vepdegestrant (ARV-471)

P1, N=6, Active, not recruiting, Pfizer | Trial completion date: Sep 2024 --> Mar 2025

P1, N=12, Not yet recruiting, Pfizer

P1, N=52, Completed, Pfizer | Active, not recruiting --> Completed

P1, N=6, Active, not recruiting, Pfizer | Trial completion date: Mar 2024 --> Sep 2024

We developed and validated a sensitive and rapid liquid chromatography-tandem mass spectrometry method to quantify vepdegestrant in rodent plasma using bavdegalutamide (formerly ARV-110) as an internal standard. In liver microsomes, vepdegestrant exhibited moderate stability in rats but was stable in mice, dogs, and humans. These findings enhance the understanding of pharmacokinetic properties of vepdegestrant supporting further development of PROTAC drugs.

P2, N=152, Completed, Arvinas Inc. | Active, not recruiting --> Completed

P3, N=560, Recruiting, Pfizer | Trial primary completion date: Aug 2024 --> Nov 2024

Progression-free survival by blinded independent central review (primary end point) will be assessed in the intention-to-treat population and ESR1 mutation-positive subpopulation. Secondary end points include overall survival, tumor response, safety, pharmacokinetics, patient-reported outcomes, and circulating tumor DNA biomarkers.Clinical trial registration: NCT05654623 (ClinicalTrials.gov).

P1, N=52, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

P3, N=1180, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

P1, N=12, Completed, Pfizer | Recruiting --> Completed

Vepdegestrant achieved greater ER degradation in-vivo compared to fulvestrant, which correlated with improved tumor growth inhibition, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.

P1, N=15, Completed, Pfizer | Recruiting --> Completed

P1/2, N=217, Active, not recruiting, Arvinas Estrogen Receptor, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Sep 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Sep 2024

P1, N=48, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1/2, N=67, Recruiting, Pfizer | Trial completion date: Aug 2027 --> Jan 2027 | Trial primary completion date: Feb 2027 --> Jul 2026

P1, N=48, Not yet recruiting, Pfizer

P1, N=16, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1/2, N=67, Recruiting, Pfizer | Trial completion date: Feb 2027 --> Aug 2027 | Trial primary completion date: Aug 2026 --> Feb 2027

P1, N=12, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1/2, N=47, Recruiting, Pfizer | Phase classification: P1b/2 --> P1/2 | N=35 --> 47 | Trial completion date: Oct 2027 --> Dec 2026 | Trial primary completion date: Apr 2026 --> Dec 2026

P1/2, N=65, Recruiting, Pfizer | Not yet recruiting --> Recruiting | Trial completion date: Nov 2026 --> Feb 2026 | Trial primary completion date: May 2026 --> Aug 2025

P1/2, N=67, Recruiting, Pfizer | Phase classification: P2 --> P1/2

P1, N=12, Not yet recruiting, Pfizer

P1/2, N=40, Recruiting, Pfizer | Phase classification: P1b/2 --> P1/2 | Trial completion date: Jun 2027 --> Dec 2025

P2, N=67, Recruiting, Pfizer

P1, N=16, Not yet recruiting, Pfizer

P2, N=67, Recruiting, Pfizer | Not yet recruiting --> Recruiting

As of the end of 2022, more than 20 drugs have entered clinical trials, with ARV-471 targeting estrogen receptor (ER) showing remarkable progress by entering phase III clinical studies...In this review, we aimed to update the PROTAC degraders as potential anticancer agents covering articles published in 2022. The design strategies, degradation effects, and anticancer activities were highlighted, which might provide an updated sight to develop novel PROTAC degraders with great potential as anticancer agents as well as favorable drug-like properties.

P1, N=32, Active, not recruiting, Arvinas Estrogen Receptor, Inc. | Recruiting --> Active, not recruiting | Phase classification: P1b --> P1

P2, N=152, Active, not recruiting, Arvinas Inc. | Recruiting --> Active, not recruiting

P1, N=9, Active, not recruiting, Pfizer | Trial primary completion date: Nov 2023 --> Mar 2024

P1, N=12, Completed, Pfizer | Active, not recruiting --> Completed

P1/2, N=65, Not yet recruiting, Pfizer

P1, N=12, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

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...Vepdegestrant is being evaluated in combination with abemaciclib (sub-study A; NCT05548127), ribociclib (sub-study B; NCT05573555), and samuraciclib (sub-study C)...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.

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). 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.

With 12 months of additional follow-up from the first data report, durable clinical activity with vepdegestrant 200 mg QD was seen in heavily pretreated patients with ER+/HER2- advanced breast cancer, in addition to sustained reduction in circulating mutant ESR1 tumor DNA levels. Vepdegestrant 200 mg QD continued to show a favorable safety profile. The ongoing global, randomized phase 3 VERITAC-2 study (NCT05654623) is evaluating vepdegestrant 200 mg QD vs intramuscular fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination CDK4/6 inhibitor therapy and endocrine therapy.

The primary endpoint, progression-free survival, will be assessed by blinded independent central review in the intention-to-treat population and the ESR1 mutation subpopulation. Secondary outcome measures include overall survival, antitumor activity (objective response rate, duration of response, and clinical benefit rate), safety, and quality of life assessments.

In xenograft models, vepdegestrant plus palbo showed substantially greater tumor growth inhibition vs fulvestrant plus palbo, supporting investigation in patients with breast cancer. The combination of vepdegestrant plus palbo showed promising clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer who had received extensive prior treatment. The safety profile of vepdegestrant plus palbo was generally consistent with the known safety profiles of the 2 agents except for an increased occurrence of grade 3/4 neutropenia, which was readily managed with laboratory monitoring and dose reductions of palbo. There is an ongoing study lead-in to the global VERITAC-3 study (NCT05909397) that is evaluating 2 doses of palbo (100 mg and 75 mg) in combination with vepdegestrant 200 mg QD to determine the recommended phase 3 combination to compare with letrozole plus palbo as first-line treatment for ER+/HER2- advanced breast cancer.

VERITAC-3 will compare vepdegestrant + palbociclib vs letrozole + palbociclib as 1st-line treatment in pts with ER+/HER2- locoregional recurrent/metastatic breast cancer; 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. In the phase 3 portion, pts (N≈1130) will be randomized to vepdegestrant + palbociclib or letrozole + palbociclib. The primary endpoint is PFS by BICR.

Conclusions The RP3D of vepdegestrant 200 mg QD was well tolerated in Japanese patients with ER+/HER2- advanced breast cancer. Vepdegestrant will be evaluated in 2 global, randomized phase 3 studies in patients with ER+/HER2- advanced breast cancer: as second/third-line monotherapy in VERITAC-2 (NCT05654623) and as first-line therapy in combination with palbociclib in VERITAC-3 (NCT05909397).