AMEERA-4: A preoperative window-of-opportunity (WOO) study to assess the pharmacodynamic (PD) activity of amcenestrant or letrozole in postmenopausal patients with ER+/HER2− primary breast cancer.
Amcenestrant (Sanofi) is an optimized oral selective ER degrader (SERD) that antagonizes and degrades the ER and has demonstrated favorable preliminary safety and antitumor activity as monotherapy and in combination with palbociclib in postmenopausal patients with ER+/ HER2− advanced breast cancer, irrespective of baseline (BL) ESR1 mutation status. The AMEERA-4 (NCT04191382) is a Phase II preoperative window-of-opportunity study that evaluated the PD activity of two dose levels of amcenestrant or letrozole using paired biopsies assessed for biomarkers. Trial enrollment in AMEERA-4 was voluntarily stopped early, as informative data supporting adjuvant development became available; therefore, no formal statistical comparisons were conducted.
Among 105 randomized patients (amcenestrant 400 mg: n = 34, amcenestrant 200 mg: n = 36, letrozole: n = 35), 95 were treated and had available pre- and post-treatment Ki67 per central review. No major imbalances in BL patient and tumor characteristics were observed. The geometric least squares means (LSM) estimate of Ki67 reduction was 75.9% for amcenestrant 400 mg, 68.2% for amcenestrant 200 mg and 77.7% for letrozole.
On the safety front, the incidence of treatment-related adverse events (TRAEs) were 21.2% for amcenestrant 400 mg, 22.2% for amcenestrant 200 mg, and 25.7% for letrozole.
Based on PD activity and safety, emerging results from AMEERA-4, and other ongoing amcenestrant clinical trials, the 200 mg QD dose of amcenestrant was selected for our ongoing study in the adjuvant setting; AMEERA-6 (NCT05128773). The failure of AMEERA-3 and Sanofi’s decision to terminate the AMEERA-4 midway while initiating the AMEERA-6 study in the larger adjuvant setting pools depicts that Sanofi wants to move fast and make amcenestrant the first SERD in the adjuvant setting.
Amcenestrant is not alone in the race; Roche and Eli Lilly are also testing their SERDs in the adjuvant setting. The emergence of several novel selective estrogen receptor degraders (SERDs) in ESR1 space has demonstrated a widespread potential for this patient population in combination and as monotherapy. Moreover, the early intervention against this mutation will definitely assist in generating a tailored treatment paradigm in the future.
Companies- Gilead, Sanofi, AstraZeneca, Eli Lilly, Radius Health, Sermonix Pharmaceuticals, Roche, Veru Pharma, and others.