FDA Approves Inluriyo for ESR1-Mutated Advanced Breast Cancer Based on Phase III EMBER-3 Trial Data

The FDA has approved Eli Lilly’s Inluriyo (imlunestrant) for the treatment of adults with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–), ESR1-mutated advanced or metastatic breast cancer (MBC) whose disease progressed after at least one line of endocrine therapy (ET).¹

EMBER-3 trial results

The approval is based on data from the ESR1-mutated MBC patient population in the Phase III EMBER-3 clinical trial (NCT04975308). In the study, Inluriyo reduced the risk of progression or death by 38% versus ET. Additionally, the oral estrogen receptor antagonist significantly improved progression-free survival (PFS) versus fulvestrant or exemestane, with a median PFS of 5.5 months versus 3.8 months.

In a press release, Jacob Van Naarden, executive vice president and president of Lilly Oncology, said: "This therapy reflects our commitment to developing treatments that improve outcomes for people with breast cancer and represents an important step toward advancing innovative, all-oral treatment approaches. We are deeply grateful to the patients, investigators, Lilly team members and clinical care teams who made this advancement possible. This therapy has the potential to make the treatment journey more manageable for those living with breast cancer."

Study design

EMBER-3 is randomized, open-label study in patients with ER+, HER2– locally advanced or metastatic breast cancer whose disease recurred or progressed after aromatase inhibitor therapy with or without a CDK4/6 inhibitor.

• The trial enrolled 874 adults, with 32% entering as first-line treatment for metastatic disease after the adjuvant setting and 64% as second-line treatment following progression on initial metastatic therapy.
• Patients were randomized to receive Inluriyo, investigator’s choice of fulvestrant or exemestane, or Inluriyo in combination with abemaciclib.²

In the press release, Komal Jhaveri, MD, FACP, FASCO, section head of Endocrine Therapy Research and clinical director of Early Drug Development at Memorial Sloan Kettering Cancer Center, and a principal investigator of EMBER-3, added: "This represents an important advancement for patients with ESR1-mutated MBC, a mutation found in nearly half of patients who have taken hormone therapies, often contributing to treatment resistance. With its demonstrated efficacy, tolerability profile and oral administration, this therapy provides a meaningful alternative treatment option for this patient population."

Safety profile

In terms of safety data from EMBER-3, most adverse events with Inluriyo were Grade 1-2 in severity.

• The most common adverse reactions (≥10%) included decreased hemoglobin, musculoskeletal pain, decreased calcium, decreased neutrophils, increased AST, fatigue, diarrhea, increased ALT, increased triglycerides, nausea, decreased platelets, constipation, increased cholesterol, and abdominal pain.
• Permanent discontinuation due to adverse events occurred in 4.6% of patients.
• Dose reductions occurred in 2.4% of patients, and dose interruptions occurred in 10%.

"The approval of Inluriyo expands the metastatic breast cancer treatment landscape for patients who test positive for the ESR1 mutation. Eligible patients will now have access to an additional treatment option, offering them the potential for flexibility in their daily lives and disease management, and—above all—renewed hope for the future,” said Jean Sachs, CEO, Living Beyond Breast Cancer, in the press release.

Ongoing EMBER-4 trial

Inluriyo is also being evaluated in the ongoing Phase III EMBER-4 study (NCT05514054) in the adjuvant setting for patients with ER+, HER2– early breast cancer (EBC) at increased risk of recurrence. The randomized, open-label study is expected to enroll approximately 8,000 patients worldwide.

• Eligible patients had previously received 2 to 5 years of adjuvant endocrine therapy and were considered at increased risk of recurrence.
• The primary objective is to assess the efficacy of imlunestrant compared with standard therapy in reducing recurrence risk.
• Study participation may extend for up to 10 years.³

References

1. U.S. FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer. News release. Eli Lilly. September 25, 2025. Accessed September 26, 2025. https://investor.lilly.com/news-releases/news-release-details/us-fda-approves-inluriyo-imlunestrant-adults-er-her2-esr1

2. 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. Updated July 11, 2025. Accessed September 26, 2025. https://clinicaltrials.gov/study/NCT04975308

3. A Study of Imlunestrant Versus Standard Endocrine Therapy in Participants With Early Breast Cancer (EMBER-4). ClinicalTrials.gov. Updated September 23, 2025. Accessed September 26, 2025. https://clinicaltrials.gov/study/NCT05514054?intr=imlunestrant&rank=5