An open-label phase I study of GDC-0927 in postmenopausal women with locally advanced or metastatic estrogen receptor positive breast cancer
Mené sur 42 patientes ménopausées atteintes d'un cancer du sein ER+ HER2- de stade localement avancé ou métastatique, cet essai de phase I détermine la dose maximale tolérée de GDC-0927 (un régulateur sélectif non stéroïdien des récepteurs des oestrogènes) et analyse ses caractéristiques pharmacodynamiques et pharmacocinétiques
Background: GDC-0927 is a novel, potent, non-steroidal, orally bioavailable, selective estrogen receptor (ER) degrader (SERD) that induces tumor regression in ER+ breast cancer xenograft models. Methods: This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2- metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans. Results: Forty-two patients received GDC-0927 once daily. The maximum tolerated dose was not reached. The most common adverse events (AEs) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and a ~40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and PR protein and mutant ESR1 ctDNA did not correlate with clinical benefit. Conclusions: GDC-0927 appeared to be well-tolerated with pharmacokinetics supporting once daily dosing. There was evidence of target engagement and preliminary evidence of anti-tumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2- breast cancer with and without ESR1 mutations.