Imlunestrant With or Without Abemaciclib Boosts PFS in ESR1+, ER+/HER2– Advanced Breast Cancer

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Single-agent treatment with the oral selective estrogen receptor degrader (SERD) imlunestrant (LY3484356) led to an improvement in progression-free survival (PFS) vs standard-of-care (SOC) endocrine therapy in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer harboring ESR1 mutations whose disease progressed on prior endocrine therapy, according to data from the phase 3 EMBER-3 trial (NCT04975308).^1,2 However, the PFS improvement was not statistically significant in the trial’s overall population, which included patients without ESR1 mutations.

Data presented at the 2024 San Antonio Breast Cancer Symposium and published simultaneously in the New England Journal of Medicine also demonstrated that the combination of imlunestrant and abemaciclib (Verzenio) 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 (n = 138) experienced a median PFS of 5.5 months (95% CI, 3.9-7.4) compared with 3.8 months (95% CI, 3.7-5.5) for those given SOC endocrine therapy (n = 118; HR, 0.62; 95% CI, 0.46-0.82; P < .001). In the overall population, the median PFS was 5.6 months (95% CI, 5.3-7.3) for imlunestrant monotherapy (n = 331) vs 5.5 months (95% CI, 4.6-5.6) for endocrine therapy (n = 330; HR, 0.87; 95% CI, 0.72-1.04; P = .12). Notably, there was no statistical difference in PFS between the two arms for patients without ESR1 mutations (HR, 1.00; 95% CI, 0.79-1.27).

In the overall population, those treated with imlunestrant plus abemaciclib (n = 213) achieved a median PFS of 9.4 months (95% CI, 7.5-11.9) vs 5.5 months (95% CI, 3.8-5.6) for those given imlunestrant alone (n = 213; HR, 0.57; 95% CI, 0.44-0.73; P < .001). Notably, the efficacy analysis for imlunestrant monotherapy vs imlunestrant plus abemaciclib 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 (95% CI, 7.4-13.7) for imlunestrant plus abemaciclib (n = 67) vs 5.5 months (95% CI, 3.8-7.2) for imlunestrant monotherapy (n = 92; HR, 0.53; 95% CI, 0.35-0.80). In patients without ESR1 mutations, the median PFS was 9.1 months (95% CI, 7.4-14.4) for the combination (n = 146) vs 5.5 months (95% CI, 3.6-5.8) for imlunestrant alone (n = 121; HR, 0.59; 95% CI, 0.43-0.81).

“Imlunestrant as monotherapy or combined with abemaciclib 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 Komal Jhaveri, MD, FACP, 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 1:1:1 to receive imlunestrant alone at 400 mg once per day; SOC endocrine therapy consisting of fulvestrant (Faslodex) or exemestane (Aromasin); or imlunestrant at 400 mg per day plus abemaciclib. Key stratification factors included prior treatment with a CDK4/6 inhibitor (yes vs no), visceral metastases (yes vs no), and region.

Investigator-assessed PFS for imlunestrant monotherapy vs endocrine therapy in the ESR1-mutated and overall populations, as well as PFS for imlunestrant plus abemaciclib vs imlunestrant alone in the overall population, served as the trial’s primary end points. Key secondary end points included overall survival (OS), blinded independent central review–assessed PFS, overall response rate (ORR), and safety. PFS and OS for the combination regimen vs SOC endocrine therapy were exploratory end points.

Per trial protocol, PFS for imlunestrant plus abemaciclib vs imlunestrant monotherapy was only tested if 1 of the PFS end points for imlunestrant monotherapy vs SOC endocrine therapy was statistically significant. OS was only tested if the corresponding PFS end point was statistically significant.

At data cutoff, 20% of patients in the imlunestrant monotherapy arm remained on treatment. Reasons for treatment discontinuation included progressive disease (PD; 72%), adverse effects (AEs; 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 abemaciclib arm remained on treatment; reasons for discontinuation comprised PD (53%), AEs (5%), death (2%), patient withdrawal (2%), and physician decision (1%).

Jhaveri explained that baseline patient characteristics were generally well balanced between the 3 arms, including in patients harboring ESR1 mutations. The median age was 61 years (range, 28-87) in the imlunestrant monotherapy arm, 62 years (range, 27-89) in the endocrine therapy arm, and 62 years (range, 36-87) in the imlunestrant plus abemaciclib arm. The majority of patients were female (99%; 99%; 99%), were postmenopausal (84%; 86%; 86%), were White (56%; 58%; 52%), had progesterone receptor–positive disease (78%; 79%; 74%), received their most recent endocrine therapy in the advanced disease setting (63%; 63%; 68%), received a prior CDK4/6 inhibitor (59%; 57%; 65%), and received a prior CDK4/6 inhibitor in the advanced disease setting (55%; 53%; 62%). Among those who received a prior CDK4/6 inhibitor, the most common was palbociclib (Ibrance; 61%; 69%; 65%). Notably, 7% of patients in the combination arm previously received abemaciclib.

Additional Efficacy and Safety Data

PFS data were consistent across subgroups for both imlunestrant monotherapy in the ESR1-mutated population and imlunestrant plus abemaciclib 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 (95% CI, 7.2-11.2) for imlunestrant plus abemaciclib (n = 139) vs 3.7 months (95% CI, 2.1-5.5) for imlunestrant monotherapy (n = 140; HR, 0.51; 95% CI, 0.38-0.68). Patients harboring a mutation in the PI3K pathway treated with the combination (n = 88) experienced a median PFS of 7.6 months (95% CI, 5.6-11.0) vs 3.8 months (95% CI, 3.1-5.5) for those given imlunestrant monotherapy (n = 84; HR, 0.61; 95% CI, 0.42-0.87).

Among patients with measurable disease, the investigator-assessed ORR was 12% (95% CI, 8%-16%) for imlunestrant (n = 262) vs 8% (95% CI, 5%-12%) for endocrine therapy (n = 251) in the overall population. The ORR was 14% (95% CI, 8%-21%) for imlunestrant alone (n = 112) vs 8% (95% CI, 2%-13%) for endocrine therapy (n = 91) in the ESR1-mutated population; the respective ORRs were 11% (95% CI, 6%-16%) and 9% (95% CI, 4%-13%) for imlunestrant (n = 150) and endocrine therapy (n = 160) in the population of patients without ESR1 mutations.

The ORR in the overall population was 27% (95% CI, 20%-34%) for imlunestrant plus abemaciclib (n = 167) vs 12% (95% CI, 7%-17%) for imlunestrant alone (n = 169) and 5% (95% CI, 2%-8%) for endocrine therapy (n = 162). In the ESR1-mutated population, the ORRs were 35% (95% CI, 22%-48%) for the combination (n = 54), 15% (95% CI, 7%-23%) for imlunestrant alone (n = 74), and 3% (95% CI, 0%-8%) for endocrine therapy (n = 58). In patients without ESR1 mutations, the ORRs for the combination (n = 113), imlunestrant alone (n = 95), and endocrine therapy (n = 104) were 23% (95% CI, 15%-31%), 10% (95% CI, 4%-15%), and 6% (95% CI, 1%-10%), 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, 2 CNS progression events were reported in the imlunestrant monotherapy arm (n = 138) vs 7 events in the endocrine therapy arm (n = 118; HR, 0.18; 95% CI, 0.04-0.90). In the overall population, 5 CNS progression events were reported in the imlunestrant arm (n = 331) vs 10 events in the endocrine therapy arm (n = 330; HR, 0.47; 95% CI, 0.16-1.38).

Regarding OS findings for imlunestrant monotherapy vs endocrine therapy, data reached 31% maturity for the ESR1-mutated population (HR, 0.55; 95% CI, 0.35-0.86; P = .008), 23% for the overall population (HR, 0.69; 95% CI, 0.50-0.96), and 18% for the population of patients without ESR1 mutations (HR, 0.87; 95% CI, 0.54-1.40). For all patients in the combination therapy comparison, OS data reached 15% maturity (HR, 1.34; 95% CI, 0.81-2.21).

Safety data showed that any-grade treatment-emergent AEs (TEAEs) occurred in 83% of patients in the imlunestrant monotherapy arm (n = 327) vs 84% of patients in the endocrine therapy arm (n = 334). The rates of grade 3 or higher TEAEs were 17% and 21%, respectively. The most common any-grade TEAEs 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 AEs occurred in 10% of patients in the imlunestrant arm vs 12% of patients in the endocrine therapy arm. In the imlunestrant monotherapy group, AEs 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 abemaciclib arm (n = 208), any-grade and grade 3 or higher TEAEs were reported in 98% and 49% of patients, respectively. The most common TEAEs 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 AEs occurred in 17% of patients. AEs led to dose reductions, treatment discontinuation, and death in 39%, 6%, and 1% of patients, respectively.

“The safety profile [of imlunestrant plus abemaciclib] was [consistent with] what we know about the abemaciclib profile, and [it] compared favorably with prior reports fulvestrant plus abemaciclib with no new added safety signal,” Jhaveri concluded.

Editor’s note: Dr Jhaveri reported serving as a consultant or in an advisory role for AbbVie, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Eisai, Eli Lilly and Company/Loxo Oncology, Genentech, Gilead Sciences, Menarini/Stemline Therapeutics, Merck, Novartis, Olema Pharmaceuticals, Pfizer, Scorpion Therapeutics, Seagen, Sun Pharma, Taiho Oncology, Bicycle Therapeutics, and Zymeworks; receiving institutional grant or research support from ADC Therapeutics, AstraZeneca, Blueprint Medicines, Context Therapeutics, Eli Lilly and Company, Genentech, Immunomedics/Gilead Sciences, Novartis, Pfizer, Puma Biotechnology, Scorpion Therapeutics, VelosBio/Merck, RayzeBio, and Zymeworks; and receiving travel, accommodations, and expenses from AstraZeneca, Eli Lilly and Company, Genentech/Roche, Gilead Sciences, Intellisphere, Jounce Therapeutics/Gilead Sciences, Pfizer, and Taiho Oncology.

References

1. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant, an oral selective estrogen receptor degrader (SERD), as monotherapy and combined with abemaciclib, for patients with ER+, HER2- advanced breast cancer (ABC), pretreated with endocrine therapy (ET): results of the phase 3 EMBER-3 trial. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-14, 2024; San Antonio, TX. Abstract GS1-01.
2. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. Published online December 11, 2024. doi:10.1056/NEJMoa2410858