FDA Approval of Imlunestrant for ER-Positive, HER2-Negative, ESR1-Mutated Breast Cancer

Metastatic breast cancer with estrogen receptor positivity (ER-positive) and HER2 negativity represents one of the most common and challenging subtypes of breast cancer. In many patients, mutations in the ESR1 gene result in resistance to endocrine therapies, making long-term disease control difficult.

On September 25, 2025, the U.S. Food and Drug Administration (FDA) approved Imlunestrant (Inluriyo, Eli Lilly and Company), an estrogen receptor antagonist, for the treatment of adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer whose disease has progressed following at least one line of endocrine therapy.

This approval was based on results from the EMBER-3 clinical trial (NCT04975308), which demonstrated improved efficacy and safety of Imlunestrant compared with standard endocrine therapy options (FDA, 2025).

Table of Contents

1. Introduction to Imlunestrant and Mechanism of Action
2. EMBER-3 Clinical Trial
3. Dosage and Administration
4. Common Adverse Events
5. Role of Guardant360 CDx as Companion Diagnostic
6. FDA Expedited Programs
7. Conclusion and Future Perspectives
8. Frequently Asked Questions (FAQs)

1. Introduction to Imlunestrant and Mechanism of Action

Imlunestrant (Inluriyo) is a selective estrogen receptor antagonist that effectively inhibits estrogen receptor signaling pathways. It is particularly beneficial for patients with ESR1 mutations, which are associated with resistance to conventional endocrine therapies (FDA, 2025).

2. EMBER-3 Clinical Trial

2.1 Study Design

The EMBER-3 trial was a randomized, open-label, multicenter study that enrolled 874 patients with ER-positive, HER2-negative breast cancer. All patients had previously received treatment with an aromatase inhibitor, either alone or in combination with a CDK4/6 inhibitor.

Patients were randomized into three study arms:

1. Imlunestrant
2. Investigator’s choice of Fulvestrant or Exemestane
3. An investigational combination regimen

2.2 Key Efficacy Outcomes

• Progression-Free Survival (PFS): In patients with ESR1 mutations, PFS was 5.5 months with Imlunestrant vs. 3.8 months with standard endocrine therapy (HR = 0.62; p = 0.0008).
• Objective Response Rate (ORR): 14.3% with Imlunestrant vs. 7.7% with standard therapy.
• Overall Survival (OS): Data were immature at the time of analysis, with 31% mortality reported (ClinicalTrials.gov, NCT04975308).

These findings demonstrated significant clinical benefit of Imlunestrant in the ESR1-mutated population.

3. Dosage and Administration

• Recommended dose: 400 mg orally once daily
• Administration: On an empty stomach (at least 2 hours before or 1 hour after food)
• Duration: Continue until disease progression or unacceptable toxicity (FDA, 2025).

4. Common Adverse Events

The most frequently reported adverse events (≥10%) include:

• Decreased hemoglobin
• Musculoskeletal pain
• Fatigue
• Diarrhea, nausea, and constipation
• Laboratory abnormalities (elevated liver enzymes, triglycerides, cholesterol, and decreased white blood cells)

All serious adverse events should be reported via the FDA MedWatch Reporting System.

5. Role of Guardant360 CDx

Concurrently with drug approval, the Guardant360 CDx assay was authorized as a companion diagnostic. This ctDNA-based test detects ESR1 mutations in the ligand-binding domain of the estrogen receptor, enabling identification of patients eligible for Imlunestrant therapy.

6. FDA Expedited Programs

• Fast Track Designation to accelerate review
• Use of the Assessment Aid to streamline FDA evaluation
• Establishes a framework for future development of targeted therapies in metastatic breast cancer.

7. Conclusion and Future Perspectives

The FDA approval of Imlunestrant represents a major advancement in the treatment of patients with ER-positive, HER2-negative, ESR1-mutated breast cancer. By improving progression-free survival and response rates compared with standard endocrine therapies, Imlunestrant offers a promising new treatment option. However, continued monitoring of long-term survival and safety data will be critical in shaping its role in clinical practice.

8. Frequently Asked Questions (FAQs)

• Who is eligible for Imlunestrant therapy?
  Adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer who have experienced disease progression following endocrine therapy.
• How does Imlunestrant differ from Fulvestrant or Exemestane?
  Unlike Fulvestrant or Exemestane, Imlunestrant is specifically designed to target ESR1-mutated tumors and has demonstrated superior efficacy in this subgroup.
• How are patients selected for Imlunestrant treatment?
  Using the Guardant360 CDx assay, which identifies ESR1 mutations in circulating tumor DNA.
• What is the recommended dosage?
  400 mg orally once daily on an empty stomach.
• What are the most common side effects?
  Fatigue, musculoskeletal pain, gastrointestinal disturbances, and laboratory abnormalities (e.g., elevated liver enzymes, decreased blood counts).