Imulnestrant Plus Abemaciclib Extends PFS Over SOC in ER+/HER2– Advanced Breast Cancer

Treatment with imlunestrant (LY3484356), an oral selective estrogen receptor degrader (SERD) (LY3484356), plus abemaciclib (Verzenio) led to a statistically significant prolongation of progression-free survival (PFS) vs standard-of-care (SOC) endocrine therapy in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer regardless of ESR1 mutation status, according to results from the EMBER-3 trial (NCT04975308).

The data, which were presented at the 42nd Annual Miami Breast Cancer Conference as an encore presentation, also demonstrated that, although single-agent Imlunestrant did not generate superior PFS vs standard-of-care (SOC) endocrine therapy was not reported in the overall study population, a statistically significant PFS improvement with the monotherapy was observed in a subgroup of patients with ESR1 mutations.

In the overall patient population, imlunestrant plus abemaciclib (n = 213) reduced the risk of progression or death by 43% (HR, 0.57; 95% CI, 0.44-0.73; P < .001). The median PFS by investigator assessment was 9.4 months (95% CI, 7.5-11.9) with imlunestrant plus abemaciclib (n = 213) vs 5.5 months (95% CI, 3.8-5.6) with imlunestrant alone (n = 213). 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.

For patients in the overall study population who received Imlunestrant monotherapy (n = 331), the median PFS was 5.6 months (95% CI, 5.3-7.3) vs 5.5 months (95% CI, 4.6-5.6) with SOC endocrine therapy (n = 330; HR, 0.87; 95% CI, 0.72-1.04; P = .12). No statistical difference in PFS was observed for patients without ESR1 mutations between the 2 treatment arms (HR, 1.00; 95% CI, 0.79-1.27).

In the ESR1-mutant subgroup, imlunestrant monotherapy (n = 138) reduced the risk of progression or death by 38% (n = 118; HR, 0.62; 95% CI, 0.46-0.82; P < .001). The median PFS was 5.5 months (95% CI, 3.9-7.4) with single-agent imlunestrant vs 3.8 months (95% CI, 3.7-5.5) with SOC endocrine therapy (n = 118).

“The treatment effect of imlunestrant monotherapy in the ESR1-mutant population and imlunestrant plus abemaciclib in the overall population across key subgroups and thesecondary end points of overall response rate [ORR] and PFS by blinded independent central review [(BICR) also] supported the primary outcomes” Komal L. Jhaveri, MD, FACP, and colleagues wrote in a poster presentation of the data. Jhaveri is 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.

Regarding safety, the toxicity profile for imlunestrant plus abemaciclib was deemed consistent with that of the known profile of abemaciclib. Moreover, investigators noted that it compared favorably with prior data on fulvestrant plus abemaciclib. No additional safety signals were reported.

EMBER-3 Trial Design

The EMBER-3 trial enrolled men and pre- or postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had either experienced disease recurrence within 12 months of completing adjuvant therapy with an aromatase inhibitor (AI) with or without a CDK4/6 inhibitor; or had disease progression after a first-line treatment with an aromatase inhibitor with or without a CDK4/6 inhibitor, in the advanced setting. No prior therapies for advanced disease were permitted.

The current analysis comprises patients enrolled onto the study from October 2021 to November 2023 across 243 sites in 22 counties. Patients were randomly assigned 1:1:1 to receive either 400 mg of imlunestrant monotherapy once daily, SOC endocrine therapy with fulvestrant (Faslodex) or exemestane (Aromasin), or imlunestrant plus abemaciclib. Stratification factors included prior CDK4/6 inhibitor treatment, the presence of visceral metastases, and geographic region.

The study’s primary end points were investigator-assessed PFS for imlunestrant monotherapy vs SOC endocrine therapy in the ESR1-mutant and overall patient populations, as well as PFS for imlunestrant plus abemaciclib vs imlunestrant alone in the overall population. Overall survival (OS), BICR–assessed PFS, ORR, and safety served as secondary end points. PFS and OS for the combination regimen vs SOC endocrine therapy were exploratory end points.

At the time of study analysis, demographic and baseline characteristics were balanced across arms. Notably, 37% of patients displayed ESR1 mutations, and approximately 60% had prior exposure to a CDK4/6 inhibitor.

Additional Safety Data

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 83% of patients in the imlunestrant monotherapy arm (n = 327) and 84% of patients in the endocrine therapy arm (n = 334). Grade 3 or higher TEAEs were reported in 17% and 21% of patients, respectively. The most common any-grade TEAEs in at least 10% of patients included fatigue (23% in the imlunestrant monotherapy arm vs 13% in the endocrine therapy arm), diarrhea (21% vs 12%), and nausea (17% vs 13%).

Serious adverse effects (AEs) occurred in 10% of patients in the imlunestrant arm and 12% in the endocrine therapy arm. In the imlunestrant monotherapy group, AEs led to dose reductions, discontinuation, and death in 2%, 4%, and 2% of patients, respectively. Respective rates in the endocrine therapy group were 0%, 1%, and 1%. Notably, no injection site TEAEs or reactions occurred with single-agent imlunestrant. In the endocrine therapy arm, respective rates were 9% and 72%.

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 in at least 20% of patients included diarrhea (any grade, 86%; grade ≥3, 8%), nausea (49%; 2%), and neutropenia (48%; 20%). Serious AEs occurred in 17% of patients. AEs led to dose reductions, discontinuation, and death in 39%, 6%, and 1% of patients, respectively.

Reference

Jhaveri K, Neven P, Casalnuovo M, et al. EMBER-3: Study of Imulnestrant alone or in combination with abemaciclib for patients with ER+ HER2- MBC following progression on previous ET. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2024; Miami, Florida. Poster 30.