need more endocrine agents in this space. Elacestrant is now FDA-approved for that subset of patients that have ESR1 mutations, and ESR1 mutations occur as a result of exposure to endocrine therapy and can be upwards of 40%, maybe sometimes as high as 50% of patients in the metastatic setting. Elacestrant is our first drug approved, specifically for ESR1 mutations, and is the first endocrine backbone approved in the past 20 years.

What were you evaluating in the ELECTRA study?

ELECTRA was looking at elacestrant in combination with abemaciclib, 1 of our CDK4/6 inhibitors. We were evaluating both the safety and the efficacy of this combination in patients with ER+, HER2–, metastatic breast cancer.

Could you summarize the findings?

There were essentially 3 different cohorts. We had elacestrant with a dose reduction and abemaciclib with a dose reduction, elacestrant at full dose with abemaciclib at 1 dose reduction, and then the combination, both at full standard dose. We determined that full doses of both elacestrant and abemaciclib were safe to give together, and that is really the recommended dose. These patients had at least 1 endocrine therapy, up to 2 prior CDK4/6 inhibitors, up to 2 prior chemotherapies. They should not have already had elacestrant or abemaciclib. About half had already been treated with 1 line of chemotherapy.

What we saw among the 26 evaluable patients was a clinical benefit rate of 73%. We did not see any drug-to-drug interactions. Again, full doses of both agents were safe to combine together. Phase 2 is currently enrolling.

Did you observe any adverse events with this treatment?

This combination demonstrated a quite safe profile with the elacestrant and abemaciclib when combined together. Most of the treatment-emergent adverse events were grade 1 or grade 2, so milder, and the most common, more severe grade 3 treatment-emergent adverse events [were] neutropenia and low neutrophil count. This is a known [adverse] event of abemaciclib and the CDK4/6 inhibitors as a class, we did not see any grade 3 diarrhea, and there were no grade 4 adverse events during the entire treatment period at all doses.

Based on these findings, what do you consider to be the main takeaways or implications?

I think 1 of the big takeaways was the safety and ability to combine elacestrant with abemaciclib of both at full doses.We see a favorable efficacy profile, 73% of patients having clinical benefit among those with ER+, HER2–advanced breast cancer. This trial will enable a convenient all-oral treatment option before use of other fulvestrant-based combinations or chemotherapy-based regimens. Hopefully, we will keep patients on endocrine combinations for longer.

What do you see as the next steps of this research?

After CDK4/6 inhibitors in the first-line space, we see some endocrine resistance, and so combinations of drugs can be an effective way to combat that. The phase 2 portion of ELECTRA is going to be looking at both agents together to get more information about safety and efficacy and look specifically at patients that have brain metastases, since we know that both elacestrant and abemaciclib can cross the blood-brain barrier.

REFERENCE:

Ibrahim N, Hamilton E, Kim S, et al. Elacestrant in combination with abemaciclib in patients (pts) with brain metastasis from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer: Preliminary data from ELECTRA, an open-label, multicenter, phase 1b/2 study. J Clin Oncol. 2024;42(suppl 16):abstr 1064. doi:10.1200/JCO.2024.42.16_suppl.1064