Arvinas, Pfizer Share New Phase 1b Trial Data on Vepdegestrant and Palbociclib

Arvinas, Inc. and Pfizer Inc. have released updated clinical data from a Phase 1b cohort study evaluating the combination of vepdegestrant, an experimental oral PROteolysis TArgeting Chimera (PROTAC®) estrogen receptor (ER) degrader, and palbociclib (IBRANCE®). The follow-up data collected over six months remain consistent with those presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2023. These findings continue to highlight the potential clinical benefits of this combination therapy for patients with heavily pre-treated ER-positive (ER+)/human epidermal growth factor 2 negative (HER2-) breast cancer. The recent data were presented at the 2024 European Society for Medical Oncology (ESMO) Breast Cancer Annual Congress.

The study results showcased significant clinical activity and safety profiles for the combination treatment of vepdegestrant and palbociclib. Noah Berkowitz, M.D., Ph.D., Chief Medical Officer at Arvinas, emphasized that the median progression-free survival (PFS) and duration of response data suggest a promising therapeutic benefit for patients, irrespective of their ESR1 mutation status.

Vepdegestrant operates as an investigational PROTAC ER degrader that leverages the body’s natural protein disposal system to target and degrade the estrogen receptor. This drug, co-developed by Arvinas and Pfizer, is undergoing evaluation as a monotherapy in the ongoing Phase 3 VERITAC-2 trial and in combination with palbociclib in the lead-in cohort of the Phase 3 VERITAC-3 trial.

Roger Dansey, M.D., Chief Development Officer at Pfizer Oncology, noted that Pfizer aims to advance the next generation of breast cancer treatments. With vepdegestrant, they aspire to establish a new standard-of-care endocrine therapy backbone for patients with ER+/HER2- breast cancer. Erika Hamilton, M.D., Director of Breast Cancer Research at the Sarah Cannon Research Institute, added that the study outcomes are consistent with previous clinical activity, safety, and tolerability data, showing promise in addressing significant unmet needs in this patient population.

The Phase 1b cohort of the ARV-471-mBC-101 study involved 46 patients with advanced or metastatic ER+/HER2- breast cancer who had undergone a median of four prior therapies. Patients were treated once daily with various doses of vepdegestrant alongside 125 mg of palbociclib for 21 days, followed by seven days off treatment in 28-day cycles. The initial data were presented at SABCS 2023.

After an additional six months of follow-up, the updated results reaffirmed the clinical benefit rate (CBR), overall response rate (ORR), progression-free survival (PFS), and safety profile previously reported at SABCS 2023. Specifically, the study showed a CBR of 63%, an ORR of 42%, and a median PFS of 11.2 months across all dose levels. At the recommended Phase 3 dose of 200 mg vepdegestrant, the median PFS was 13.9 months.

Exploratory circulating tumor DNA (ctDNA) analyses revealed a significant reduction in tumor fraction following one treatment cycle, regardless of ESR1 mutation status. Moreover, robust on-treatment decreases in mutant ESR1 ctDNA levels were sustained through multiple cycles.

The safety profile of the combination therapy was consistent with previous reports, with neutropenia and decreased white blood cell counts being the most common Grade 3/4 treatment-related adverse events. No grade 5 treatment-related adverse events or febrile neutropenia were reported.

Vepdegestrant is an investigational oral PROTAC protein degrader designed to target and degrade the estrogen receptor, developed for treating ER+/HER2- breast cancer both as a monotherapy and in combination therapies. Arvinas and Pfizer announced a global collaboration in July 2021 for the co-development and co-commercialization of vepdegestrant. The U.S. Food and Drug Administration (FDA) has granted vepdegestrant Fast Track designation as a monotherapy for ER+/HER2- locally advanced or metastatic breast cancer previously treated with endocrine-based therapy.

Overall, these findings underscore the potential of vepdegestrant in combination with palbociclib as a promising treatment option for patients with advanced ER+/HER2- breast cancer, addressing significant unmet medical needs in this patient population.