Elacestrant PFS Increase ER+ HER2- Dr. Kaklamani, MD SABCS 2022
What is the EMERALD Trial In ER-positive, HER2-negative Metastatic Breast Cancer Patients? The EMERALD trial is a phase 3 clinical trial in women with ER-positive, HER2-negative metastatic breast cancer, were randomized after receiving and progressing on a CDK4/6 inhibitor to receive either Elacestrant, which is an oral SERT, or standard of care endocrine therapy, which was either Fulvestrant or an aromatase inhibitor depending on what endocrine therapy they had received previously.
There were two primary endpoints for the trial. The first one was progression-free survival, and the second one was progression-free survival in patients whose tumors had an ERS1 mutation, the trial was presented last year by Dr. Bardia, showing that the trial met both of its primary endpoint and endpoints and improved progression-free survival and progression-free survival in tumors with ESR1 mutations.
This year, what we presented was the length of a CDK4/6 inhibitor prior to enrollment to the trial. Now we found that the longer the duration of the CDK4/6 inhibitor, the longer that subsequent PFS was. Importantly, we showed that women that were randomized to the tran arm. Had better benefit and they had an improvement in median PFS versus standard endocrine therapy.
This was more pronounced in women that had been on a CDK for six inhibitor for at least 12 months, showing that, for example a woman whose ER-positive, HER2-negative metastatic breast cancer had an ERS1 mutation if she had been on a CDK for six inhibitor for at least 12 months, should a median progression-free survival in L Astrin of 8.6 months compared to only two months with standard of care endocrine therapy.
So the standard of care for women that have metastatic ER-positive, HER2-negative breast cancer is for first line to receive a CDK4/6 inhibitor combined with endocrine therapy, typically an aromatase inhibitor, but then the cancers progress. They typically progress within 20 – 24 months or so.
And then the question is, what do we do in that second line setting? And so far what we’ve been doing is testing the tumor for PIK3CA mutations. And if the tumor does have a PIK3CA mutation, then we can give a drug called Alpelisib in combination again with endocrine therapy, or we can give Everolimus in combination with endocrine therapy.
The benefit of the EMERALD trial and the use of Elacestrant (versus standard endocrine therapy) is that now we have an option, which is a single agent It’s monotherapy, it’s endocrine therapy without any other targeted therapy, which also gives us the chance of not having as many adverse events from our medication. And for the right patients, it will give a statistically significant benefit as far as median progression-free survival.
The EMERALD trial was designed as a pivotal phase 3 clinical trial. It was a registrational trial, so this is a trial that the FDA is going to look at to decide whether to approve Elias Astern or not. And the reason it was designed this way was because it was trying to incorporate how we use in the United States the treatments for ER-positive, HER2-negative metastatic breast cancer.
So we wanted to make sure that every patient had previously been on a CDK4/6 inhibitor, which is exactly what happened. And then, because we didn’t know, there really wasn’t a standard of care endocrine therapy, some patients would be on Fulvestrant, some patients would be on an aromatase inhibitor.
So that’s why we made that standard of care arm as our standard arm. Then we also knew that patients with ERS1 mutations, typically they’re, these patients don’t do as well with our standard endocrine therapy. But the data, the initial data we had showed that Elacestrant works well in this overall patient population. So that’s what we included in our analysis, mutated tumors for ERS1.
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5 Key Takeaways about the EMERALD Phase 3 Trial On Elacestrant
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Mutations in ESR1 cause estrogen-independent ER activation and, therefore, resistance to AIs but not to ER inhibitors.
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Elacestrant is a novel, nonsteroidal, oral SERD that inhibits estradiol-dependent ER-directed gene transcription and tumor growth in in vitro and in vivo preclinical models, including those with ESR1 mutations associated with endocrine resistance.
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Eligible patients for this clinical trials with breast cancer were postmenopausal women or men age 18 years or older with histologically or cytologically proven ER-positive/HER2-negative breast adenocarcinoma and either locoregionally recurrent or metastatic disease. Disease progression must have occurred during or within 28 days after treatment with one or two prior lines of endocrine therapy for advanced/metastatic disease. For advanced/metastatic disease, progression during or within 12 months of adjuvant endocrine therapy was included as a line of endocrine therapy. Required was progression on prior CDK4/6 inhibitor therapy in conjunction with fulvestrant or an AI. One chemotherapy treatment was permitted in advanced/metastatic disease.
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Patients with breast cancer were randomly allocated to receive either elacestrant or SOC. Random assignment was stratified by ESR1 mutation status, occurrence of visceral metastases, and prior treatment (prior endocrine therapies) of fulvestrant. Elacestrant was dosed 400 mg orally once day, with decreases to 300 mg or 200 mg daily tolerated for toxicity. SOC was treated with fulvestrant, anastrozole, letrozole, or exemestane monotherapy, as determined by the investigator, and dosed according to the labeling. This recommendation advocated administration of a different endocrine therapy than the patient had received previously. Specifically, fulvestrant was advised for patients with breast cancer who had not previously received it, and AI therapy was selected based on prior AI treatment.
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477 patients with breast cancer were randomly randomized to undergo elacestrant (239 patients breast cancer) or SOC treatment (238 patients breast cancer) at 228 sites in 17 countries between February 2019 and October 2020. 228 individuals (47.2%) exhibited detectable ESR1 mutations; the median age was 63 years (range: 24-89).
What Is Some Highlights EMERALD Trial In Breast Cancer?
My take home message from the EMERALD trial is looking at duration of CDK4/6 inhibitors and mostly the enrolled patients who had tumors with ERS1 mutation. So when you look at the, this patient population, women that had been on a prior CDK4/6 inhibitor for at least 12 months, those women, if their cancers were ESR, one mutated, had a median progression free survival on Elacestrant 8.6 months compared to two months with standard of care endocrine therapy and if they had been on a CDK4/6 inhibitor for at least 18 months, then those re, those results were actually pretty similar with an 8.6 month median PFS on AOS Astrin and around two month median PFS on standard of care endocrine therapy.
What Questions Do Your Colleagues Have About This Clinical Trial?
Those common questions that I get asked is why Elacestrant, and the answer is our phase one data was pretty impressive. Showing benefit in patients treated and that had ERS1 mutation tumors. Had previously been on a CDK4/6 inhibitor, had previously been on Fulvestrant and aromatase inhibitor. So this looks like a very nice not just well tolerated but effective endocrine monotherapy.
The other questions have to do with toxicity. Is this drug an easy drug to take? The initial data suggest ed some reflux with the drug, but we changed the formulation of the medication and since then, the adverse events have been very mild with the medication. No grade four events, the rate of discontinuation was only 1.3% and 8% of on the medication, and 8% of patients on the medication received an antiemetic, whereas 10% of patients on an aromatase inhibitor received an antiemetic.
The primary endpoints of the trial were two. The first one was medium progression-free survival in the whole patient population, and the second one was medium progression-free survival in patients with tumors that had ESR1 mutations. And both of those endpoints were met with statistical significance.
Key Takeaway Message About the Phase III EMERALD Trial
So the takeaway from this study is that we now have a very effective and safe monotherapy endocrine therapy for our patients with ER-positive, HER2-negative breast cancers. This treatment is not gonna be for every patient. We have to make a decision as oncologists. Do we think that this breast cancer is still endocrine sensitive or not?
If we think that it is, Then we should consider endocrine monotherapy because of the efficacy, but as well as toxicity profile. But if we don’t think that this is an endocrine sensitive tumor, then we way wanna move to either combination, endocrine therapies, or chemotherapy.
Virginia G. Kaklamani, MD – About The Author, Credentials, and Affiliations
Virginia G. Kaklamani, MD, is a professor of medicine and a doctor of Medical Oncology in the division of hematology/oncology at UT Health San Antonio and the director of the Breast Cancer Program at the UT Health MD Anderson Cancer Center. Dr. Kaklamani completed her medical training at the University of Athens and her internal medicine residency at Newton-Wellesley Hospital in Boston with honors. She finished her hematology/oncology fellowship at Northwestern University.
Northwestern University additionally granted her a master of science in clinical investigation. She was the director of the Translational Breast Cancer Program and co-director of the cancer genetics program at Northwestern University. Her scientific interests include the investigation of high-risk families and the identification of genetic abnormalities associated with an increased risk of breast, colon, and prostate cancer. She has uncovered a number of obesity-related genetic alterations that raise the risk of breast cancer. Dr. Kaklamani is an expert in designing clinical studies using targeted medications as a clinical investigator.