Abstract PS2-07-24: Circulating tumor DNA (ctDNA) biomarker analyses of a phase 1/2 study evaluating vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in ER-positive/human epidermal growth factor receptor 2 (HER

Abstract Background: Vepdegestrant, an oral PROTAC ER degrader, showed encouraging clinical activity and was well tolerated in a phase 1/2 study (NCT04072952) including patients (pts) with heavily pretreated ER+/HER2- aBC. In a subsequent phase 3 trial (VERITAC-2, NCT05654623), vepdegestrant demonstrated statistically significant and clinically meaningful improvement in progression-free survival vs fulvestrant among pts with previously treated ER+/HER2- aBC and ESR1 mutations (ESR1m). Here, we report exploratory ctDNA biomarker analyses from the phase 1/2 study evaluating vepdegestrant monotherapy. Methods: This multicenter, open-label study included a 3+3 dose escalation (phase 1; vepdegestrant doses: 30−700 mg daily) and dose expansion (phase 2; vepdegestrant 200 mg or 500 mg once daily). Eligible pts had ER+/HER2- metastatic, recurrent, or locally advanced unresectable breast cancer previously treated with ≥1 cyclin-dependent kinase 4/6 inhibitor and ≥2 (phase 1) or ≥1 (phase 2) endocrine regimens. Baseline (cycle [C] 1 day [D] 1) and on-treatment (C1D28) circulating-free DNA (cfDNA) samples from the majority of pts treated with vepdegestrant (all at doses ≥100 mg/day) were analyzed using F1LCDx from Foundation Medicine. For these exploratory analyses of the pooled phase 1/2 dataset, baseline and on-treatment changes in variant allele fraction (VAF) of ESR1-mutated ctDNA and tumor fraction (TF; percentage of cfDNA that originates from the tumor) were assessed in association with the clinical benefit rate (CBR; complete response, partial response, or stable disease for ≥24 weeks) and analyzed by Firth’s penalized logistic regression. Results: Among 154 pts treated with vepdegestrant, 138 had ctDNA samples analyzed with the F1LCDx platform (all had received vepdegestrant ≥100 mg/day). Of these, 81 pts (59%) had ESR1m (D538G 41%; Y537S 39%; Y537N 22%; E380Q 8%; L536P 6%; L536R 5%). When analyzed as single variables, ESR1m VAF and TF at baseline were not positively or negatively associated with CBR; among pts with ESR1m, mean (95% CI) baseline ESR1m VAF was 9.1% (5.7-12.4) in pts with clinical benefit (n=34) and 7.4% (2.6-12.1) in pts without clinical benefit (n=32) and mean baseline TF (95% CI) was 18.4% (12.0-24.8) and 22.2% (15.4-29.0), respectively. However, when baseline ESR1m VAF was normalized to baseline TF, a higher ESR1m VAF/TF ratio was significantly associated with better CBR; mean ESR1m VAF/TF (95% CI) of 0.59 (0.47-0.72) vs 0.35 (0.25-0.45) in pts with vs without clinical benefit (p=0.005). Robust reductions in ESR1m VAF were observed across Y537X, D538X and L536X variants of ESR1 after 1 cycle of treatment, with 87% of ESR1m alleles showing ≥50% reduction from baseline at C1D28. Robust reductions in TF were also observed, with 81.5% of pts with ESR1m demonstrating ≥50% reduction in TF from baseline at C1D28. Among pts with ESR1m, change in TF was significantly associated with clinical benefit; the median percentage change in TF from C1D1 to C1D28 was −99.2% in pts with clinical benefit (n=33) vs −50.4% in pts without clinical benefit (n=32; p<0.001). Conclusions: Patients with higher baseline ESR1m VAF/TF, a likely indicator of ESR1m clonality, had better clinical outcomes with vepdegestrant than pts with lower ESR1m VAF/TF. Greater decreases in ctDNA TF after 1 cycle of treatment were associated with increased likelihood of achieving clinical benefit. Overall, these exploratory biomarker analyses provide potentially clinically useful insights on pt responses to vepdegestrant and add to a growing body of evidence on the use of ctDNA in decisions around treatment continuation for pts with ER+/HER2- aBC. Citation Format: S. A. Wander, H. S. Han, E. P. Hamilton, S. A. Hurvitz, M. Lachowicz, W. Wu, J. Corradi, A. Van Acker, M. A. Dorso, E. Duperret, S. Lonning, S. Dychter, C. Ma. Circulating tumor DNA (ctDNA) biomarker analyses of a phase 1/2 study evaluating vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in ER-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-07-24.