Monotherapy of Imlunestrant, an investigational, oral selective estrogen receptor degrader (SERD), in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC), whose disease progressed on a prior aromatase inhibitor (AI), with or without a CDK4/6 inhibitor, significantly reduced the risk of progression or death by 38% compared to standard endocrine therapy (ET) in patients with ESR1 mutations.
As combination therapy, imlunestrant plus abemaciclib (Verzenio®; Lilly & Co) significantly reduced the risk of progression or death by 43%, compared to imlunestrant alone, in all patients, regardless of ESR1 mutation status.
These conclusions are based on the outcome of the Phase 3 EMBER-3 trial (NCT04975308), a randomized, open-label study of imlunestrant, investigator’s choice of endocrine therapy, and imlunestrant in combination with abemaciclib.
The trial enrolled 874 adult patients, 32% of which enrolled from the adjuvant setting into first-line treatment of ABC and 64% in second-line treatment following progression on initial therapy for ABC. Enrolled trial participants were randomized between imlunestrant, investigator’s choice of fulvestrant or exemestane, or imlunestrant plus abemaciclib.
The results were published simultaneously in the New England Journal of Medicine (NEJM) [1] and presented at the San Antonio Breast Cancer Symposium (SABCS), held December 10 – 13, 2024.
Imlunestrant is a brain-penetrant, oral selective estrogen receptor degrader (SERD), that delivers continuous ER inhibition, including in ESR1-mutant cancers. The estrogen receptor (ER) is the key therapeutic target for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Novel degraders of ER may overcome endocrine therapy resistance while providing consistent oral pharmacology and convenience of administration.
Study outcomes
“The median progression-free survival observed in EMBER-3 is among the most compelling we’ve seen in CDK4/6 pre-treated ER+, HER2- advanced breast cancer patients and indicates a potential shift in the therapy options we provide for these patients, which are currently very limited,” said Komal Jhaveri, MD, section head, endocrine therapy research and clinical director, early drug development at Memorial Sloan Kettering Cancer Center, and one of the study’s principal investigators.
“The benefit and safety profile of the imlunestrant and abemaciclib combination signal a potential new all-oral option for patients,” Jhaveri further noted.
In the EMBER-3 study, patients were randomized 1:1:1 to receive imlunestrant alone, SOC ET, or the imlunestrant-abemaciclib combination. Randomization was stratified by prior CDK4/6 inhibitor use, the presence of visceral metastases, and geographic region. Patients enrolled as first-line (1L) treatment for ABC (32%), following disease recurrence on or within 12 months of completing adjuvant AI, with or without CDK4/6 inhibitor for early breast cancer (EBC), or as second-line (2L) treatment for advanced or metastatic breast cancer (64%), following progression on AI, with or without CDK4/6 inhibitor as initial therapy for ABC.
Primary endpoints were investigator-assessed PFS of imlunestrant versus SOC ET therapy in patients with ESR1 mutations, imlunestrant versus SOC ET in all patients, and imlunestrant-abemaciclib versus imlunestrant in all patients.
Imlunestrant versus standard of care
Imlunestrant significantly improved PFS versus SOC ET in patients with an ESR1 mutation. In patients with an ESR1 mutation, the median PFS was 5.5 months with imlunestrant versus 3.8 months with SOC ET [HR=0.62 (95% CI 0.46-0.82); p-value<0.001]. The overall response rate (ORR) with imlunestrant was 14% compared to 8% with SOC ET in patients with an ESR1 mutation. In all patients, the median PFS was 5.6 months with imlunestrant versus 5.5 months with SOC ET [HR=0.87 (95% CI 0.72-1.04); p-value 0.12] and did not reach statistical significance.
Consistent with preclinical data demonstrating central nervous system (CNS) penetrance and CNS-activity of imlunestrant, CNS progression rates from a post-hoc analysis were lower with imlunestrant in all patients (HR=0.47; 95% CI, 0.16-1.38), as well as patients with an ESR1 mutation (HR=0.18; 95% CI, 0.04-0.90), however, these analyses are limited by low event numbers and lack of mandated serial asymptomatic CNS imaging in all patients.
Abemaciclib versus imlunestrant
Imlunestrant-abemaciclib significantly improved PFS compared to imlunestrant in all patients, regardless of ESR1 mutation status, with median PFS of 9.4 months for imlunestrant-abemaciclib versus 5.5 months for imlunestrant alone [HR=0.57 (95% CI 0.44-0.73); p-value <0.001]. The PFS benefit of the combination was consistent across subgroups, regardless of ESR1 mutation, or phosphatidylinositol-3-kinase (PI3K) pathway mutation status, including in patients who had previously received CDK4/6 inhibitor treatment. In all patients, the ORR with imlunestrant-abemaciclib was 27% compared to 12% with imlunestrant alone.
Safety in the imlunestrant-abemaciclib arm was consistent with the known safety profile of fulvestrant in combination with abemaciclib, with mostly low-grade adverse events including diarrhea (86%), nausea (49%), neutropenia (48%) and anemia (44%), and had a low discontinuation rate (6.3%).[2][3]
Overall survival (OS) results for EMBER-3 were immature at the time of analysis. The trial will continue to assess OS as a secondary endpoint.
“EMBER-3 is the first Phase 3 trial to show a benefit of combining an oral SERD with a CDK4/6 inhibitor for a patient population where an all-oral regimen would represent a meaningful advance,” noted David Hyman, M.D., Chief Medical Officer, Lilly.
“We’re highly encouraged by these data for both imlunestrant as monotherapy and in combination with abemaciclib, as well as the safety and tolerability profile, which demonstrate the potential for imlunestrant to be a meaningful new oral endocrine therapy option for patients. We look forward to sharing these results with the oncology community and completing regulatory submissions to global health authorities,” Hyman added.
An estimated 70 to 80% of hormone receptor-positive breast cancers are ER+ and after progression on initial endocrine therapy, are predominantly treated with fulvestrant, which is administered by intramuscular injection in a doctor’s office. [4][5]
According to patient-reported outcomes data from EMBER-3, 72% of patients receiving fulvestrant in the standard ET group reported injection site pain, swelling, or redness. Imlunestrant is an orally administered, brain-penetrant, pure ER antagonist that delivers continuous ER target inhibition.
Imlunestrant is also being investigated in the adjuvant setting in people with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence. This Phase 3 trial, EMBER-4, is expected to enroll 6,000 EBC patients worldwide.
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Poster presentation
- Title: Imlunestrant, an Oral Selective Estrogen Receptor Degrader (SERD), as Monotherapy & 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.
- Presentation Number: GS1-01/Abstract SESS-3617
- Presenter: Komal Jhaveri, M.D.
- Onsite Poster display date: Wednesday, December 11, 2024
Clinical trials
A Study of Imlunestrant, Investigator’s Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3) – ClinicalTrials.gov ID NCT04975308
A Study of Imlunestrant Versus Standard Endocrine Therapy in Participants With Early Breast Cancer (EMBER-4) – ClinicalTrials.gov ID NCT05514054
A Study of LY3484356 in Participants With Advanced or Metastatic Breast Cancer or Endometrial Cancer (EMBER) – ClinicalTrials.gov ID NCT04188548
A Study of LOXO-783 in Patients With Breast Cancer/Other Solid Tumors (PIKASSO-01) – ClinicalTrials.gov ID NCT05307705
Highlights of Prescribing Information
Abemaciclib (Verzenio®; Lilly & Co)[Prescribing Information]
References
[1] Jhaveri KL, Neven P, Casalnuovo ML, Kim SB, Tokunaga E, Aftimos P, Saura C, O’Shaughnessy J, Harbeck N, Carey LA, Curigliano G, Llombart-Cussac A, Lim E, García Tinoco ML, Sohn J, Mattar A, Zhang Q, Huang CS, Hung CC, Martinez Rodriguez JL, Ruíz Borrego M, Nakamura R, Pradhan KR, Cramer von Laue C, Barrett E, Cao S, Wang XA, Smyth LM, Bidard FC; EMBER-3 Study Group. Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. N Engl J Med. 2024 Dec 11. doi: 10.1056/NEJMoa2410858. Epub ahead of print. PMID: 39660834.
[2] André F, Ciruelos EM, Juric D, Loibl S, Campone M, Mayer IA, Rubovszky G, Yamashita T, Kaufman B, Lu YS, Inoue K, Pápai Z, Takahashi M, Ghaznawi F, Mills D, Kaper M, Miller M, Conte PF, Iwata H, Rugo HS. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021 Feb;32(2):208-217. doi: 10.1016/j.annonc.2020.11.011. Epub 2020 Nov 25. PMID: 33246021.
[3] Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, Hu X, Jhaveri K, Krivorotko P, Loibl S, Morales Murillo S, Okera M, Park YH, Sohn J, Toi M, Tokunaga E, Yousef S, Zhukova L, de Bruin EC, Grinsted L, Schiavon G, Foxley A, Rugo HS; CAPItello-291 Study Group. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1;388(22):2058-2070. doi: 10.1056/NEJMoa2214131. PMID: 37256976; PMCID: PMC11335038.
[4] Hanker AB, Sudhan DR, Arteaga CL. Overcoming Endocrine Resistance in Breast Cancer. Cancer Cell. 2020 Apr 13;37(4):496-513. doi: 10.1016/j.ccell.2020.03.009. PMID: 32289273; PMCID: PMC7169993.
[5] Hua H, Zhang H, Kong Q, Jiang Y. Mechanisms for estrogen receptor expression in human cancer. Exp Hematol Oncol. 2018 Sep 19;7:24. doi: 10.1186/s40164-018-0116-7. PMID: 30250760; PMCID: PMC6148803.
Featured image: Komal Jhaveri, MD speaks during the San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo courtesy: © 2024 AACR/SABCS/Todd Buchanan
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