Imlunestrant: A Promising Oral Therapy Option for Patients with ER+/HER2- Advanced Breast Cancer

A groundbreaking international study has found that imlunestrant plus abemaciclib significantly improved progression-free survival (PFS) versus imlunestrant monotherapy in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer, regardless of prior CDK 4/6 inhibitors, ESR1 or PI3K pathway mutations.

Imlunestrant is an oral, next-generation, brain-penetrant, selective estrogen receptor degrader (SERD) and pure ER antagonist that delivers continuous ER inhibition. Abemaciclib is an oral CDK4/6 inhibitor.

Komal Jhaveri, MD, FACP, International Study Chair and member of the steering committee for EMBER-3, and principal investigator of the study at Memorial Sloan Kettering Cancer Center (MSK), presented the findings from the phase 3 trial, known as EMBER-3 (NCT04975308), at the San Antonio Breast Cancer Symposium (SABCS) on December 11, 2024. The study was published simultaneously in the New England Journal of Medicine.  ⁽¹⁾

Median PFS for the combination of imlunestrant plus abemaciclib versus imlunestrant monotherapy was 9.4 months versus 5.5 months (hazard ratio (HR) = 0.57, p < 0.001).  ⁽¹⁾

“These results represent the largest PFS advantage reported to date for patients with advanced ER+/HER2- breast cancer, indicating that imlunestrant plus abemaciclib may be an attractive second-line treatment option in the metastatic setting, including for patients previously treated with CDK4/6 inhibition and without needing to screen for ESR1 or PI3KCA pathway mutations,” said Dr. Jhaveri, Section Head of the Endocrine Therapy Research Program and Clinical Director of the Early Drug Development Service at MSK. “Additionally, imlunestrant demonstrated significant improvement in PFS as monotherapy compared to standard endocrine therapy for patients whose tumors harbor ESR1 mutations.”

Dr. Jhaveri noted that MSK has been involved from the beginning, collaborating alongside the manufacturer on the drug development plan. She was also the principal investigator of the phase 1 EMBER trial and lead author of the paper summarizing its results published in September 2024 in the Journal of Clinical Oncology.  ⁽²⁾

Challenges with Current Treatments

ER+/HER2- breast cancer is the most common subtype, found in about 70% of all individuals with breast cancer. ⁽³⁾ Disease progression after standard treatment with aromatase inhibition with or without a CDK4/6 inhibitor remains challenging for this patient population: Currently, the five-year survival for patients with distant disease is about 35%.  ⁽³⁾

ESR1 mutations, found in about 40% to 50% of all ER+/HER2- advanced breast cancers, arise primarily in the metastatic setting under the selective pressure of aromatase inhibitors, leading to ER-dependent pathway activation.  ⁽¹⁾

“Fulvestrant, the only SERD broadly approved as monotherapy and in combination for patients with ESR1 mutations, is administered via intramuscular injection in the clinic, which many patients find painful and onerous,” said Dr. Jhaveri. “As an oral SERD, imlunestrant was designed to provide improved efficacy and patient experience through ease of administration, while permitting adjuvant development and combination therapy use for patients with advanced disease.”

Study Design

EMBER-3 was a phase 3, open-label, randomized controlled trial of imlunestrant monotherapy in combination with abemaciclib. The study was conducted at 195 international sites in 22 countries. The primary completion date was June 2024, and the study is no longer recruiting, with an estimated final completion date of August 2027.  ⁽¹⁾

At the SABCS 2024, Dr. Jhaveri presented results for 874 patients randomized 1:1:1 to receive imlunestrant 400 mg once daily (n=331); standard endocrine therapy (n=330, 88% fulvestrant intramuscular injection and 10% oral exemestane); or oral imlunestrant plus oral abemaciclib (n=213).  ⁽¹⁾

Tumor assessments by computed tomography or magnetic resonance imaging were conducted at baseline and every 8 weeks for 12 months, then every 12 weeks until disease progression. ESR1 mutation status was assessed via blood samples.  ⁽¹⁾

Study Results

As Monotherapy: Imlunestrant led to a 38% reduction in PFS or risk of death in patients with ESR1 mutations compared to standard endocrine therapy: The median PFS for the imlunestrant group was 5.5 months versus 3.8 months for the standard endocrine therapy group (HR = 0.62, p < 0.001). This PFS benefit was consistent across subgroups of patients, regardless of visceral metastases, prior CDK4/6 therapy, or PI3K mutation status.  ⁽¹⁾

In the overall population (including patients with and without ESR1 mutations), imlunestrant monotherapy did not significantly improve PFS versus standard endocrine therapy (HR = 0.87).  ⁽¹⁾ Notably, in the majority of patients without ESR1 mutations there was no difference in PFS (HR 1.00). 

In Combination: Imlunestrant plus abemaciclib led to a 43% reduction in PFS or risk of death (9.4 versus 5.5 months) compared to imlunestrant alone in all patients (HR = 0.57), regardless of ESR1 status. The benefit was the same across subgroups, including among patients with visceral metastases, prior CDK4/6 therapy, or PI3K pathway mutation status.  ⁽¹⁾

“Imlunestrant as monotherapy or in combination with abemaciclib provided a consistent benefit across clinically relevant subgroups,” said Dr. Jhaveri. “This was reassuring since most patients eligible for second-line therapy have already received a CDK4/6 inhibitor, and many second-line therapies require biomarker selection.” In EMBER-3, 65% of participants had received prior CDK4/6 therapy.

Central Nervous System (CNS) Progression: Dr. Jhaveri and colleagues conducted a post hoc exploratory analysis of CNS progression rates, given preclinical evidence that the drug is brain penetrant.“We observed a lower CNS progression rate of 2% with imlunestrant compared to 7% for standard therapy in patients with an ESR1 mutation,” said Dr. Jhaveri. “However, given the low number of events, and the fact that the study did not mandate serial CNS imaging, we can only say we observed a promising directional signal.”

Safety and Tolerability: Imlunestrant as monotherapy had a generally favorable safety profile with a 17% incidence of grade 3 or higher treatment-related adverse events versus 21% with standard endocrine therapy. The most common adverse events were fatigue, diarrhea, and nausea (with a 10% or less increase versus standard endocrine therapy and predominantly grade 1), and with no oral SERD-specific safety signals, such as ocular toxicity or bradycardia. The safety of imlunestrant plus abemaciclib was consistent with prior studies of fulvestrant plus abemaciclib with a low discontinuation rate of 6% versus available combination regimens, which range from 13% to 26%.  ⁽¹⁾

Interim Survival Results: Data for overall survival (OS) was 31% mature for patients with ESR1 mutations, 23% for all patients, and demonstrated a favorable trend. OS analyses were less mature in patients without ESR1 mutations (18%) and 15% within the combination therapy comparison.

“We will continue to collect data as it matures for both the monotherapy and combination regimens in EMBER-3 and plan to report OS, PFS, time to chemotherapy, and results from subgroup analyses at future meetings and publications,” Dr. Jhaveri said.

Advancing Breast Cancer Research

Dr. Jhaveri is International Co-Chair and Steering Committee Member, and principal investigator at MSK for the international EMBER-4 trial (NCT05514054) evaluating imlunestrant versus standard endocrine therapy in patients with early-stage ER+/HER2- breast cancer. The phase 3 study is underway at almost 700 sites, actively recruiting patients who have already taken endocrine therapy for two to five years and with a higher-than-average risk of recurrence. The sponsor expects the trial to last up to 10 years with an enrollment goal of 6,000 study participants.

“Soon, we will see reports of other novel endocrine agents with targeted therapies, including CDK4/6 inhibitors, selective cell cycle kinase inhibitors, and agents targeting the PI3K-AKT-mTOR pathway. While we don’t expect head-to-head trials comparing novel endocrine therapy plus cell cycle inhibitors with novel endocrine therapy plus a PI3K-AKT-mTOR pathway agent, safety and efficacy data from ongoing or planned trials in the second-line metastatic setting will inform whether the latter combination might be a better approach for patients whose tumors harbor an ESR1 or PIK3CA pathway mutation,” said Dr. Jhaveri.

“However, today, EMBER-3 is the only prospective phase 3 trial that has reported data for an oral SERD plus CDK4/6 inhibitor (imlunestrant+ abemaciclib), with a median PFS of 9.4 months, the longest we have seen to date compared to other contemporary phase 3 trials in the second-line metastatic setting despite prior CDK4/6 inhibitors in a majority of patients and regardless of prior ESR1 or PI3K pathway mutations with a low discontinuation rate and no new safety signals. As such, it is an attractive all-oral second-line treatment option for ER+/HER2- metastatic breast cancer,” she said.

The study was sponsored by Eli Lilly and Company. The authors also acknowledged support from the National Institutes of Health/National Cancer Institute Cancer Center Grant to MSK (P30 CA008748) and an Institut Curie Women’s Cancer Institute grant (ANR-23-IAHU-0006). Access disclosures for Dr. Jhaveri.

Learn more about breast cancer clinical trials at MSK.