A new drug that stops advanced breast cancer from progressing in some people with tumors resistant to standard therapy has been approved by the Food and Drug Administration (FDA), based on results from a clinical trial led by Memorial Sloan Kettering Cancer Center (MSK).
The drug, imlunestrant (Inluriyo), is approved for people with ER-positive, HER2-negative advanced or metastatic breast cancer that has an ESR1 mutation who had previously been treated with hormone therapy.
In the international, phase 3 clinical trial leading to the FDA approval, imlunestrant reduced the risk of progression or death by 38% compared with hormone therapy in this patient group.
ER-positive, HER2-negative is the most common subtype of breast cancer, accounting for about 70% of cases. Imlunestrant is taken as a pill, making ongoing treatment simple for patients.
“These results offer a new option for treating many breast cancers,” says Memorial Sloan Kettering Cancer Center medical oncologist Komal Jhaveri, MD, FACP, chair of the international study and its principal investigator at MSK. “The ESR1 mutation is found in nearly half of patients who have taken hormone therapies, often contributing to treatment resistance.”
Imlunestrant Combination Therapy Effective When Hormone Therapy Stops Working, Regardless of ESR1 Gene Mutation
Beyond the approval for imlunestrant when given alone to this patient group, the phase 3 clinical trial, called EMBER-3, is also testing imlunestrant in combination with other drugs. Results show imlunestrant has been especially effective when combined with a second drug, abemaciclib (Verzenio).
The 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 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.
“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 another treatment option without needing to test for these markers.”
Imlunestrant Clinical Trial Results Show Improved Breast Cancer Survival
Dr. Jhaveri presented the results from the phase 3 EMBER-3 clinical trial at the San Antonio Breast Cancer Symposium (SABCS), held December 10–13, 2024. The findings were reported simultaneously in the New England Journal of Medicine.
The multicenter study 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 with fulvestrant, imlunestrant alone, or imlunestrant in combination with abemaciclib.
- When given alone, imlunestrant reduced the risk of progression or death by 38% in patients with ESR1 mutations compared with fulvestrant. The median PFS improved by 1.7 months — 5.5 months in the imlunestrant group versus 3.8 months in the fulvestrant group.
- The big benefit came when the drugs were combined: Compared with imlunestrant alone, imlunestrant and abemaciclib together were associated with a 43% reduced risk of cancer progression or death — regardless of ESR1 status.
- For people in the combination group, median progression-free survival was 9.4 months. For people in the imlunestrant-alone group, it was 5.5 months.
- The treatment — both imlunestrant alone and in combination with abemaciclib — did not cause significant side effects.
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.
“It’s reassuring to see this broad benefit because most patients eligible for second-line therapy have already received a CDK4/6 inhibitor,” Dr. Jhaveri says. “These results suggest we have an effective new treatment option when previous therapies have failed.
Imlunestrant is taken as a pill, making ongoing treatment simple for patients. It also can penetrate the blood-brain barrier, offering the possibility that it could potentially treat breast cancer that has spread to the brain.
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.
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, 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, like 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, 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 potentially one not dependent on ESR1 status, if given in combination with abemaciclib.
“Imlunestrant offers advantages over fulvestrant, which is the only SERD now approved for patients with ESR1 mutations,” Dr. Jhaveri says. “Fulvestrant is given by intramuscular injection in the clinic, which many patients find painful and burdensome. Imlunestrant was designed to be taken as a pill, which makes life much easier for those being treated.”
