- The phase 3 EMBER-3 trial is evaluating imlunestrant, a next-generation oral selective estrogen receptor degrader (SERD), alone or in combination with CDK4/6 inhibitor abemaciclib in patients with ER-positive/HER2- advanced breast cancer after progression on endocrine therapy.
- Primary progression-free survival (PFS) results from this phase 3 study show that imlunestrant monotherapy significantly prolonged PFS versus standard therapy in patients with mutations in the ESR1 gene; and with the imlunestrant-abemaciclib combination over imlunestrant in all patients, regardless of ESR1-mutation status.
- These late-breaking data were presented at the San Antonio Breast Cancer Symposium®, December 10-13, by lead investigator Komal L. Jhaveri of the Memorial Sloan Kettering Cancer Center (MSKCC).
- Results of this study, co-authored by Cristina Saura, Head of the Vall d’Hebron University Hospital’s Breast Cancer Unit and the Vall d’Hebron Institute of Oncology’s (VHIO) Breast Cancer Group, published simultaneously in The New England Journal of Medicine.
Primary progression-free survival data from the phase 3 EMBER-3 trial for imlunestrant, a next-generation oral selective estrogen receptor degrader (SERD), were reported today at the San Antonio Breast Cancer Symposium (SABS)1, December 10-13, San Antonio, Texas. Presented by corresponding author Komal L. Jhaveri, Section Head, the Endocrine Therapy Research Program and Clinical Director of the Early Drug Development Service at the Memorial Sloan Kettering Cancer Center in New York, these data published in parallel in The New England Journal of Medicine2.
Results showed that in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer whose disease had progressed while receiving adjuvant endocrine therapy or within 12 months after treatment, or while receiving first-line treatment for advanced breast cancer with an aromatase inhibitor, alone or with a CDK4/6 inhibitor, imlunestrant significantly improved progression-free survival (PFS) over standard therapy in patients with ESR1 mutations, but not in the overall population. The imlunestrant-abemaciclib combination substantially prolonged PFS in all patients, regardless of ESR1-mutation status.
Female breast cancer is the second leading cause of global cancer incidence in 2022, with an estimated 2.3 million new cases, comprising 11.6% of all cancer cases3. ER+/HER2- breast cancer is the most common breast cancer type, accounting for approximately 70% of all breast cancer cases.
The optimization of endocrine therapy through the development of current and emerging estrogen receptor-targeted therapies has incrementally improved treatment outcomes. These include selective ER modulators (SERM) that inhibit ER; aromatase inhibitors that block estrogen production; and SERDs that directly antagonize and destabilize ER, leading to its blockade and degradation.
“Most of these tumors ultimately develop resistance to current endocrine therapies and frequently acquire mutations in the gene encoding ER, ESR1, which associates with a poorer prognosis. To improve patient outcomes, we must continue to develop and validate new therapeutic options and strategies. Novel oral SERDs could potentially provide a new targeted treatment for this patient population,” said Cristina Saura, Head of the Vall d’Hebron University Hospital’s Breast Cancer Unit and VHIO’s Breast Cancer Group, and a co-author of this present study.
The promise of next-generation SERD imlunestrant
Imlunestrant is a next-generation, brain-penetrant, oral SERD and ER antagonist that delivers continuous ER inhibition, including ESR1-mutant cancers. In the phase 1 EMBER study, imlunestrant, both alone and in combination with abemaciclib, demonstrated mainly low-grade toxicity, favorable pharmacokinetics and encouraging antitumor activity in patients with ER+/HER2- advanced breast cancer.
The EMBER-3 open-label phase 3 trial included 874 patients who were randomized at 195 sites across 22 countries to imlunestrant monotherapy, imlunestrant-abemaciclib in combination or standard endocrine therapy.
In the subgroup of patients with ESR1 mutation, imlunestrant monotherapy increased median PFS; 5.5 months versus 3.8 months with standard therapy. However, in the global population —without considering genomic profile status—imlunestrant alone did not show significant benefits.
For the combination therapy in all patients, median PFS was 9.4 months in the imlunestrant-abemaciclib group compared to 5.5 months in the imlunestrant group.
“While this novel SERD is not yet approved by regulatory agencies for use in standard clinical practice, results from the EMBER-3 trial support continued investigations aimed at developing next-generation SERDs as a potential new therapeutic option for patients with advanced ER+ HER2 breast cancer after progression on endocrine therapy. Findings also point to the optimization of these novel agents based on the genomic characteristics of tumors,” concluded Saura.
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References
1. San Antonio Breast Cancer Symposium®, December 10-13, 2023. Henry B. Gonzalez, Convention Center, San Antonio, Texas, USA.
General Session 1: Wednesday, December 11, 9:15 – 11:30 am (CST).
Location: Hall 1
Moderators: Alexandra Thomas, Duke Cancer Institute, Durham, North Carolina, and Reshma Mahtani, Miami Cancer Institute, Miami, Florida
GS1-01: Imlunestrant, an Oral Selective Estrogen Receptor Degrader (SERD), as Monotherapy and Combined with Abemaciclib, for Patients w/ ER+, HER2- Advanced Breast Cancer (ABC), Pretreated w/ Endocrine Therapy (ET): Results of the Phase 3 EMBER-3 trial.
Presenter: Komal Jhaveri, Memorial Sloan Kettering Cancer Center, New York, New York.
Presentation time: 9:15 – 9:30 am (CST).
2.Komal L. Jhaveri, M.D.,1 Patrick Neven, M.D.,2 Monica Lis Casalnuovo, M.D.,3 Sung-Bae Kim, M.D.,4 Eriko Tokunaga, M.D.,5 Phillippe Aftimos, M.D.,6 Cristina Saura, M.D.,7 Joyce O’Shaughnessy, M.D.,8 Nadia Harbeck, M.D.,9 Lisa A. Carey, M.D.,10 Giuseppe Curigliano, M.D.,11,12 Antonio Llombart-Cussac, M.D.,13 Elgene Lim, M.D.,14 María de la Luz García Tinoco, M.D.,15 Joohyuk Sohn, M.D.,16 André Mattar, M.D., Ph.D.,17 Qingyuan Zhang, M.D.,18 Chiun-Sheng Huang, M.D.,19 Chih-Chiang Hung, M.D.,20 Jorge Luis Martinez Rodriguez, M.D.,21 Manuel Ruiz Borrego, M.D.,22 Rikiya Nakamura, M.D.,23 Kamnesh R. Pradhan, M.D.,24 Christoph Cramer von Laue, Ph.D.,24 Emily Barrett, M.Sc.,24 Shanshan Cao, Ph.D.,24 Xuejing Aimee Wang, Ph.D.,24 Lillian M. Smyth, M.D.,24 and François-Clément Bidard, M.D.25, for the EMBER-3 Study Group. Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. NEJM. Published December 11, 2024. DOI: 10.1056/NEJMoa2410858
3. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263.
