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A phase I/II study shows a preliminary antitumor activity and no safety concerns for amcenestrant, an orally bioavailable selective estrogen receptor degrader, but trials are being discontinued
The phase I/II study AMEERA, recently published on Nature Communications showed that the orally bioavailable selective estrogen receptor (ER) degrader (SERD) amcenestrant has a preliminary antitumor activity in postmenopausal women with ER+/HER2− advanced breast cancer.
AMEERA-1 is a Phase I/II open-label single-arm study evaluating once-daily amcenestrant in postmenopausal women with ER+/HER2− advanced breast cancer who were mostly heavily pretreated, including targeted therapies and fulvestrant. Compared with other SERD agents, amcenestrant provides optimal ER antagonism and degradation and robustly inhibits the ER signaling pathway in multiple ER+ breast cancer cell lines, including fulvestrant- and tamoxifen-resistant lines, as well as cell lines harboring ER mutations. Preclinical data show that amcenestrant degrades the ER with high efficacy and potency comparable to fulvestrant in vitro activity, is metabolically stable, and has no off-target activity. Thus, AMEERA study tested several doses (20-600 mg) of amcenestrant in a dose-escalation phase; 400 mg once daily was selected as recommended phase II dose. No grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported; confirmed objective response rate was 0.9% at the final analysis and the overall clinical benefit rate was 28.3%. The overall clinical benefit rate among patients with baseline wild-type and mutated ESR1 were 34.6% and 21.1%, respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations. «Amcenestrant at a recommended phase II dose of 400 mg once daily for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status, authors conclude.
Despite these results, Sanofi recently announced there discontinuation of the global clinical development program of amcenestrant due to the outcome of the Phase 3 AMEERA-5 trial evaluating amcenestrant in combination with palbociclib compared with letrozole in combination with palbociclib in patients with ER+/HER2- advanced breast cancer: an Independent Data Monitoring Committee (IDMC) found that amcenestrant in combination with palbociclib did not meet the criteria for continuation in comparison with the control arm and recommended stopping the trial. No new safety signals were observed and the company will continue to review the data and plans to share the results with the scientific community in the future.