A New Era in Breast Cancer Treatment with Eli Lilly's Next-Generation SERD Imlunestrant

Although many treatments are now available for hormone receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer, resistance to hormone-suppressing therapies remains a major challenge. Imlunestrant aims to address these challenges as a next-generation selective estrogen receptor degrader (SERD) that can be taken orally and penetrate the brain. On 11 December 2024, NEJM published the EMBER-3 study, which assessed treatment approaches using imlunestrant alone or abemaciclib in combination with imlunestrant, with the aim of evaluating their efficacy.

SERDs (Selective Estrogen Receptor Degraders) are a class of medicines that target estrogen receptors, disrupt their function, and cause their degradation. They aim to prevent the growth of resistant tumors, particularly in hormone receptor-positive breast cancer.

Conventional SERDs such as fulvestrant have disadvantages, including the difficulties of intramuscular injection into the buttock and limited efficacy against ESR1 mutations. These limitations are important considerations in treatment. ESR1 is the gene encoding the estrogen receptor. In metastatic hormone receptor-positive breast cancer, hormonal treatment frequently leads to changes in ESR1 in the form of mutations that develop during therapy. ESR1 mutations are most commonly seen in breast cancers that have progressed during aromatase inhibitor treatment.

As a next-generation oral selective estrogen receptor degrader (SERD), imlunestrant could overcome ESR1 mutation-related resistance and improve the patient experience. Unlike other SERDs, it can penetrate the brain by crossing the blood-brain barrier and could therefore be effective even in patients with central nervous system metastases. Oral administration avoids the discomfort of intramuscular injections while providing high bioavailability and sustained ER inhibition (estrogen receptor suppression). These characteristics make imlunestrant a more effective, patient-friendly treatment option.

Details of the EMBER-3 Study

EMBER-3 was a phase 3 open-label clinical trial conducted at 195 centers and involving 874 patients across these study sites.

Patients enrolled in EMBER-3 had previously received systemic treatment for advanced breast cancer. Specifically, all had received an aromatase inhibitor, and some had also received a CDK4/6 inhibitor during or after that treatment. However, they must not have received any other systemic treatment for advanced breast cancer. This meant that the population consisted of patients who had developed treatment resistance or disease progression.

Patients were randomly assigned in a 1:1:1 ratio to three groups:

1. Oral imlunestrant alone,
2. Standard endocrine monotherapy (oral exemestane or intramuscular fulvestrant), or
3. Imlunestrant combined with abemaciclib.

The groups were compared after stratification by factors such as prior CDK4/6 inhibitor treatment, the presence of visceral metastases, and geographical region.

The primary endpoints were the effect of imlunestrant versus standard therapy in patients with ESR1 mutations and in the overall population on progression-free survival (PFS) and the efficacy of the imlunestrant-abemaciclib combination compared with monotherapy.

Findings

• Among the patients, 38.7% had ESR1 mutations. In this group, imlunestrant provided a significant progression-free survival (PFS) benefit over standard therapy (5.5 months versus 3.8 months; HR=0.62; 95% CI=0.46–0.82; P<0.001). In patients carrying ESR1 mutations, imlunestrant reduced the risk of progression or death by 38%.
• In the overall patient population, PFS with imlunestrant did not differ from standard therapy (5.6 months versus 5.5 months; HR=0.87; 95% CI=0.72–1.04; P=0.12).
• Combination treatment with imlunestrant-abemaciclib significantly improved progression-free survival compared with imlunestrant alone (9.4 months versus 5.5 months; HR=0.57; 95% CI=0.44–0.73; P<0.001). This effect was observed regardless of ESR1 mutation status, with similar benefits in patients with PI3K pathway mutations and those previously treated with CDK4/6 inhibitors.

• Independent investigator assessments and central imaging reviews were consistent across all endpoints. Among all patients with measurable disease, overall response rates were 12% with imlunestrant, 8% with standard therapy, and 27% with imlunestrant-abemaciclib.
• All survival analyses remain immature and ongoing. In patients with ESR1 mutations, positive trends toward improved survival with imlunestrant versus standard therapy were observed (HR=0.55; 95% CI=0.35–0.86; P<0.01). A similar trend was seen in the overall population (HR=0.69; 95% CI=0.50–0.96).
• Low-grade side effects such as fatigue (23% versus 13%), diarrhea (21% versus 12%), and nausea (17% versus 13%) were more frequent with imlunestrant than with standard therapy. Diarrhea (86%), nausea (49%), and neutropenia (48%) were more frequent with combination treatment. However, rates of grade ≥3 side effects were reported as 17% with imlunestrant, 21% with standard therapy, and 49% with the combination. Treatment-related discontinuation rates remained low (4% with imlunestrant and 6% with imlunestrant-abemaciclib).

Conclusion

EMBER-3 demonstrated that imlunestrant is an effective treatment option in advanced ER+ HER2- breast cancer. It provided a significant progression-free survival benefit in patients with ESR1 mutations, while combination approaches demonstrated broader benefits in the overall patient population.

These findings highlight the potential of targeted oral treatments to improve efficacy and the patient experience in advanced breast cancer. As monotherapy or combination treatment, imlunestrant offers a promising option for patients who have developed resistance to endocrine therapy.