FDA Expands Approval for Imlunestrant To Treat ER+, HER2-, ESR1-mutated Advanced Breast Cancer That Resists Standard Therapy

This story was originally published in 2024 and was last updated in September 2026 to reflect a new FDA approval. 

The U.S. Food and Drug Administration (FDA) has approved a new treatment combination shown to be effective at stopping advanced breast cancer from progressing in some people with tumors that have grown resistant to standard therapy. 

The combination includes a drug, imlunestrant (Inluriyo™), given with a second drug, abemaciclib (Verzenio^®), to patients with ER-positive, HER2-negative advanced breast cancer who have an ESR1 gene mutation and have previously been treated with hormone therapy. 

ER-positive, HER2-negative is the most common subtype of breast cancer, making up about 70% of cases. The ESR1 mutation is found in nearly half of breast cancer patients who have taken hormone therapies, often contributing to treatment resistance.

The new FDA approval is based on results from the EMBER-3 clinical trial, which showed this drug combination given to these patients resulted in the longest progression-free survival ever seen — 11.1 months. For people who received imlunestrant alone (monotherapy), progression-free survival was 5.5 months. (Progression-free survival is the length of time in which the disease does not get worse.)

Imlunestrant was previously approved by the FDA as a monotherapy in September 2025 for this patient group. 

“This latest approval will change how many breast cancers are treated,” says Memorial Sloan Kettering Cancer Center (MSK) medical oncologist Komal Jhaveri, MD, FACP, FASCO, chair of the international study and its principal investigator at MSK. “Combining therapies that work on two distinct drivers of tumor growth provides a significantly longer-lasting benefit than imlunestrant alone. The combination doubled progression-free survival compared with monotherapy.”

Both imlunestrant and abemaciclib are manufactured by Eli Lilly and company. The drugs are taken as pills, making ongoing treatment simple for patients. 

Dr. Jhaveri notes that MSK has been involved with the testing of imlunestrant from the beginning, collaborating with the manufacturer on the drug development plan.

 

Durable benefit from imlunestrant

Improvement in progression-free survival from imlunestrant — with or without abemaciclib — was first reported by Dr. Jhaveri at the San Antonio Breast Cancer Symposium in December 2024, with simultaneous publication in the New England Journal of Medicine. In December 2025, she reported updated results at that year’s symposium, along with simultaneous publication in the Annals of Oncology, which suggested the combination therapy could also improve overall survival.  

In the EMBER-3 trial, the treatment — both imlunestrant alone and in combination with abemaciclib — did not cause significant side effects. The most common were fatigue, diarrhea, nausea, and neutropenia (low white blood cells). 

Effective in resistant breast cancers

EMBER-3 has shown that the drug combination improved progression-free survival in patients with ER-positive, HER2-negative advanced breast cancer despite prior progression on CDK4/6 inhibitor therapy. CDK4/6 is an enzyme that is important for cell division.

Notably, the combined drugs were effective regardless of progression on a prior CDK4/6 inhibitor, whether there was a mutation in the ESR1 gene or in the PI3K pathway. PI3K is part of a signaling pathway that regulates cell growth. When PI3K is mutated, it can lead to uncontrolled growth and fuel cancer.

EMBER-3 clinical trial details

EMBER-3 included 874 patients with ER-positive, HER2-negative advanced breast cancer whose disease had recurred or progressed during or after hormone therapy given alone or with a CDK4/6 inhibitor.

Participants were randomly assigned to receive either standard therapy, imlunestrant alone, or imlunestrant in combination with abemaciclib. At a median follow-up of 28.5 months:

• In patients with ESR1-mutated ER-positive, HER2-negative advanced breast cancer, median overall survival was nearly 50% longer for people receiving imlunestrant monotherapy compared with people receiving standard therapy (34.5 months vs. 23.1 months).
• The updated analysis reinforced the combination’s benefit, with median progression-free survival of 11.1 months versus 5.5 months for imlunestrant alone. Additionally, a favorable overall survival trend was seen with the combination. (It is still too early to confirm overall survival is improved.)
• Imlunestrant monotherapy delayed the start of chemotherapy for patients with ESR1 mutations by 5.5 months. In the combination group, regardless of ESR1 mutation, the delay was 12.2 months.

“Delaying the start of chemotherapy is especially meaningful for patients with advanced breast cancer because chemotherapy often negatively affects quality of life,” Dr. Jhaveri says.

The benefit of the combination therapy was consistent across patient subgroups, including among patients who had received prior CDK4/6 therapy and regardless of PI3K pathway mutation status.

“The effectiveness of the combined therapy despite prior CDK4/6 inhibitors and regardless of ESR1 mutation or PI3K pathway mutation status is a major advance,” says Dr. Jhaveri. “Second-line therapies have traditionally been chosen partly based on whether the patient carried the mutations. Now there is potentially another treatment option without needing to test for these markers.”

Imlunestrant can penetrate the blood-brain barrier, offering the possibility that it could potentially treat breast cancer that has spread to the brain.

Side effect details

The imlunestrant label contains a warning and precaution for embryo-fetal toxicity. See prescribing information for full details. The abemaciclib label contains warnings and precautions for severe diarrhea, neutropenia, interstitial lung disease/pneumonitis, hepatotoxicity, and venous thromboembolism. See prescribing information for full details.

 

Selective estrogen receptor degraders (SERDs) are a new class of cancer treatments

What are SERDs, and how did MSK help develop them?

Imlunestrant is part of a class of drugs called selective estrogen receptor degraders (SERDs). These drugs bind with estrogen receptors to stop estrogen from attaching to cancer cells and fueling their growth. They also degrade the receptor protein.

The SERD fulvestrant (Faslodex) was approved in 2002 and has been given to patients whose breast cancer became resistant to hormone therapy. But many tumors also begin to grow resistant to fulvestrant.

In 2013, MSK breast cancer specialist Sarat Chandarlapaty, MD, PhD, published important research showing how ESR1 gene mutations play a key role in resistance to hormone therapy — and to fulvestrant as well. This helped lay the groundwork for the next-generation SERDs.

The latest generation of SERDs combat fulvestrant resistance

The newer SERDs, such as imlunestrant, are proving to be effective in people who develop resistance to fulvestrant. In 2023, the FDA approved the first of these next-generation SERDs, a drug called elacestrant (Orserdu™), for people whose tumors were ER-positive, HER2-negative, had continued to grow after hormone therapy, and had an ESR1 mutation.

Now imlunestrant offers an additional oral SERD therapy — and one that has especially lasting benefit when given in combination with abemaciclib. This includes patients who may not have an ESR1 or PI3K mutation.

“Imlunestrant offers advantages over fulvestrant,” Dr. Jhaveri says. “Fulvestrant is given by intramuscular injection in the clinic, which many patients find painful and burdensome. Being able to take imlunestrant as a pill makes life much easier for those being treated.”

Dr. Jhaveri serves as a consultant/advisor for Lilly/Loxo Oncology and receives institutional research funding from the company.

A more complete list of Dr. Jhaveri’s disclosures are available on her profile page.

Key Takeaways

• Imlunestrant is a drug that is effective at treating ER-positive, HER2-negative advanced breast cancer the most common subtype.
• It is especially effective when combined with a second drug, abemaciclib.
• The FDA has approved this combination for ER-positive, HER2-negative advanced breast cancer that carries a mutation in the ESR1 gene.
• The approval will change how many breast cancers are treated.