As reported in the Journal of Clinical Oncology by Javier Cortés, MD, PhD, and colleagues, the phase III AMEERA-5 trial of first-line treatment with the selective estrogen receptor degrader (SERD) amcenestrant plus palbociclib vs letrozole plus palbociclib in estrogen receptor (ER)-positive, HER2-negative advanced/metastatic breast cancer was discontinued due to futility at interim analysis.
Javier Cortés, MD, PhD
Study Details
In the double-blind trial, 1,068 patients (pre- and postmenopausal women and men) from sites in 30 countries were randomly assigned between October 2020 and December 2021 to receive amcenestrant at 200 mg once daily plus standard palbociclib at 125 mg once daily for 21 days on/7 days off (n = 534) or letrozole at 2.5 mg once daily plus standard palbociclib (n = 534). The primary endpoint of the trial was investigator-assessed progression-free survival.
Progression-Free Survival
An interim analysis at a median follow-up 8.4 months found the stratified hazard ratio (HR) for progression-free survival for the amcenestrant/palbociclib group vs the letrozole/palbociclib group was 1.209 (95% confidence interval [CI] = 0.939–1.557, P = .9304); the stopping boundary of hazard ratio > 1.1 was met, and the study was stopped for futility on the basis of independent data monitoring committee recommendation. Progression-free survival rates at 6 months were 82.7% (95% CI = 79.0%–85.8%) in the amcenestrant/palbociclib group vs 86.9% (95% CI = 83.5%–89.6%) in the letrozole/palbociclib group.
Objective response rates were 32.2% vs 42.3% and clinical benefit rates were 76.0% vs 82.4%, respectively. Overall survival data were not mature; the stratified hazard ratio for overall survival was 1.086 (95% CI = 0.613–1.926).
Adverse Events
Grade ≥ 3 adverse events occurred in 46.3% of patients in the amcenestrant/palbociclib group vs 60.8% of the letrozole/palbociclib group, most commonly neutropenia in both groups (29.8% vs 51.4%). The most common adverse events of any grade in the amcenestrant/palbociclib group were neutropenia or neutrophil count decrease (31.1%), arthralgia (18.4%), fatigue (16.3%), and hot flush (15.8%); in the letrozole/palbociclib group, the most common adverse events were neutropenia or neutrophil count decrease (52.7%), arthralgia (17.1%), fatigue (17.1%), nausea (16.7%), and stomatitis (16.1%). No treatment-related deaths were reported.
The investigators concluded, “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.”
They added, “On the basis of the results of AMEERA-5, along with the negative results of AMEERA-3 showing numerically similar progression-free survival between amcenestrant monotherapy and physician’s choice of endocrine monotherapy … the global clinical development program of amcenestrant was discontinued. Results of other phase III trials of oral SERDs in combination with CDK4/6 inhibitors are eagerly awaited.”
Aditya Bardia, MD, MPH, of the University of California Los Angeles Jonsson Comprehensive Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Sanofi. For full disclosures of the study authors, visit ascopubs.org.
