Endpoints
cancer, tumor, overdose, Cancer
ADVERSE EVENT, TUMOR, CANCER, SECONDARY, PHOTOSENSITIVITY, CANCER
The primary endpoint was antiproliferative activity, measured as the change in Ki67 between the baseline and post-treatment (i.e., Day 15) tumor biopsies. Ki67 staining and scoring was assessed by IHC using tissue samples from paired pretreatment (baseline) and post-treatment biopsies and was performed at a central laboratory to minimize bias. Ki67 (and receptor H-scores; see following) was assessed using digitally scanned slides prepared from biopsy tissue. Two pathologists, who worked independently from each other and were blinded to treatment allocation, provided baseline and post-treatment scores for each biopsy pair. Then, for each participant, the means of the two baseline values and the two post-treatment values were computed and used in subsequent analyses.The key secondary endpoints were: (i) the proportion of participants with a relative decrease in Ki67, between baseline and Day 15, of ≥ 50%; (ii) the absolute change from baseline in ER H-score; and (iii) safety and tolerability, assessed as the incidence and severity of treatment-emergent AEs (TEAEs) and treatment-related AEs (TRAEs).H-score is an IHC-derived measure of receptor expression in a tissue sample. Briefly, the H-score reflects the percentage of stained cells at each level of staining intensity, which in AMEERA-4 was measured on an interval scale from 0 (no staining) to 3 (most intensely stained). The maximum possible H-score was 300 (i.e., if 100% of cells had an intensity score of 3). The change in H-score between the baseline and post-treatment biopsies was considered to reflect the extent of receptor degradation in biopsy tissue.TEAEs were defined as AEs that developed, worsened, or became serious during the 14-day treatment period or the 30-day safety follow-up period. AEs were coded according to Medical Dictionary for Regulatory Activities (MedDRA) version 24.0, and severity was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.Four AEs of special interest (AESI) were prespecified in the protocol: pregnancy, symptomatic overdose, Grade ≥ 2 ALT elevation, and photosensitivity. Exploratory endpoints included change in PgR H-score; molecular subtype, as assessed using the ProsignaIn participants randomized to amcenestrant, blood samples were drawn for pharmacokinetic analysis immediately before the last dose was taken (on Day 14) and at 3 h post-dose. Mutations of genes related to cancer and/or response to amcenestrant were analyzed at baseline in tumor biopsies and cell-free DNA (cfDNA). For tumor mutational profiling, DNA extracted from formalin-fixed paraffin-embedded tumor tissue slides underwent whole exome sequencing. For cfDNA extracted from plasma samples, the AVENIO ctDNA expanded panel assay (Roche Diagnostics; Indianapolis, IN, USA) was used to identify genomic aberrations in 77 genes.