Eli Lilly's investigational oral selective estrogen receptor degrader (SERD), imlunestrant, has shown promising results in a Phase 3 trial (EMBER-3) for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). The study, presented at the San Antonio Breast Cancer Symposium (SABCS) and published in The New England Journal of Medicine, highlights imlunestrant's potential as both a monotherapy and in combination with abemaciclib (Verzenio).
Imlunestrant Monotherapy
In patients with ESR1 mutations, imlunestrant monotherapy significantly reduced the risk of disease progression or death by 38% compared to standard endocrine therapy. The median progression-free survival (PFS) was 5.5 months with imlunestrant versus 3.8 months with standard endocrine therapy [HR=0.62 (95% CI 0.46-0.82); p-value<0.001]. However, in the overall study population, the improvement in PFS with imlunestrant monotherapy was not statistically significant.
Imlunestrant and Abemaciclib Combination
Imlunestrant in combination with abemaciclib demonstrated a statistically significant improvement in PFS compared to imlunestrant alone in all patients, regardless of ESR1 mutation status. The median PFS was 9.4 months for the combination versus 5.5 months for imlunestrant alone [HR=0.57 (95% CI 0.44-0.73); p-value <0.001].
Komal Jhaveri, M.D., section head, endocrine therapy research at Memorial Sloan Kettering Cancer Center and a principal investigator of the study, noted, "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."
EMBER-3 Trial Design
The EMBER-3 trial enrolled 874 patients with ER+, HER2- advanced breast cancer whose disease had progressed on a prior aromatase inhibitor, with or without a CDK4/6 inhibitor. Patients were randomized 1:1:1 to receive imlunestrant alone, standard of care endocrine therapy, or the imlunestrant-abemaciclib combination. The primary endpoints were investigator-assessed PFS of imlunestrant versus standard endocrine therapy in patients with ESR1 mutations, imlunestrant versus standard endocrine therapy in all patients, and imlunestrant-abemaciclib versus imlunestrant in all patients.
Safety and Tolerability
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%).
Impact and Future Directions
David Hyman, M.D., Chief Medical Officer, Lilly, stated, "We're highly encouraged by these data for both imlunestrant as monotherapy and in combination with Verzenio, 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."
Imlunestrant is also being investigated in the adjuvant setting in people with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence in the Phase 3 EMBER-4 trial, which is expected to enroll 6,000 EBC patients worldwide.
