Lilly's Oral SERD Advances in Breast Cancer with Phase 3 Results

In a recent development, Eli Lilly has announced promising results from its Phase 3 EMBER-3 study, which examined the efficacy of its oral selective estrogen receptor degrader (SERD) known as imlunestrant in the treatment of second-line breast cancer. The trial, which involved 874 patients with ER-positive, HER2-negative breast cancer, aimed to assess the benefits of imlunestrant, both as a standalone treatment and in conjunction with Lilly’s CDK4/6 inhibitor, Verzenio. The primary goal was to improve progression-free survival (PFS) compared to standard endocrine therapies such as Faslodex or Aromasin.

The study revealed that imlunestrant significantly reduced the risk of progression or death by 38% in patients with ESR1 mutations, a subgroup known to respond better to SERD treatments. Specifically, these patients saw a PFS of 5.5 months in comparison to 3.8 months in the control group. This subgroup constituted about 30% of the 256 patients enrolled with ESR1 mutations. Despite this success, imlunestrant did not demonstrate a PFS benefit across the broader population of participants, with results showing a negligible difference from standard care (5.6 months versus 5.5 months).

While data related to overall survival are still maturing, early observations suggest positive trends for imlunestrant monotherapy, especially among those with ESR1 mutations. A noteworthy observation is that if imlunestrant shows an overall survival benefit regardless of mutation status, it could mark a significant advancement for Lilly.

Currently, Menarini's Orserdu is the only approved oral SERD for treatment in second-line breast cancer, specifically for ESR1-mutated patients. Menarini's EMERALD trial demonstrated a 45% improvement in PFS versus standard treatments but did not show an overall survival advantage.

Lilly aims to submit the EMBER-3 data to regulatory authorities to seek approval for both imlunestrant as a monotherapy and in combination with Verzenio. The combination treatment showed a substantial 43% reduction in risk of progression or death in the overall study population versus imlunestrant alone. Additionally, overall response rates were notably higher in the combination group, demonstrating 27% effectiveness compared to 12% with imlunestrant alone and 8% with conventional endocrine therapy.

However, the data from the combination treatment group are less mature, suggesting that regulators might hold off on approval until more information is available. In the interim, Lilly anticipates that the monotherapy could receive approval, with practical application likely involving its use alongside Verzenio, albeit off-label.

The EMBER-3 study found that most adverse events experienced by patients in the imlunestrant/Verzenio arm were mild, including diarrhea, nausea, neutropenia, and anemia, with only 6.3% of participants discontinuing the trial due to these effects.

In addition to the findings from EMBER-3, Lilly is also advancing its research with the EMBER-4 trial, targeting the adjuvant setting. This trial could offer an alternative to AstraZeneca’s intramuscular SERD, Faslodex, which is less convenient due to its requirement for monthly injections over several years. The oral administration of imlunestrant presents a transformative opportunity in this context, potentially improving patient adherence and quality of life.