ABSTRACT: BACKGROUND:Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16?-18F-fluoro-17?-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). METHODS:Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ??6?months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400?mg elacestrant once daily (QD) and one treated with 200?mg elacestrant QD with dose escalation to 400?mg QD after 14?days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4?h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14?days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. RESULTS:Patients (n?=?16; median age, 53.5?years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400?mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400?mg). Residual ER availability (>?25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400?mg (3/78, 37.5%) and 1 patient receiving 400?mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in >?20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. CONCLUSION:Elacestrant 200?mg and 400?mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02650817 . Registered on 08 January 2016.
