Eli Lilly’s Phase III EMBER-3 study has demonstrated that imlunestrant, an investigational oral selective estrogen receptor degrader (SERD), significantly improves outcomes in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. This disease, often resistant to current therapies, is challenging to treat, but imlunestrant’s ability to target the estrogen receptor holds promise.
Imlunestrant’s oral administration makes it more convenient than injectable therapies like fulvestrant, which is often associated with injection site pain and discomfort.
As a monotherapy, imlunestrant reduced the risk of progression or death by 38 percent compared to standard endocrine therapy in patients with ESR1 mutations, significantly improving progression-free survival (PFS). In combination with Verzenio (abemaciclib), a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, the therapy reduced the risk of progression or death by 43 percent, offering an even more compelling option for patients.
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Imlunestrant works by degrading the estrogen receptor, a key target in ER+, HER2- breast cancer, especially in patients with ESR1 mutations, who may develop resistance to traditional endocrine therapies.
Verzenio enhances the combination with imlunestrant by inhibiting CDK4/6, blocking the cell cycle and further inhibiting cancer growth. This dual mechanism has significantly improved PFS, particularly in patients previously treated with CDK4/6 inhibitors.
In the EMBER-3 trial, patients receiving imlunestrant alone demonstrated a median PFS of 5.5 months, compared to 3.8 months with standard endocrine therapy. The combination treatment showed even better results, with a median PFS of 9.4 months. The safety profile was consistent with expectations, showing manageable side effects such as diarrhea, nausea and neutropenia, with a low discontinuation rate of 6.3 percent.
As for survival data, while overall survival results are still being tracked, the improvement in PFS is promising. These early findings raise the potential for longer periods of disease control, which could offer a novel option for clinicians managing advanced breast cancer.
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In addition to imlunestrant, giredestrant (Roche) and vepdegestrant (Arvinas) are oral SERDs with similar mechanisms of action. Both are in Phase III trials, with giredestrant showing early promise in pivotal studies. Vepdegestrant is being tested both as a monotherapy and in combination with CDK4/6 inhibitors, including abemaciclib, with early results from the TACTIVE-U sub-study showing a clinical benefit rate of 62.5 percent and an overall response rate of 26.7 percent for the combination.
Other oral SERDs in development include elacestrant by Menarini, which is being studied in combination with abemaciclib in Phase Ib/II trials, showing favorable PFS, and camizestrant being developed by AstraZeneca, which has also shown superior PFS over fulvestrant in patients with ESR1 mutations. These investigational compounds are part of an expanding pipeline that could offer new treatment options for patients with ER+, HER2- advanced breast cancer.
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