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Abstract Background: Vepdegestrant (ARV-471) is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader. In the phase 2 portion (VERITAC) of a first-in-human phase 1/2 study (NCT04072952), vepdegestrant 200 mg once daily (QD) was well tolerated and had clinical activity in heavily pretreated patients with ER+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer and was selected as the recommended phase 3 dose (RP3D) for vepdegestrant monotherapy. A phase 1b cohort of the phase 1/2 study is evaluating the safety and clinical activity of vepdegestrant plus palbociclib in patients with ER+/HER2- breast cancer after prior endocrine-based therapy; prior cyclin-dependent kinase (CDK)4/6 inhibitor therapy was permitted. Preliminary results showed encouraging activity for the combination based on clinical benefit rate (CBR; rate of confirmed complete response, partial response, or stable disease ≥24 weeks); an increase in palbociclib exposure was observed relative to historical palbociclib pharmacokinetic data and was accompanied by a higher incidence of grade 3/4 neutropenia compared with prior palbociclib and endocrine therapy combination studies, which was managed by monitoring and standard palbociclib dose modifications. The global, randomized phase 3 VERITAC-3 study (NCT05909397) will compare the efficacy and safety of vepdegestrant plus palbociclib vs letrozole plus palbociclib as first-line treatment for patients with ER+/HER2- advanced breast cancer. An open-label study lead-in (SLI) will evaluate the safety and tolerability of vepdegestrant 200 mg QD plus 2 doses of palbociclib (100 mg QD and 75 mg QD) in patients with ER+/HER2- advanced breast cancer to select the RP3D of palbociclib for this combination. Trial Design: Approximately 50 and 1130 patients will be enrolled in the SLI and the phase 3 parts of the study, respectively. Eligible patients (aged ≥18 years) must have histologically or cytologically confirmed ER+/HER2- locoregionally recurrent or metastatic breast cancer, with no prior treatment in the advanced setting, and no prior treatment in any setting with CDK4/6 inhibitors, vepdegestrant, fulvestrant, elacestrant, or other investigational agents (including novel endocrine therapy, selective ER degraders, selective ER covalent antagonists, and complete ER antagonists). Patients with measurable disease per RECIST v1.1 or nonmeasurable bone-only disease are eligible. Patients with disease recurrence during or ≤12 months after completion of adjuvant endocrine therapy are excluded. For the SLI, patients are randomized 1:1 to receive vepdegestrant 200 mg QD in combination with palbociclib 100 mg QD or 75 mg QD and are treated in 28-day cycles with vepdegestrant given continuously and palbociclib given for 21 days followed by 7 days off treatment. The objective of the SLI is to identify the RP3D of palbociclib in combination with vepdegestrant, which will be determined through the primary outcome measures of incidence of grade 4 neutropenia, study drug dose reduction, and study drug discontinuation within the first 4 cycles of treatment. Secondary outcome measures include safety, antitumor activity (objective response rate, CBR, and duration of response), and plasma concentrations of study drugs. In the planned phase 3 portion of the trial, patients will be randomized to vepdegestrant plus palbociclib or letrozole plus palbociclib. The primary efficacy endpoint of the phase 3 portion is progression-free survival based on blinded independent central review. Enrollment began June 2023 and is ongoing. Citation Format: Seth Wander, Erika Hamilton, Mario Campone, Michael Danso, Sara Hurvitz, Hiroji Iwata, Colombe Chappey, Derek Yang, Julia Perkins Smith, Yuan Liu, Yuanyuan Zhang, Sibyl Anderson, Michelino de Laurentiis. VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced 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 PO2-20-03.
Wander et al. (Thu,) studied this question.