Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer Journal Article
| Authors: | Campone, M.; De Laurentiis, M.; Jhaveri, K.; Hu, X.; Ladoire, S.; Patsouris, A.; Zamagni, C.; Cui, J.; Cazzaniga, M.; Çil, T. |
| Article Title: | Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer |
| Abstract: | Abstract Background Vepdegestrant is an oral proteolysis-Targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly harnesses the ubiquitin-proteasome system. Methods In this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who had received one previous line of cyclin-dependent kinase 4 and 6 inhibitor therapy plus one line of endocrine therapy (and up to one additional line of endocrine therapy). Patients were randomly assigned in a 1:1 ratio to receive vepdegestrant at a dose of 200 mg orally once every day of each 28-day cycle or fulvestrant at a dose of 500 mg, administered intramuscularly, on day 1 and day 15 of cycle 1 and on day 1 of subsequent cycles, with randomization stratified according to ESR1-mutation status and presence or absence of visceral disease. The primary end point was progression-free survival as assessed by blinded independent central review among the patients with ESR1 mutations and among all the patients who underwent randomization. Progression-free survival was estimated with Kaplan-Meier methods and hazard ratios with a stratified Cox proportional-hazards model. Results A total of 624 patients underwent randomization; 313 were assigned to receive vepdegestrant, and 311 to receive fulvestrant. Among the 270 patients with ESR1 mutations, the median progression-free survival was 5.0 months (95% confidence interval [CI], 3.7 to 7.4) with vepdegestrant and 2.1 months (95% CI, 1.9 to 3.5) with fulvestrant (hazard ratio, 0.58 [95% CI, 0.43 to 0.78]; P<0.001). Among all the patients, the median progression-free survival was 3.8 months (95% CI, 3.7 to 5.3) with vepdegestrant and 3.6 months (95% CI, 2.6 to 4.0) with fulvestrant (hazard ratio, 0.83 [95% CI, 0.69 to 1.01]; P=0.07). Adverse events of grade 3 or higher occurred in 23.4% of the patients in the vepdegestrant group and in 17.6% of the patients in the fulvestrant group. Adverse events led to treatment discontinuation in 2.9% and 0.7% of the patients, respectively. Conclusions Among patients with ER-positive, HER2-negative advanced breast cancer, vepdegestrant was associated with significantly longer progression-free survival than fulvestrant in the subgroup with ESR1 mutations but not in the full patient population. (Funded by Pfizer and Arvinas Estrogen Receptor; VERITAC-2 ClinicalTrials.gov number, NCT05654623.) © 2025 Elsevier B.V., All rights reserved. |
| Keywords: | adult; cancer chemotherapy; controlled study; aged; aged, 80 and over; middle aged; major clinical study; overall survival; genetics; mutation; clinical trial; fatigue; mortality; neutropenia; drug efficacy; drug safety; adjuvant therapy; follow up; ubiquitin; metastasis; progression free survival; proteasome; breast cancer; anemia; protein degradation; randomized controlled trial; epidermal growth factor receptor 2; cohort analysis; pathology; breast neoplasms; backache; alanine aminotransferase; aspartate aminotransferase; liver metastasis; multicenter study; breast tumor; receptors, estrogen; hormonal therapy; phase 3 clinical trial; antineoplastic agents, hormonal; kaplan meier method; estrogen receptor; drug therapy; administration, oral; antineoplastic hormone agonists and antagonists; cyclin dependent kinase 4; fulvestrant; oral drug administration; cyclin dependent kinase 6; progression-free survival; kaplan-meier estimate; estrogen receptor alpha; hematology/oncology; very elderly; cancer; humans; human; male; female; article; palbociclib; abemaciclib; ribociclib; ecog performance status; treatments in oncology; genetics general; proteolysis targeting chimera; esr1 protein, human; vepdegestrant; zomiradomide |
| Journal Title: | New England Journal of Medicine |
| Volume: | 393 |
| Issue: | 6 |
| ISSN: | 15334406 |
| Publisher: | Elsevier B.V. |
| Date Published: | 2025-01-01 |
| Start Page: | 556 |
| End Page: | 568 |
| Language: | English |
| DOI: | 10.1056/NEJMoa2505725 |
| PUBMED: | 40454645 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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