Figure S3.
Early changes from baseline in ESR1 ctDNA VAFs. Absolute ESR1 VAF by giredestrant dose (A) or by clinical benefit (B) at baseline, C1D15 and C2D1. (A–B) Individual lines represent matched ESR1 ctDNA results from a single patient across time points. (C) Boxplots of absolute
ESR1 VAF grouped by treatment and clinical benefit. (A–C) ESR1 VAF is represented as the sum of all detected ESR1 VAFs at each time point. The giredestrant 100 mg +palbociclib ±LHRH cohort includes three patients from the cardiac evaluation cohort who initiated single-agent
giredestrant 100 mg on cycle 1, day –14, and then continued on giredestrant 100 mg +palbociclib on cycle 1, day 1. Relative change of ESR1 VAF from baseline by giredestrant dose (D) or by clinical benefit (E). (D–E) Only patients with detectable ESR1 VAF at baseline are included. Bars represent mean relative change with standard deviation; dots represent individual relative changes. (C–E) For patients with results from more than one ctDNA baseline sample, the sum ESR1 VAF from the sample collected closest to C1D1 was used for calculating relative change.
ARTICLE ABSTRACT
Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor–positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797).
Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy.
As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only–related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors.
Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.