FDA approves Inluriyo, an oral pill for ESR1-mutated advanced breast cancer
A once-daily oral drug is now an option for a breast cancer mutation that shows up in about half of patients after hormone therapy, but only for tumors that test positive for it.
The FDA approved Inluriyo (imlunestrant) on Sept. 25, 2025, for adults whose estrogen receptor-positive, HER2-negative breast cancer is advanced or metastatic, carries an ESR1 mutation, and has grown despite at least one prior endocrine therapy, Eli Lilly announced [1]. It is a 200 mg tablet taken once a day as a 400 mg dose, on an empty stomach — at least two hours before food or one hour after [1].
The decision rests on EMBER-3, a randomized, open-label Phase 3 study that enrolled 874 adults and tested the drug against an investigator's choice of fulvestrant or exemestane, and also against Inluriyo combined with abemaciclib [1]. Within that study, 256 patients had tumors with an ESR1 mutation. Among them, median progression-free survival was 5.5 months on Inluriyo and 3.8 months on the comparator endocrine therapies (HR=0.62; 95% CI, 0.46-0.82; p=0.0008), which Lilly characterized as a 38% reduction in the risk of progression or death [1]. Of those 256 patients, 21% received the drug as a first-line metastatic treatment after recurrence on an adjuvant aromatase inhibitor, with or without a prior CDK4/6 inhibitor, and 79% received it second-line after progressing on an aromatase inhibitor, again with or without a prior CDK4/6 inhibitor [1].
Inluriyo works by binding the estrogen receptor, blocking it and speeding its breakdown, an approach the company says can include cancers with ESR1 mutations, in which the receptor becomes overactive and fuels tumor growth [1]. Lilly's oncology president, Jacob Van Naarden, called the therapy "an important step toward advancing innovative, all-oral treatment approaches" [1].
Most side effects in the trial were Grade 1 or 2. The most common reactions, counting laboratory abnormalities and occurring in at least 10% of patients on the drug, were lower hemoglobin and musculoskeletal pain (30% each), lower calcium and lower neutrophils (26% each), higher AST (25%), fatigue (23%), diarrhea (22%), higher ALT and higher triglycerides (21% each), nausea (17%), lower platelets (16%), constipation, higher cholesterol and abdominal pain (10% each) [1]. Serious reactions occurred in 10% of patients, with pleural effusion the most frequent above 1% (1.2%), and fatal reactions occurred in 1.8%, including cardiac arrest, acute myocardial infarction, right ventricular failure, hypovolemic shock and upper gastrointestinal hemorrhage, each at 0.3% [1]. Slightly under 5% of patients stopped treatment permanently because of side effects, 2.4% needed a dose reduction and 10% had a dose interruption [1].
The label warns that the drug can harm a developing fetus. It advises against use in pregnancy, calls for effective contraception during treatment and for one week after the final dose in women who could become pregnant and in men with female partners who could become pregnant, and says women should not breastfeed during treatment or for one week afterward [1]. The label also flags interactions with strong CYP3A inhibitors and inducers and with P-gp and BCRP substrates, and calls for reduced dosing in patients with moderate or severe liver impairment [1].
Why it matters for patients
An estimated half of people with ER-positive, HER2-negative metastatic breast cancer develop an ESR1 mutation while on or after an aromatase inhibitor, and those changes often help drive resistance to hormone therapy [1]. Because the approval is tied to that mutation, the drug is only for patients whose tumors have been tested and found positive, and whose disease has already advanced on endocrine treatment [1]. Komal Jhaveri, M.D., of Memorial Sloan Kettering Cancer Center, a principal investigator on EMBER-3, said the drug offers "a meaningful alternative treatment option for this patient population" [1]. The practical trade-offs are visible in the data: the median gain before progression was roughly 1.7 months, a small share of patients had serious or fatal reactions, and the treatment is a daily pill taken on an empty stomach rather than the injections or other pills used as comparators [1].
What happens next
Lilly said the drug should be available in the United States in the coming weeks [1]. It is also being tested in EMBER-4, an ongoing Phase 3 trial in early breast cancer at higher risk of recurrence that aims to enroll about 8,000 patients worldwide [1]. A U.S. list price has not been disclosed, and there has been no word on how insurers will cover the drug [1].
Sources
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