The oral selective estrogen receptor degrader (SERD) imlunestrant improved progression-free survival (PFS) compared with standard-of-care (SOC) endocrine therapy for the treatment of patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer with ESR1 mutations with progression on previous endocrine therapy, according to data from the phase 3 EMBER-3 trial.
The findings, which were presented at the 2024 San Antonio Breast Cancer Symposium and published simultaneously in The New England Journal of Medicine, also demonstrated that PFS improvement was not statistically significant in the overall population, which included patients without ESR1 mutations.
In addition, results also showed that the combination of imlunestrant and Verzenio (abemaciclib) improved PFS compared with imlunestrant alone in the overall population of EMBER-3, irrespective of ESR1 mutation status.
Findings showed that patients with ESR1-mutated disease treated with imlunestrant monotherapy (138 patients) experienced a median PFS of 5.5 months compared with 3.8 months for those given SOC endocrine therapy (118 patients). In the overall population, the median PFS was 5.6 months for imlunestrant monotherapy (331 patients) versus 5.5 months for endocrine therapy (330 patients). Notably, there was no statistical difference in PFS between the two treatment groups for patients without ESR1 mutations.
In the overall population, those treated with imlunestrant plus Verzenio (213 patients) achieved a median PFS of 9.4 months versus 5.5 months for those given imlunestrant alone (213 patients). Notably, the efficacy analysis for imlunestrant monotherapy versus imlunestrant plus Verzenio was confined to the imlunestrant monotherapy population enrolled concurrently with patients in the combination arm.
In patients harboring ESR1 mutations, the median PFS was 11.1 months for imlunestrant plus Verzenio (67 patients) versus 5.5 months for imlunestrant monotherapy (92 patients. In patients without ESR1 mutations, the median PFS was 9.1 months for the combination (146 patients) versus 5.5 months for imlunestrant alone (121 patients.
“Imlunestrant as monotherapy or combined with [Verzenio] provides an all-oral targeted therapy option after progression on endocrine therapy for patients with ER-positive, HER2-negative advanced breast cancer,” lead study author Dr. Komal Jhaveri, said in a presentation of the data. Jhaveri is the section head of the Endocrine Therapy Research Program Clinical, director of the Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.
EMBER-3 Design and Patient Characteristics
EMBER-3 enrolled men and pre- or postmenopausal women with ER-positive, HER2-negative advanced breast cancer. Patients were allowed to enroll if they experienced disease recurrence on or within 12 months of completing adjuvant treatment with an aromatase inhibitor (AI) with or without a CDK4/6 inhibitor, or if they had disease progression after first-line treatment with an AI with or without a CDK4/6 inhibitor in the advanced disease setting. No other prior treatments for advanced breast cancer were permitted.
Patients were randomly assigned to receive imlunestrant alone; SOC endocrine therapy consisting of Faslodex (fulvestrant) or Aromasin (exemestane); or imlunestrant plus Verzenio.
PFS for imlunestrant monotherapy versus endocrine therapy in the ESR1-mutated and overall populations, as well as PFS for imlunestrant plus Verzenio versus imlunestrant alone in the overall population, served as the trial’s main areas of focus. Other areas of interest included overall survival (OS), overall response rate (ORR) and safety. PFS and OS for the combination regimen versus SOC endocrine therapy were exploratory areas of interest.
At data cutoff, 20% of patients in the imlunestrant monotherapy arm remained on treatment. Reasons for treatment discontinuation included progressive disease (PD; 72%), side effects (3%), death (2%), patient withdrawal (1%), and protocol deviation (1%). In the SOC endocrine therapy arm, 13% of patients remained on study treatment; reasons for treatment discontinuation included PD (78%), death (2%), patient withdrawal (3%), protocol deviation (1%) and physician decision (1%). Thirty-five percent of patients in the imlunestrant plus Verzenio arm remained on treatment; reasons for discontinuation comprised PD (53%), side effects (5%), death (2%), patient withdrawal (2%) and physician decision (1%).
Additional Efficacy and Safety Data
PFS data were consistent across subgroups for both imlunestrant monotherapy in the ESR1-mutated population and imlunestrant plus Verzenio in the overall population.
Findings from a subgroup analysis showed that among patients who received a prior CDK4/6 inhibitor, the median PFS was 9.1 months for imlunestrant plus Verzenio (139 patients) versus 3.7 months for imlunestrant monotherapy (140 patients). Patients harboring a mutation in the PI3K pathway treated with the combination (88 patients) experienced a median PFS of 7.6 months versus 3.8 months for those given imlunestrant monotherapy (84 patients).
Among patients with measurable disease, the investigator-assessed ORR was 12% for imlunestrant (262 patients) versus 8% for endocrine therapy (251 patients) in the overall population. The ORR was 14% for imlunestrant alone (112 patients) versus 8% for endocrine therapy (91 patients) in the ESR1-mutated population; the respective ORRs were 11% and 9% for imlunestrant (150 patients) and endocrine therapy (160 patients) in the population of patients without ESR1 mutations.
The ORR in the overall population was 27% for imlunestrant plus Verzenio (167 patients) versus 12% for imlunestrant alone (169 patients) and 5% for endocrine therapy (162 patients). In the ESR1-mutated population, the ORRs were 35% for the combination (54 patients), 15% for imlunestrant alone (74 patients) and 3% for endocrine therapy (58 patients). In patients without ESR1 mutations, the ORRs for the combination (113 patients), imlunestrant alone (95 patients) and endocrine therapy (104 patients) were 23%, 10% and 6%, respectively.
Data from an exploratory analysis showed that imlunestrant monotherapy was associated with an improvement in central nervous system (CNS) progression. However, Jhaveri explained the data should be interpreted with caution due to the low rate of CNS events. In the ESR1-mutated population, two CNS progression events were reported in the imlunestrant monotherapy arm (138 patients) versus seven events in the endocrine therapy arm (118 patients). In the overall population, five CNS progression events were reported in the imlunestrant arm (331 patients) versus 10 events in the endocrine therapy arm (330 patients).
Safety data showed that any-grade treatment-emergent side effects occurred in 83% of patients in the imlunestrant monotherapy arm (327 patients) versus 84% of patients in the endocrine therapy arm (334 patients). The rates of grade 3 (severe)or higher treatment-emergent side effects were 17% and 21%, respectively. The most common any-grade treatment-emergent side effects reported in at least 10% of patients included fatigue (imlunestrant, 23%; endocrine therapy, 13%), diarrhea (21%; 12%), nausea (17%; 13%), arthralgia (14%; 14%), increased aspartate aminotransferase levels (13%; 13%), back pain (11%; 7%), increased alanine aminotransferase levels (10%; 10%), anemia (10%; 13%) and constipation (10%; 6%).
Serious side effects occurred in 10% of patients in the imlunestrant arm versus 12% of patients in the endocrine therapy arm. In the imlunestrant monotherapy group, side effects led to dose reductions, treatment discontinuation and death in 2%, 4%, and 2% of patients, respectively. These respective rates were 0%, 1%, and 1% in the endocrine therapy group.
In the imlunestrant plus Verzenio arm (208 patients), any-grade and grade 3 or higher treatment-emergent side effects were reported in 98% and 49% of patients, respectively. The most common treatment-emergent side effects reported in at least 20% of patients included diarrhea (any grade, 86%; grade ≥3, 8%), nausea (49%; 2%), neutropenia (48%; 20%), anemia (44%; 8%), fatigue (39%; 5%), vomiting (31%; 1%), leukopenia (26%; 4%), hypercreatinemia (22%; 1%), abdominal pain (20%; 2%) and decreased appetite (20%; 1%). Serious side effects occurred in 17% of patients. Side effects led to dose reductions, treatment discontinuation and death in 39%, 6%, and 1% of patients, respectively.
“The safety profile [of imlunestrant plus Verzenio] was [consistent with] what we know about the [Verzenio] profile, and [it] compared favorably with prior reports Faslodex plus [Verzenio] with no new added safety signal,” Jhaveri concluded.
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