Messaggi chiave
- EMBER-3 è uno studio randomizzato, in aperto, di fase III, volto a valutare l’efficacia di imlunestrant – in monoterapia e in combinazione con abemaciclib – in pazienti con carcinoma mammario (BC) avanzato ER+/HER2- con recidiva/progressione della malattia durante o dopo trattamento con un inibitore delle aromatasi ± un inibitore CDK4/6 (CDK4/6i). Si presentano in questa sede i risultati dell’analisi primaria.
- È stato arruolato un totale di 874 pazienti (imlunestrant, n = 331; terapia endocrina [ET] standard, n = 330; imlunestrant-abemaciclib, n = 213). Nei 256 pazienti con mutazioni di ESR1, la sopravvivenza libera da progressione (PFS) mediana con imlunestrant rispetto all’ET standard è stata di 5,5 vs 3,8 mesi, con un restricted mean survival time a 19,4 mesi di 7,9 vs 5,4 mesi (differenza, 2,6 mesi; IC 95%, 1,2-3,9; p <0,001). Nella popolazione complessiva, la PFS mediana è risultata pari a 5,6 vs 5,5 mesi, rispettivamente (hazard ratio [HR], 0,87; IC 95%, 0,72-1,04; p = 0,12). Dal confronto tra i bracci imlunestrant-abemaciclib e imlunestrant in monoterapia, è emersa una PFS di 9,4 vs 5,5 mesi (HR, 0,57; IC 95%, 0,44-0,73; p <0,001). L’incidenza di eventi avversi di grado ≥3 è stata del 17,1, 20,7 e 48,6% nei bracci imlunestrant, ET standard e imlunestrant-abemaciclib, rispettivamente.
- Imlunestrant rispetto alla terapia standard ha prodotto un miglioramento significativo degli esiti di PFS nei pazienti con BC ESR1-mutato; inoltre, la sua combinazione con abemaciclib è stata associata a un prolungamento significativo della PFS rispetto a imlunestrant da solo in tutti i pazienti, a prescindere dallo stato mutazionale e dal pregresso trattamento con CDK4/6i. Non sono emersi segnali di sicurezza inattesi.
Abstract
Background
- Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα (ESR1).
Methods
- In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor.
- Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib.
- Primary end points were investigator-assessed progression-free survival with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently.
Results
- Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant-abemaciclib.
- Among 256 patients with ESR1 mutations, the median progression-free survival was 5.5 months with imlunestrant and 3.8 months with standard therapy.
- The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; p <0.001).
- In the overall population, the median progression-free survival was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; p = 0.12).
- Among 426 patients in the comparison of imlunestrant-abemaciclib with imlunestrant, the median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; p <0.001).
- The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant-abemaciclib.
Conclusions
- Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population.
- Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status.