The Impact of the EMBER-3 Trial & Imlunestrant Changing Practice: Better Data for Women With Advanced ER+/HER2- Breast Cancer

Results of the phase III EMBER-3 trial indicate the promise and efficacy of imlunestrant, a novel oral selective estrogen receptor degrader (SERD), in treating estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer that has progressed on prior aromatase inhibitor, with or without CDK4/6 inhibitor. 

“The data is telling us that regardless of the biomarker, we might be able to see the benefit and we might be able to offer this as a second-line option for many patients,” Dr. Komal Jhaveri, breast medical oncologist at Memorial Sloan Kettering Cancer Center and study author, tells SurvivorNet Connect about the research’s impact.

The results of the trial, which are being presented at the 2024 San Antonio Breast Cancer Symposium (SABCS), have the potential to help a huge percentage of women with advanced breast cancer, Dr. Jhaveri says. 

In the trial, imlunestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) as a monotherapy in patients with an ESR1 mutation versus the standard of care endocrine therapy, reducing the risk of disease progression or death by 38%. What’s more, imlunestrant in combination with CDK4/6 inhibitor abemaciclib (Verzenio) reduced the risk of disease progression or death by 43% versus imlunestrant alone in all patients.

This study’s primary and secondary endpoints are to assess PFS compared to standard endocrine therapies and evaluate overall survival, objective response rates, and quality of life measures. The exciting new data is being submitted to global health authorities. 

‘Filling a void’

“Certainly, the impact these data might have is going to be for a very large group of patients,” Dr. Jhaveri explains.

“While it’s very attractive to have a monotherapy option for patients, those are fewer patients. Not very many patients will be somebody with slowly progressing disease who are very endocrine sensitive who have this ESR1 mutation. And for those patients, certainly monotherapy is a very, very appropriate option — but for others who have had disease progression on a CDK4/6 inhibitor in the first-line setting, we are usually utilizing a combination regiment. So, imlunestrant plus abemaciclib does fill that void in many ways for patients because not only has it shown the longest PFS of any other contemporary phase III trial in that setting, but it’s also thought to be very, very safe with a low discontinuation rate of 6%.”

This combination could be offered to a large group of patients, regardless of biomarker status, Dr. Jhaveri says, to delay chemotherapy.

Clinical Aspects of EMBER-3 Phase 3 Trial

The EMBER-3 trial is a randomized, multicenter, and open-label phase III study comparing imlunestrant to standard-of-care endocrine therapies in postmenopausal women with ER+, HER2- advanced or metastatic breast cancer. The main goal is to determine whether imlunestrant can improve progression-free survival compared to current treatments. 

Thanks to its oral presentation, this drug offers a comfortable and convenient alternative to injectable SERDs, potentially improving patients’ adherence and, consequently, quality of life. 

“We’re trying to overcome the issues that we see with currently available agents … whether it’s tolerance issues or pharmacokinetic,” Dr. Jhaveri says. “…We’re able to now see that there are these agents that are able to overcome these and will become a standard, a new standard for our patients which will actually have an impact on their survival, actually have an impact on their safety tolerability profiles and how they feel on it, and improve their quality of life.”

Who May Benefit and Who May Not?

The inclusion criteria of this study selected patients with postmenopausal status (either natural or surgical), who have progressed on or after previous endocrine therapies, such as aromatase inhibitors or selective estrogen receptor modulators, and individuals exhibiting resistance to first-line hormonal therapies. 

The following groups may benefit:

-Postmenopausal Women: Specifically those diagnosed with HR+, HER2- advanced or metastatic breast cancer.
-Patients Who Underwent Prior Endocrine Therapy: Patients who have progressed on or after previous endocrine therapies, such as aromatase inhibitors alone or combined with a cyclin-dependent kinase 4 and 6 (CDK4/6).
-Patients Resistant to Existing Treatments: Individuals exhibiting resistance to first-line hormonal therapies may find a new option in imlunestrant.

Patients with prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), fulvestrant, or any investigational ER-directed therapy (including SERDs and non-SERDs), any PI3K, mTOR, or AKT inhibitor, or patients with severe dysfunctional status (ECOG > 1, liver or renal dysfunction, cerebral metastasis) were considered not suitable for this trial. 

Ineligible patient groups:

-Hormone Receptor-Negative Patients: Those whose tumors do not express estrogen or progesterone receptors are unlikely to benefit.
-HER2-Positive Patients: Imlunestrant is not designed to target HER2 overexpressing tumors.
-Patients with Severe Liver Impairment: Patients with significant hepatic dysfunction may require alternative treatments due to metabolism considerations.

Potential Advantages

The potential advantages of imlunestrant include enhanced efficacy — the drug may offer improved anti-tumor activity due to its potent estrogen receptor degradation — and the convenience of oral therapy. An oral SERD eliminates the need for intramuscular injections, potentially enhancing patient comfort and compliance.

With the data from the EMBER-3 trial, imlunestrant may be established as a new standard of care treatment or subsequent therapy in this setting of patients, and current treatment paradigms may be reshaped, providing new hope for patients who have limited options after standard endocrine therapies.

“Seventy percent of patients are ER+,” Dr. Jhaveri explains. “So, 70% of ER+ patients are eligible for endocrine-based regimen therapy. All [or the majority] will get first-line therapy with a CDK4/6 with endocrine therapy. When they progress … we are thinking about different ways of treating them based on their biomarkers. But here, the data is telling us that regardless of the biomarker, we might be able to see the benefit and we might be able to offer this as a second-line option for many patients.

“So I think this is very attractive from that perspective because it’s not necessarily focusing on the 40% with PIK3CA mutation status or the 50% with ESR1 mutation, but saying that this could be a reasonable regimen that you could consider for all — and you don’t have to necessarily bucket it to one subgroup because — at least in the analysis we did — whether you looked at it one way or another, the benefits seem to be there for this regimen both ways.”

What About Side Effects?

Dr. Jhaveri stresses that the safety data from the EMBER-3 trial looks very promising.

“While we know that GI toxicity is something that we see with abemaciclib alone, and we did see diarrhea and nausea in addition to fatigue, these are predominantly grade 1 toxicities,” she explains.

For most patients, researchers were able to intervene to address side effects.

“We offer them anti-diarrhea, the anti-nausea medication should they need them. But they are reassured that this is grade 1. The majority of the patients did not discontinue from the trial and they actually just had single episodes,” Dr. Jhaveri explains. 

Key Points Addressed by EMBER-3

1. Efficacy Comparison: Does imlunestrant provide superior or equivalent efficacy relative to current endocrine therapies?
2. Safety Profile: Is the safety and tolerability of imlunestrant acceptable for long-term use?
3. Quality of Life: Does the oral administration of imlunestrant improve patient adherence and overall well-being?
4. Resistance Mechanisms: Can imlunestrant overcome resistance observed with other hormonal treatments?