Eli Lilly announces results from EMBER-3 study of imlunestrant

Eli Lilly (LLY) announced results from the Phase 3 EMBER-3 study of imlunestrant, an investigational, oral selective estrogen receptor degrader, or SERD, in patients with estrogen receptor positive, human epidermal growth factor receptor 2 negative, or HER2-, advanced breast cancer, or ABC, whose disease progressed on a prior aromatase inhibitor, with or without a CDK4/6 inhibitor. Imlunestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival as monotherapy in patients with an ESR1 mutation versus standard of care endocrine therapy, reducing the risk of disease progression or death by 38%. Imlunestrant in combination with Verzenio reduced the risk of progression or death by 43% versus imlunestrant alone, in all patients. These results were published in The New England Journal of Medicine and will be shared in a late-breaking oral presentation at the San Antonio Breast Cancer Symposium, or SABCS, Wednesday, December 11 at 9:15 AM CT/10:15 AM ET. These data are being submitted to regulatory health authorities globally. In the EMBER-3 study, patients were randomized 1:1:1 to receive imlunestrant alone, SOC ET, or the imlunestrant-abemaciclib combination. Randomization was stratified by prior CDK4/6 inhibitor use, the presence of visceral metastases and geographic region. Patients enrolled as first line treatment for ABC, following disease recurrence on or within 12 months of completing adjuvant AI, with or without CDK4/6 inhibitor for early breast cancer, or as second line treatment for ABC, following progression on AI, with or without CDK4/6 inhibitor as initial therapy for ABC. Primary endpoints were investigator-assessed PFS of imlunestrant versus SOC ET therapy in patients with ESR1 mutations, imlunestrant versus SOC ET in all patients, and imlunestrant-abemaciclib versus imlunestrant in all patients. Imlunestrant significantly improved PFS versus SOC ET in patients with an ESR1 mutation. In patients with an ESR1 mutation, median PFS was 5.5 months with imlunestrant versus 3.8 months with SOC ET. The overall response rate with imlunestrant was 14% compared to 8% with SOC ET in patients with an ESR1 mutation. In all patients, the median PFS was 5.6 months with imlunestrant versus 5.5 months with SOC ET and did not reach statistical significance. Consistent with preclinical data demonstrating central nervous system penetrance and CNS-activity of imlunestrant, CNS progression rates from a post-hoc analysis were lower with imlunestrant in all patients, as well as patients with an ESR1 mutation, however, these analyses are limited by low event numbers and lack of mandated serial asymptomatic CNS imaging in all patients. Imlunestrant significantly improved PFS versus SOC ET in patients with an ESR1 mutation. In patients with an ESR1 mutation, median PFS was 5.5 months with imlunestrant versus 3.8 months with SOC ET. The overall response rate with imlunestrant was 14% compared to 8% with SOC ET in patients with an ESR1 mutation. In all patients, the median PFS was 5.6 months with imlunestrant versus 5.5 months with SOC ET and did not reach statistical significance. Consistent with preclinical data demonstrating central nervous system penetrance and CNS-activity of imlunestrant, CNS progression rates from a post-hoc analysis were lower with imlunestrant in all patients, as well as patients with an ESR1 mutation, however, these analyses are limited by low event numbers and lack of mandated serial asymptomatic CNS imaging in all patients. Imlunestrant-abemaciclib significantly improved PFS compared to imlunestrant in all patients, regardless of ESR1 mutation status, with median PFS of 9.4 months for imlunestrant-abemaciclib versus 5.5 months for imlunestrant alone. The PFS benefit of the combination was consistent across subgroups, regardless of ESR1 mutation, or PI3K pathway mutation status, and including in patients who had previously received CDK4/6 inhibitor treatment. In all patients, the ORR with imlunestrant-abemaciclib was 27% compared to 12% with imlunestrant alone. 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, nausea, neutropenia and anemia and had a low discontinuation rate. Overall survival results for EMBER-3 were immature at the time of analysis. The trial will continue to assess OS as a secondary endpoint. An estimated 70% to 80% of hormone receptor positive breast cancers are ER+ and after progression on initial endocrine therapy, are predominantly treated with fulvestrant, which is administered by intramuscular injection in a doctor’s office. According to patient-reported outcomes data from EMBER-3, 72% of patients receiving fulvestrant in the standard ET group reported injection site pain, swelling, or redness. Imlunestrant is an orally administered, brain penetrant, pure ER antagonist that delivers continuous ER target inhibition. Imlunestrant is also being investigated in the adjuvant setting in people with ER+, HER2- early breast cancer with an increased risk of recurrence. This Phase 3 trial, EMBER-4, is expected to enroll 6,000 EBC patients worldwide.