The FDA has approved the oral selective estrogen receptor degrader (SERD) imlunestrant (Inluriyo, Eli Lilly) for estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer that has progressed after at least one line of endocrine therapy.

The agency also approved the Guardant360 CDx assay to identify patients with the mutation.

Imlunestrant is the second oral SERD in the US market for the indication following the approval of elacestrant (Orserdu, Menarini) in 2023. An older generic SERD, fulvestrant, is also in the market for a similar indication, but it’s not as effective as the oral options and, because it’s an intramuscular injection, not as patient friendly.

First line treatment for advanced ER-positive, HER2-negative breast cancer generally includes an aromatase inhibitor and a cyclin-dependent kinase (CDK) 4/6 blocker, but patients sometimes develop an ESR-1 mutation that makes the aromatase inhibitor less effective. In those cases, a SERD is often swapped in to take its place.

Imlunestrant, however, was approved as monotherapy, not in combination with a CDK 4/6 blocker, based on the EMBER-3 trial in 256 patients with ESR1 mutations who had progressed on prior endocrine therapy; the study was presented at San Antonio Breast Cancer Symposium (SABCS) 2024.

Patients were randomized evenly to either imlunestrant (400 mg once daily), investigator’s choice of endocrine monotherapy with either fulvestrant or the aromatase inhibitor exemestane, or a combination arm with imlunestrant plus the CDK 4/6 inhibitor abemaciclib.

The median PFS in the imlunestrant monotherapy arm was 5.5 months vs 3.8 months with investigator’s choice of endocrine monotherapy. Overall survival data are immature.

Although the new approval is for imlunestrant monotherapy and not for combination therapy with a CDK 4/6 blocker, PFS was best in EMBER-3 in the imlunestrant plus abemaciclib arm regardless of ESR1 mutation status.

A major limit of EMBER-3 is that it did not compare imlunestrant plus abemaciclib against fulvestrant plus abemaciclib, which would have been a true standard-of-care control, Kathy Miller, MD, a breast oncologist at Indiana University, Indianapolis, told Medscape Medical news at the SABCS meeting.

She was also concerned that one of the comparator arms was physician’s choice of endocrine monotherapy.

“Monotherapy hormone therapy is not what people would be treated with” after progression. They would typically get fulvestrant with either a targeted therapy or everolimus, she said.

Without appropriate control individuals, “the data are impossible to interpret” in the context of current practice, Miller said.

Elacestrant’s approval trial EMERALD also did not compare it against fulvestrant on a background of CDK 4/6 inhibition, but patients were required to have progressed after a CDK 4/6 blocker. In EMBER-3, patients could have progressed after exposure to the drug class, but it wasn’t required.

Serious adverse reactions to imlunestrant in EMBER-3 included pleural effusion (1.2%) and fatal cardiac arrest, acute myocardial infarction, right ventricular failure, hypovolemic shock, and upper gastrointestinal hemorrhage (0.3% each).

The most common adverse reactions were hemoglobin decrease (30%), musculoskeletal pain (30%), calcium decrease (26%), neutrophils decrease (26%), aspartate aminotransferase increase (25%), fatigue (23%), diarrhea (22%), alanine aminotransferase increase (21%), triglycerides increase (21%), nausea (17%), platelets decrease (16%), constipation (10%), cholesterol increase (10%), and abdominal pain (10%).

Imlunestrant’s label contains a warning and precaution for embryo-fetal toxicity.

The drug is now being studied in EMBER-4 for adjuvant ER-positive, HER2-negative early breast cancer at increased risk for recurrence.

Lilly expects to launch imlunestrant in the coming weeks. The US list price will be $22,500 for 28 days with two 200 mg tablets once daily, a spokesperson said.

Thirty once-daily 345 mg tablets of elacestrant would cost $24,217.04, according to drugs.com.

Miller did not have any disclosures.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.