Approximately 90% of breast cancer cases are detected in the early stages, with HR+/HER2- subtype accounting for about 70% of all cases. While the prognosis for early-stage HR+/HER2- breast cancer is generally favorable, high-risk patients face a threefold higher risk of recurrence, often progressing to incurable metastatic disease. Nearly one in three early-stage breast cancer cases eventually becomes metastatic, and the five-year survival rate for HR+/HER2- metastatic disease is only 30%.

Imlunestrant (LY3484356) is a next-generation oral, brain-penetrant, selective estrogen receptor degrader (SERD) designed to deliver continuous ER target inhibition, including ESR1-mutant BC. Imlunestrant is currently under investigation in both the Phase I EMBER-2 trial for early-stage ER+/HER2- breast cancer and the Phase I EMBER trial for advanced-stage ER+/HER2- breast cancer. These developments represent significant progress in breast cancer treatment. It has demonstrated consistent and robust engagement with its target across various doses and has been well-tolerated in the early-stage breast cancer population. These findings support its potential use as an adjuvant treatment in the EMBER-4 study. Additionally, Imlunestrant as a monotherapy has shown promising safety, pharmacokinetics, and initial efficacy in heavily pre-treated patients with advanced ER+ breast cancer.

The EMBER-2 trial, a Phase I study presented at ESMO 2023, focused on post-menopausal women with Stage I-III estrogen receptor-positive, HER2-negative breast cancer and the effects of LY3484356. Among the seventy-five evaluated patients (divided into three dosage groups: 200 mg, 400 mg, and 800 mg), baseline characteristics were similar, with a median age of 64 years, and a majority having invasive ductal carcinoma (69%) and being at Stage I (55%) or Stage II (40%).

The trial revealed a relative reduction in potential disease (PD) biomarkers within just 16 days of Imlunestrant treatment. Importantly, this effect was consistent across different Imlunestrant dosages. Furthermore, Imlunestrant demonstrated excellent tolerability. These results represent a significant step forward in understanding the potential of Imlunestrant for the treatment of ER+/HER2- EBC.

 

The EMBER study, a pioneering global Phase Ia/Ib trial, reported as of October 6, 2022, that 114 patients received Imlunestrant as a monotherapy, while 42 patients received it in combination with everolimus, and 21 patients combined it with alpelisib. Baseline characteristics among these combination cohorts were quite similar, with 46% of patients having visceral disease and 46% displaying an ESR1 mutation at the study's outset. In the combination groups, the median number of prior therapies for advanced breast cancer was one, including prior endocrine therapy (100%), CDK4/6 inhibitors (100%), fulvestrant (35%), and chemotherapy (17%).

ESMO 2023 results from this Phase Ia/Ib EMBER study are of great significance. They reveal that Imlunestrant, whether administered alone or in combination with abemaciclib, demonstrated excellent safety, pharmacokinetics, and a promising clinical benefit rate. These findings represent a significant advancement in the development of imlunestrant as a potential treatment for advanced breast cancer, especially among patients with certain challenging characteristics.

KOL insights

“I’m looking for trials such as the phase 3 EMBER-3 [trial; NCT04975308], which is looking at oral SERD [selective estrogen receptor degrader] imlunestrant plus abemaciclib in one of the arms in that study. So if imlunestrant alone [is] superior to standard-of-care endocrine therapy, we will then look at in imlunestrant versus imlunestrant-abemaciclib. So that would be an attractive trial to keep an eye on to see if that can push the needle forward.”– MD, FACP - MSK Breast Oncologist & Early Drug Development Specialist, United State

Conclusion: Imlunestrant, a pioneering oral SERD still in its investigational stage, is strategically engineered to sustain uninterrupted inhibition of the estrogen receptor (ER), even in the presence of ESR1 mutations within breast cancer. The data from the Phase I, EMBER-2, and EMBER trial is encouraging for breast cancer.

As a monotherapy, Imlunestrant has exhibited compellingly favorable attributes in terms of safety, pharmacokinetics, and early efficacy among patients facing the challenging landscape of heavily pre-treated ER+ advanced breast cancer. In a significant milestone, the conclusive pharmacodynamic biomarker findings have emerged from the preoperative EMBER-2 WOO study (NCT04647487), including an in-depth analysis of the expanded dataset for the 200 mg dose level. This study scrutinized Imlunestrant in ER+, HER2- early-stage breast cancer (EBC). Impressively, Imlunestrant has consistently demonstrated robust engagement with the intended molecular target at all assessed dosage levels. Additionally, it was well-tolerated within the EBC patient population, thereby providing a strong foundation for its advancement in the adjuvant setting, as supported by the forthcoming EMBER-4 study.

While in the Phase Ia/b EMBER study, imlunestrant in combination with everolimus or alpelsib, demonstrated robust efficacy in CDK4/6 inhibitor pretreated, ER+/HER2– advanced breast cancer patients, and also supporting further study of Imlunestrant with standard of care targeted therapies. In terms of safety, the toxicities of the combination regimes were consistent with the known safety profiles of alpelisib or everolimus with standard endocrine therapy. No drug-drug interaction was observed between imlunestrant and alpelisib or everolimus, and no new safety signals with the imlunestrant. Pivotal registration trials of imlunestrant are ongoing for ER+/HER2– advanced breast cancer previously treated with ET in EMBER-3 trials.

The treatment landscape for HR+/HER2– breast cancer currently encompasses a range of therapies, including CDK4/6 inhibitors, PARP inhibitors, SERDS, PI3K-alpha inhibitors, and others. However, the emergence of novel strategies such as oral SERDs, CERANs, SERCAs, PROTAC ER degraders, and CDK7 inhibitors presents promising solutions to combat resistance to ERα-targeted therapy. The pipeline for HR+/HER2– breast cancer treatment is robust and characterized by a wealth of innovative therapies with distinct mechanisms of action. These encouraging treatment options have the potential to address unmet medical needs and are poised to significantly boost market growth in the near future. 

Among HR+/HER2– breast cancer patients in the United States, fewer patients are diagnosed with distant HR+/HER2– breast cancer.

 

As per DelveInsight’s estimates, in 2023, out of total breast cancer patients, contribution of early (localized and locally advanced) stage is approximately 90%, and metastatic stage is approximately 6% in the US. For more insight into the Breast cancer types including Metastatic HR+/HER2− Breast Cancer and HER2-Negative Breast Cancer, their varying geographical patient burden, treatment, and changing market landscape-related advancements, refer to these reports:

• HER2-Negative Breast Cancer Market Insight and Market Forecast Report
• Metastatic HR+/HER2− Breast Cancer Market Insight and Market Forecast Report