FDA Approves Imlunestrant for ESR1-Mutated ER+, HER2- Breast Cancer

The FDA has approved imlunestrant (Inluriyo) for ESR1-mutated ER+, HER2- metastatic breast cancer. With elacestrant already on the market, patients now have two oral SERDs — raising questions of sequencing, safety, and access.

The U.S. Food and Drug Administration (FDA) has approved imlunestrant (Inluriyo, Eli Lilly) for the treatment of adult patients with estrogen receptor (ER)–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer whose disease has progressed after prior endocrine therapy.

EMBER-3 Trial Results

The approval was based on the global Phase 3 EMBER-3 trial (NCT04975308):

• In patients with ESR1 mutations, imlunestrant achieved a median progression-free survival (PFS) of 5.5 months versus 3.8 months with standard endocrine therapy.
• This translated into a 38% reduction in the risk of disease progression or death (HR ≈ 0.62).
• The recommended dosing is 400 mg orally once daily on an empty stomach.

Key adverse events (≥10%) included decreased hemoglobin, musculoskeletal pain, neutropenia, hypocalcemia, elevated liver enzymes, fatigue, diarrhea, nausea, constipation, and lipid abnormalities.
Imlunestrant carries a warning for embryo-fetal toxicity, and dose adjustments may be required with CYP3A inhibitors or hepatic impairment.

Elacestrant Paved the Way

Imlunestrant follows elacestrant (Orserdu, Stemline/Menarini), approved in January 2023, which became the first therapy specifically indicated for ESR1-mutated disease.

• Approval was based on the EMERALD trial (NCT03778931).
• In the ESR1-mutated subgroup (n = 228), elacestrant delivered a median PFS of 3.8 months vs. 1.9 months with standard endocrine therapy (HR 0.55).
• Dosed at 345 mg orally once daily with food, elacestrant’s common adverse events included nausea, musculoskeletal pain, fatigue, GI upset, and elevated liver enzymes.
• The Guardant360 CDx liquid biopsy was co-approved as the companion diagnostic for detecting ESR1 mutations.

What the Imlunestrant Approval Means

The approval of imlunestrant has several implications:

1. More Options, More Competition
   Patients now have two FDA-approved oral ER-targeted therapies for ESR1-mutated disease, creating competition in a previously single-agent market.
2. Potential Differences in Activity
   Imlunestrant showed a longer median PFS (5.5 months) than elacestrant (3.8 months), though cross-trial comparisons must be made with caution.
3. Differential Safety Profiles
   Hematologic side effects such as neutropenia were more prominent with imlunestrant, while GI-related adverse events were more common with elacestrant.
4. Refining Biomarker Testing
   Sensitive and standardized ESR1 mutation testing will be critical to guide use, especially as multiple targeted options become available.
5. Future Outlook
   Lilly is already advancing imlunestrant into earlier-stage settings (e.g., EMBER-4 adjuvant trial) to test whether selective ER degraders can improve long-term outcomes.

Outlook

The availability of a second ESR1-directed oral therapy underscores the growing importance of precision oncology in endocrine-resistant breast cancer. As oncologists weigh sequencing strategies, safety trade-offs, and payer access issues, real-world data will help clarify how imlunestrant and elacestrant fit into clinical practice.

References

• FDA announcement – Imlunestrant approval
• Lilly. U.S. FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer. News release. September 25, 2025.
• A Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3). ClinicalTrials.gov identifier: NCT04975308. Updated July 11, 2025.
• Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. N Engl J Med. 2025;392:1189-1202. doi:10.1056/NEJMoa2410