The investigational next-generation oral selective estrogen receptor degrader (SERD) imlunestrant improved progression-free survival both as monotherapy in patients with ESR1 mutations and in combination with the CDK4/6 inhibitor abemaciclib regardless of ESR1 mutational status in patients with endocrine therapy–pretreated estrogen receptor (ER)-positive, HER2-negative advanced breast cancer. These results from the phase III EMBER-3 trial were presented at the 2024 San Antonio Breast Cancer Symposium (SABCS) and published simultaneously in The New England Journal of Medicine.1,2
As monotherapy, compared with standard-of-care endocrine therapy (mainly fulvestrant), imlunestrant significantly reduced the risk of disease progression or death (ie, progression-free survival) by 38% in patients with ESR1 mutations—but achieved no difference in progression-free survival vs standard endocrine therapy in the overall study population. As combination therapy, imlunestrant plus abemaciclib improved progression-free survival by 43% vs imlunestrant alone in all patients regardless of ESR1 mutation status.
“These promising results mean that imlunestrant is potentially another single-agent option for the many patients whose recurrent breast cancers harbor ESR1 mutations,” said lead author Komal Jhaveri, MD, FACP, who presented these results. Dr. Jhaveri is the Patricia and James Cayne Chair for Junior Faculty, a breast medical oncologist as well as early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, and Associate Professor of Clinical Medicine at Weill Cornell Medical College.
These promising results mean that imlunestrant is potentially another single-agent option for the many patients whose recurrent breast cancers harbor ESR1 mutations.— Komal Jhaveri, MD, FACP
Tweet this quote
According to Dr. Jhaveri, these data are potentially practice-changing. “The consistency of benefit from imlunestrant plus abemaciclib across clinically relevant subgroups is reassuring, given that most patients eligible for second-line therapy have received a CDK4/6 inhibitor previously, and many currently available second-line therapies require biomarker selection,” she stated.
Background
Although patients are often treated with CDK4/6 inhibitors and aromatase inhibitors in the first-line metastatic setting, combining a selective estrogen receptor degrader with a CDK4/6 inhibitor can be beneficial upon disease progression. Existing selective estrogen receptor degraders, such as fulvestrant, have some limitations, including the need for monthly intramuscular injections and limited efficacy in patients who develop ESR1 mutations. These mutations occur in about 50% of patients who experience disease progression on endocrine therapy.
Imlunestrant, by contrast with fulvestrant, is orally available and penetrates the blood-brain barrier, theoretically targeting the central nervous system, Dr. Jhaveri noted. “Novel SERDs, such as imlunestrant, are being developed with the goal of improving efficacy and patient experience through ease of administration,” she added.
Study Details
The global, open-label, phase III EMBER-3 trial enrolled 874 male and female patients with advanced breast cancer regardless of menopausal status who experienced disease progression on adjuvant endocrine therapy but received no other therapy in the advanced breast cancer setting. Patients were randomly assigned to one of three groups: group A–imlunestrant at 400 mg/d vs standard-of-care endocrine therapy (fulvestrant or exemestane); group B–standard-of-care endocrine therapy; and group C (added as a protocol amendment early in the study)–imlunestrant plus abemaciclib vs imlunestrant alone. Progression-free survival was compared between groups A and B in patients with ESR1 mutations and between groups A and B in all patients. Analysis of imlunestrant plus abemaciclib vs imlunestrant was tested only if one of the imlunestrant vs standard-of-care endocrine therapy endpoints was significant.
Baseline characteristics were well balanced between the three arms. About 37% had ESR1 mutations, and about 38% had PI3K pathway mutations. About 30% of patients recurred within 12 months of adjuvant endocrine therapy, and about 66% experienced disease progression on first-line therapy. Overall, 60% had received prior CDK4/6 inhibitor therapy (mostly palbociclib or ribociclib).
Key Results
At the landmark analysis, in patients with ESR1 mutations, median progression-free survival was 5.5 months with imlunestrant (group A) vs 3.8 months with standard endocrine therapy (group B), representing a statistically significant 38% reduction in the risk of disease progression or death (P < .001). “However, there was no progression-free survival difference [between the two treatment arms] in all patients,” Dr. Jhaveri emphasized.
As for the combination of imlunestrant plus abemaciclib vs imlunestrant alone in all patients, median progression-free survival was 9.4 months vs 5.5 months, respectively, representing a statistically significant 43% reduction in the risk of disease progression or death (P < .001). “The benefit [of the combination] was observed regardless of the presence of ESR1 mutations,” Dr. Jhaveri told listeners.
Median progression-free survival was 11.1 months with the combination vs 5.5 months with imlunestrant alone among patients with ESR1 mutations. Among those without ESRI mutations, the corresponding numbers were 9.1 months vs 5.5 months.
For both the monotherapy analysis and the combination therapy analysis, consistent benefits were observed among key subgroup, regardless of the presence or absence of visceral metastases, prior CDK4/6 inhibitor treatment, and PI3K pathway mutation status.
Safety Profile
“The safety data from EMBER-3 were reassuring,” Dr. Jhaveri stated.
The most common toxicities with monotherapy were diarrhea, fatigue, and nausea. They were mainly grade 1, with a frequency of less than a 10% increase over standard therapy. The incidence of grade 3 and 4 toxicities was 17% in the imlunestrant arm and 21% in the standard-of-care endocrine therapy arm. Treatment discontinuation rate was low at 4%, with no signal of cardiac or ocular toxicity.
“From a patient perspective, 72% reported injection-site redness, swelling, or discomfort on fulvestrant, which is not a concern with the oral medication,” Dr. Jhaveri noted.
Moving on to safety with the combination of imlunestrant and abemaciclib, “we expected to see more diarrhea,” she continued. “Although diarrhea was the most common toxicity with the combination, adverse events were predominantly grade 1, and the safety profile was consistent with what we see with abemaciclib and what has been previously reported with fulvestrant and abemaciclib,” Dr. Jhaveri added. The treatment discontinuation rate for the combination was 6%.
Expert Point of View
Formal discussant of the EMBER-3 trial, Harold J. Burstein, MD, PhD, Professor of Medicine at Harvard Medical School and a medical oncologist at Dana Farber Cancer Institute, Boston, said these data suggest imlunestrant is a well-tolerated oral selective estrogen receptor degrader (SERD).
Harold J. Burstein, MD, PhD
“As monotherapy, new oral SERDs (including imlunestrant and previously elacestrant) appear to be more active than fulvestrant in estrogen receptor–positive advanced breast cancer among tumors with ESR1 mutations, likely owing to bioavailability/dosing considerations,” Dr. Burstein said.
Emerging data suggest that combining new oral selective estrogen receptor degraders including imlunestrant with second-line CDK4/6 inhibition using abemaciclib may achieve substantial durations of tumor control irrespective of tumor ESR1 mutation status or PIK3CA status, likely foreshadowing a future treatment option. The results of this study underscore the importance of ongoing targeting of the estrogen receptor and related crosstalk pathways in estrogen receptor–dependent tumors,” he told listeners.
DISCLOSURE: Dr. Jhaveri has served as a consultant or advisor to Novartis, Pfizer, Taiho Oncology, Genentech, AbbVie, Eisai, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Sun Pharma Advanced Research Company, Ltd., Menarini/Stemline Therapeutics, Gilead Sciences, Scorpion Therapeutics, Olema Pharmaceuticals, Bicycle Therapeutics, Lilly/Loxo Oncology, and Zymeworks; and has received institutional research funding from Novartis, Genentech, AstraZeneca, Pfizer, Lilly/Loxo Oncology, Zymeworks, Immunomedics/Gilead Sciences, Puma Biotechnology, and Merck Pharmaceuticals, Context Therapeutics, Scorpion Therapeutics, Eisai, RayzeBio, and Blueprint Medicines. Dr. Burstein has received a research grant from the National Cancer Institute.
REFERENCES
- Jhaveri K: Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and combined with abemaciclib, for patients with ER+ HER2– advanced breast cancer, pretreated with endocrine therapy: Results of the phase 3 EMBER-3 Trial. 2024 San Antonio Breast Cancer Symposium. Abstract GS01-1. Presented December 11, 2024.
- Jhaveri KL, Neven P, Casalnuovo ML, et al: Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. December 11, 2024 (early release online).
