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Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen
Javier Cortés1,2,3, Sara A Hurvitz4, Joyce O'Shaughnessy5
1Oncology Department, International Breast Cancer Center (IBCC), Pangaea Oncology, Quironsalud Group, Barcelona, Spain.
Purpose:
AMEERA-5 investigated amcenestrant (oral selective estrogen receptor [ER] degrader) plus palbociclib versus letrozole plus palbociclib as first-line treatment for ER-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced/metastatic breast cancer (aBC).
Materials And Methods:
In AMEERA-5 (ClinicalTrials.gov identifier: NCT04478266), a double-blind, double-dummy, international phase III trial, adult pre-/post-menopausal women and men without previous systemic therapy for ER+/HER2- aBC were randomly assigned 1:1 to amcenestrant 200 mg once daily + standard palbociclib dosage (125 mg once daily, 21 days on/7 days off) or letrozole 2.5 mg once daily + standard palbociclib dosage, stratified by de novo metastatic disease, postmenopausal women, and visceral metastasis. The primary end point was progression-free survival (PFS), compared using a stratified log-rank test with one-sided type I error rate of 2.5%. Secondary end points included overall survival (key secondary), pharmacokinetics, and safety.
Results:
Between October 14, 2020, and December 2, 2021, 1,068 patients were randomly assigned to amcenestrant + palbociclib (N = 534) or letrozole + palbociclib (N = 534). At the interim analysis (median follow-up 8.4 months), the stratified hazard ratio for PFS was 1.209 (95% CI, 0.939 to 1.557; one-sided P value = .9304); therefore, the study was stopped for futility. The 6-month PFS rate was 82.7% (95% CI, 79.0 to 85.8) with amcenestrant + palbociclib versus 86.9% (95% CI, 83.5 to 89.6) with letrozole + palbociclib. In the amcenestrant + palbociclib versus letrozole + palbociclib groups, treatment-emergent adverse events (any grade) occurred in 85.6% versus 85.4% of patients and grade ≥3 events in 46.3% versus 60.8%, respectively.
Conclusion:
The AMEERA-5 study was discontinued on the basis of the recommendation of the data monitoring committee at the interim futility analysis. No new safety signals were identified.
Insights
The AMEERA-5 trial investigating amcenestrant plus palbociclib for advanced breast cancer was stopped early for futility. Letrozole plus palbociclib showed a similar or better progression-free survival rate.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Advanced/metastatic breast cancer (aBC) requires effective first-line treatments.
- Selective estrogen receptor (ER) degraders offer a targeted approach.
- Palbociclib is a standard CDK4/6 inhibitor in ER-positive breast cancer.
Purpose of the Study:
- To compare amcenestrant (an oral ER degrader) plus palbociclib against letrozole plus palbociclib.
- To evaluate efficacy and safety as first-line therapy for ER+/HER2- aBC.
Main Methods:
- Phase III, double-blind, double-dummy, international trial (AMEERA-5).
- Randomized 1:1 assignment to amcenestrant + palbociclib or letrozole + palbociclib.
- Primary endpoint: progression-free survival (PFS).
Main Results:
- Study stopped at interim analysis due to futility (HR for PFS 1.209, P=.9304).
- 6-month PFS rates: 82.7% (amcenestrant) vs. 86.9% (letrozole).
- Similar rates of treatment-emergent adverse events; fewer Grade ≥3 events with amcenestrant.
Conclusions:
- AMEERA-5 discontinued based on futility analysis recommendation.
- Amcenestrant plus palbociclib did not demonstrate superior efficacy compared to letrozole plus palbociclib.
- No new safety signals were identified for amcenestrant.
