A new therapy was effective against ER-positive, HER2-negative breast cancers, the most common subtype. “These results will change how many breast cancers are treated,” says medical oncologist Dr. Komal Jhaveri.
An experimental drug stops advanced breast cancer from progressing in some people with tumors that have grown resistant to standard therapy, new results from a clinical trial show. The drug, imlunestrant, was especially effective when combined with a second drug, abemaciclib (Verzenio®).
The combination reduced the risk of cancer progression or death by more than 40%, compared with imlunestrant alone.
In the international, phase 3 clinical trial, imlunestrant improved progression-free survival (PFS) in patients with ER-positive, HER2-negative advanced breast cancer who had previously been treated with hormone therapy. Progression-free survival is the time the cancer remains under control without getting worse.
ER-positive, HER2-negative is the most common subtype of breast cancer, accounting for about 70% of cases.
“These results will change how many breast cancers are treated,” says Memorial Sloan Kettering Cancer Center medical oncologist Komal Jhaveri, MD, FACP, chair of the international study and its principal investigator at MSK.
New Breast Cancer Treatment When Hormone Therapy Stops Working, Regardless of ESR1 Gene Mutation
When given alone, imlunestrant was effective in patients with breast cancer that contained a mutation in the ESR1 gene. The mutation is present in 40-50% of patients whose disease progresses on hormone therapy.
More significant, when imlunestrant was combined with the targeted therapy abemaciclib, it improved progression-free survival despite prior progression on CDK4/6 inhibitor therapy. CDK4/6 is an enzyme that is important for cell division.
Notably, the combined drugs were also 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.
- 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.
- 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 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.
“In addition, the results suggest imlunestrant could soon be another single-drug option for the many patients whose recurrent breast cancers harbor ESR1 mutations,” she adds.
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.”
