FDA Approves Inluriyo / Imlunestran: Oncology Guidance for ESR1-Mutated Breast Cancer

Introduction: A New Tool for Breast Cancer Treatment

On September 25, 2025, the FDA approved Inluriyo (imlunestrant), an oral selective estrogen receptor degrader (SERD), for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer (MBC) after progression on endocrine therapy (ET). 0 For oncologists, this Inluriyo FDA approval offers a targeted oral therapy to tackle ET resistance. Consequently, this post provides key trial results, safety data, dosing details, and practical steps for oncology practice.

Who Qualifies for Inluriyo?

Inluriyo is approved for adults with ER+, HER2-, ESR1-mutated advanced or MBC after prior ET, such as aromatase inhibitors with or without CDK4/6 inhibitors. 1 ESR1 mutations, found in about 40-50% of ER+ MBC cases after aromatase inhibitor use, cause ET resistance by activating the estrogen receptor without hormones. 9

EMBER-3 trial eligibility included:

• Prior ET with aromatase inhibitors (± CDK4/6 inhibitors)
• ESR1 mutations in the ligand-binding domain, verified by Guardant360 CDx
• Exclusions: Patients suitable for PARP inhibitors; no prior fulvestrant or exemestane in the control group

Since the trial stratified patients by prior CDK4/6 inhibitor use, visceral metastases, and region, it reflects diverse oncology settings. 2 Therefore, oncologists should use ctDNA testing to find eligible patients early.

EMBER-3 Trial: Key Efficacy Results

The Inluriyo FDA approval is based on the EMBER-3 trial (NCT04975308), a randomized, open-label phase 3 study with 874 patients, comparing Inluriyo to standard ET (fulvestrant or exemestane). 3 For the ESR1-mutated group (n=256), Inluriyo showed strong results.

Endpoint	Inluriyo (n=138)	Standard ET (n=118)	HR (95% CI); P-value
Median PFS (mo)	5.5 (3.9-7.4)	3.8 (3.7-5.5)	0.62 (0.46-0.82); 0.0008
Response Rate	14.3%	7.7%	N/A
Survival	Immature (31% deaths); trend (HR 0.55, 0.35-0.86; P<0.01)	–	–

Progression-free survival (PFS) followed RECIST v1.1 standards. 7 Additionally, early data suggest a 9.4-month PFS with Inluriyo plus abemaciclib, pointing to future combination possibilities. 4 Thus, Inluriyo significantly delays progression in ET-resistant MBC.

Safety and Side Effects

In EMBER-3, Inluriyo had a manageable safety profile, with most side effects being mild (grade 1-2). 6 Severe side effects (grade ≥3) occurred in 22% of patients, compared to 18% in the control group.

Common side effects (≥10%):

• Low hemoglobin (25%)
• Joint or muscle pain (20%)
• Fatigue (18%)
• Diarrhea (15%)
• Nausea (14%)
• High liver enzymes (ALT/AST, 12% each)
• Low neutrophils, calcium, or platelets (11% each)
• High triglycerides or cholesterol (10% each)
• Constipation or abdominal pain (10% each)

Only 5% of patients stopped Inluriyo due to side effects (vs. 4% control). Importantly, Inluriyo may cause harmირ

System: harm to an unborn baby, so contraception is advised. 3 Oncologists should check blood counts, liver, and lipid levels every three months. The oral dosing may boost patient compliance compared to injectable SERDs like fulvestrant.

Dosing and Administration

• Dose: 400 mg (two 200 mg tablets) orally once daily.
• Administration: Take on an empty stomach (≥2 hours before or ≥1 hour after food).
• Monitoring: Regular checks for blood counts, liver function, and lipids; adjust for CYP3A drug interactions.
• Duration: Continue until disease progression or severe side effects.

No major warnings; full details on Drugs@FDA. 1 This simple regimen fits well with outpatient oncology care.

Impact on Oncology Practice

The Inluriyo FDA approval provides a new oral option for ESR1-mutated MBC, addressing ET resistance. 7 Since Guardant360 CDx testing can identify 40-50% of eligible patients, it should become standard in second-line settings. 0 For instance, integrating ctDNA testing ensures precision treatment plans.

Ongoing studies:

• EMBER-4 (NCT05514054): Testing in early breast cancer.
• Trials with CDK4/6 inhibitors for broader use.

Oncologists should discuss options with teams, considering patient history and preferences.

Resources for Oncology Specialists

Related: Endocrine Resistance Strategies

FDA Approval Details

EMBER-3 Trial

Eli Lilly Oncology: Inluriyo prescribing and support programs

ASCO Guidelines: ESR1 testing updates

Links:

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imlunestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast

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EMBER-3 Reveal: Imlunestrant – Standalone Star or Team Player with Abemaciclib?