Abstract PO2-20-04: TACTIVE-U: phase 1b/2 umbrella study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER–positive advanced or metastatic breast cancer
Authors: Isaacs Claudine , Jerzak Katarzyna , Hilton John , Guimarães José Luiz Miranda , Layman Rachel , Lu Dongrui , Mo Gary , Calella Anna Maria , Valota Olga , Anderson Sibyl , Ma Cynthia 
Published: May 2024

Abstract
Background: Vepdegestrant (ARV-471), an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in the first-in-human phase 1/2 study in heavily pretreated patients with ER+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer (NCT04072952). The cyclin-dependent kinase (CDK)4/6 inhibitors abemaciclib and ribociclib are approved in combination with an aromatase inhibitor or fulvestrant, or as monotherapy (abemaciclib), for ER+/HER2- advanced or metastatic breast cancer. In preclinical studies, vepdegestrant combined with abemaciclib or ribociclib showed evidence of synergistic interactions in ER+ breast cancer cells and greater tumor growth inhibition in a xenograft breast cancer model compared with fulvestrant in combination with these agents. Inhibitors targeting different CDKs, such as samuraciclib (oral CDK7 inhibitor), are in clinical development for solid tumors. The open-label, phase 1b/2 TACTIVE-U umbrella study will evaluate the safety, efficacy, and pharmacokinetics of vepdegestrant in combination with other anticancer treatments in patients with ER+ advanced or metastatic breast cancer. Vepdegestrant is being evaluated in combination with abemaciclib (sub-study A; NCT05548127), ribociclib (sub-study B; NCT05573555), and samuraciclib (sub-study C).
Trial Design: Patients eligible for current sub-studies of TACTIVE-U are aged ≥18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection, and have received prior therapy for advanced or metastatic disease, including any CDK4/6 inhibitor–based regimen in any setting. In each sub-study, patients will receive vepdegestrant orally once daily (QD) continuously in a dose escalation/de-escalation approach. Abemaciclib will be given orally twice daily continuously in sub-study A, ribociclib will be given orally QD for 21 days followed by 7 days off treatment in sub-study B, and samuraciclib will be given orally QD continuously in sub-study C. For all sub-studies, the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of vepdegestrant in combination with the other anticancer treatment. Secondary endpoints of phase 1b are antitumor activity (objective response, clinical benefit rate [CBR], and duration of response [DOR]), progression-free survival (PFS), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drugs. The phase 2 portion of each sub-study will further evaluate the antitumor activity of the combinations; the primary endpoint is objective response and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Future combination sub-studies will be included in TACTIVE-U.
Citation Format: Claudine Isaacs, Katarzyna Jerzak, John Hilton, José Luiz Miranda Guimarães, Rachel Layman, Dongrui Lu, Gary Mo, Anna Maria Calella, Olga Valota, Sibyl Anderson, Cynthia Ma. TACTIVE-U: phase 1b/2 umbrella study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER–positive advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-04.