vepdegestrant (ARV-471) / Arvinas, Pfizer - LARVOL DELTA

A Study to Learn How a Tablet Compared With an IV Infusion of the Study Medicine Called Vepdegestrant is Taken up Into the Blood in Healthy Adults (clinicaltrials.gov) - P1 | N=10 | Not yet recruiting | Sponsor: Pfizer

New P1 trial

Discovery of a highly potent and orally bioavailable ER PROTAC degrader for the treatment of breast cancer (AACR 2025) - "A promising therapeutic strategy to overcome endocrine resistance in ER+ breast cancer is the development of ER degraders using the proteolysis targeting chimera (PROTAC) technology.Facilitated by our new cereblon ligand library, we have discovered a potent and orally bioavailable ER PROTAC degrader GLR203801, with its binding affinity to cereblon increased by 20-fold than that of ARV-471. GLR203801 also effectively inhibited the viability of breast-cancer patient derived ER+ organoids. The good tolerance of GLR203801 in toxicity study both in SD rats and beagle dogs supports it as a promising preclinical candidate for further clinical development."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CRBN • ER

Vepdegestrant for the treatment of HR+/HER2- breast cancer. (PubMed, Expert Opin Pharmacother) - "The results of the phase III VERITAC-2 study, comparing vepdegestrant with fulvestrant, are expected to be available in 2025, and will provide the first data on the true clinical significance of vepdegestrant. Several phase III studies of combinations with vepdegestrant including + atirimociclib (a cyclin-dependent kinase 4 inhibitor) have been or are planned to be conducted. The results of these may not only transform the treatment landscape for advanced HR+/HER2- breast cancer but may pave the way for PROTAC as a new class of anti-cancer drugs that may make previously undruggable targets druggable."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER • HER-2

Analysis of the Main Directions in the Development of Mono and Combination Pharmacotherapy Acting on Hormonal Signaling Pathways of Breast Cancer According to the FDA Databases and Clinicaltrials.gov. (PubMed, Curr Med Chem) - "It is evident that traditional endocrine treatments play a pivotal role in the management of HR+ BC. However, the emergence of resistance necessitates the development of novel therapeutic strategies. These strategies should be based on pharmacokinetics, further investigation of the molecular signaling pathways of BC, such as new SERMs, SERDs, PROTACs, as well as new drug groups, like SERCAs, CERANs, SHERPAs. Combination therapy represents the most promising avenue for BC treatment. While PROTAC combination with new monotherapeutic agents for BC treatment has yet to be investigated, we believe that such combinations have the potential to make the treatment more selective, effective, and personalised in the future."

Journal • Breast Cancer • Endocrine Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CDK4

Conquering PROTAC molecular design and drugability. (PubMed, Bioanalysis) - "Clinical successes, including ARV-110 for castration-resistant prostate cancer and ARV-471 for breast cancer, exemplify their ability to overcome resistance and provide durable effects. By addressing challenges in pharmacokinetics, safety, and scalability, PROTACs are poised to revolutionize precision medicine. This article presents a forward-looking perspective on conquering the molecular design and drugability of PROTACs, paving the path for transformative therapies."

Journal • Breast Cancer • Castration-Resistant Prostate Cancer • CNS Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation

Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial (GlobeNewswire) - P3 | N=624 | VERITAC-2 (NCT05654623) | Sponsor: Pfizer | "The trial met its primary endpoint in the estrogen receptor 1-mutant (ESR1m) population, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to fulvestrant. The results exceeded the pre-specified target hazard ratio of 0.60 in the ESR1m population. The trial did not reach statistical significance in improvement in PFS in the intent-to-treat (ITT) population....Overall survival was not mature at the time of the analysis, with less than a quarter of the required number of events having occurred. The trial will continue to assess overall survival as a key secondary endpoint....Detailed results from VERITAC-2 will be submitted for presentation at a medical meeting later this year, and these data will be shared with global regulatory authorities to potentially support regulatory filings."

P3 data: top line • Breast Cancer

C4891024: TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer. (Sub-Study C) (clinicaltrials.gov) - P1/2 | N=11 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=67 ➔ 11 | Trial completion date: Jan 2027 ➔ Nov 2025 | Trial primary completion date: Jul 2026 ➔ Nov 2025

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Arvinas Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "As part of Arvinas global collaboration with Pfizer, the companies plan to: Announce topline data for the VERITAC-2 Phase 3 monotherapy clinical trial evaluating vepdegestrant in patients with ER+/HER2- metastatic breast cancer (mBC) in a topline press release 1Q25 and present full results of the trial at a medical conference in 2025. Initiate two new Phase 3 combination trials in patients with ER+/HER2- mBC (pending emerging data and regulatory feedback) in 2025...With the prioritization of the vepdegestrant plus atirmociclib combination for the first-line setting, the VERITAC-3 Phase 3 clinical trial evaluating vepdegestrant plus palbociclib in the first-line will not proceed beyond the study lead-in."

New P3 trial • P3 data: top line • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Arvinas Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "As part of Arvinas global collaboration with Pfizer, the companies plan to: Continue to collect safety and efficacy data from ongoing TACTIVE-U sub-studies evaluating combination of vepdegestrant with abemaciclib, ribociclib, or samuraciclib (ClinicalTrials.gov Identifiers: NCT05548127, NCT05573555, and NCT06125522) and submit key data for presentation at medical conference. Continue enrollment in the Phase 2 TACTIVE-K clinical trial (atirmociclib + vepdegestrant) and submit initial Phase 1b data for presentation at a medical conference."

P1 data • P1/2 data • Breast Cancer

A Study to Learn About the Study Medicine Called Vepdegestrant (ARV-471, PF-07850327) in People With ER+/HER2- Advanced Breast Cancer in China (clinicaltrials.gov) - P1 | N=9 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Unleashing the Power of Covalent Drugs for Protein Degradation. (PubMed, Med Res Rev) - "Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field."

Journal • Review • Oncology • Solid Tumor • Targeted Protein Degradation • BTK • DDB1 • EGFR • KEAP1 • KRAS

Arvinas Updates Guidance for First- and Second-Line Phase 3 Combination Trials with Vepdegestrant, Highlights Upcoming Milestones, and Provides Corporate Update (GlobeNewswire) - "As part of Arvinas’ global collaboration with Pfizer, in 2025 the companies plan to: Announce topline data for the VERITAC-2 Phase 3 monotherapy clinical trial in patients with second-line-plus ER+/HER2- metastatic breast cancer (mBC) (1Q25). Initiate two new Phase 3 combination trials in patients with ER+/HER2- mBC (pending emerging data and regulatory feedback): First-line Phase 3 combination trial with Pfizer’s novel investigational CDK4 inhibitor, atirmociclib. Second-line Phase 3 combination trial with a CDK4/6 inhibitor. With the prioritization of the vepdegestrant plus atirmociclib combination for the first-line setting, the VERITAC-3 trial evaluating vepdegestrant plus palbociclib in the first-line will not proceed beyond the study lead-in."

New P3 trial • P3 data: top line • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

C4891038: A Study to Learn How Different Tablets of the Study Medicine Vepdegestrant Are Taken up Into the Blood in Healthy Adults (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open

PRISM high-throughput screening to elucidate how tumor microenvironments modulate drug responses of breast cancer cells (SABCS 2024) - "Media filtering reduced the drug effects of fulvestrant but not ARV-471, suggesting that ARV-471 efficacy may be less sensitive to the tumor microenvironment than fulvestrant. Lapatinib (HER2/neu and EGF receptor inhibitor) was more effective in killing HER2+ than HER2- negative breast cancer cells, with cells cultured in EGF-spiked media being more sensitive to lapatinib, whereas media filtration diminished its effects. We did not observe breast cancer subgroup specific killing by alpelisib (PI3K inhibitor) or olaparib (PARP inhibitor), but breast cancer cells became less sensitive to alpelisib when cultured in either insulin- or EGF-spiked media, and less sensitive to olaparib in EGF-spiked media. Overall, our study highlights how the PRISM 900+ cell panel can provide insights into drug specificity, cancer subtype selectivity, and to uncover clinically relevant targets. The breast cancer specific pool can further increase the throughput of understanding how drug..."

Biomarker • Tumor microenvironment • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • ABCB1 • ER

Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader, Plus Abemaciclib in ER-Pos/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced or Metastatic Breast Cancer: TACTIVE-U Prelim Phase 1b Results (SABCS 2024) - P1/2 | "All pts (100%) received prior CDK4/6 inhibitors (ribociclib [n=8], palbociclib [n=7], and abemaciclib [n=1]), 14 (88%) prior aromatase inhibitors, 11 (69%) prior chemotherapy, and 5 (31%) prior fulvestrant. The safety profile of vepdegestrant plus abemaciclib in pts with ER+/HER2- advanced or metastatic breast cancer was generally consistent with the known profiles of each agent, and no DLTs were observed. Neutropenia was manageable with dose modifications. The impact of vepdegestrant on abemaciclib exposure was minor and indicated no significant drug interaction."

Metastases • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Evaluating CYP3A4-Mediated Drug Interaction Risks for Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader, in Combination With Cyclin-Dependent Kinase (CDK)4/6 Inhibitors and Everolimus (SABCS 2024) - P1, P1/2 | "Static mechanistic models1,2,3, incorporating findings of this clinical study and drug interaction mechanisms as victim of CYP3A4-mediated metabolism for each combination partner, were used to calculate the predicted effect of vepdegestrant 200 mg QD administration on the PK of palbociclib, abemaciclib, ribociclib, and everolimus, represented as the ratio of area under the concentration-time curve (AUC) in the presence and absence of vepdegestrant (AUCr). Vepdegestrant shows a weak inhibitory effect on CYP3A4-mediated metabolism in the clinical study with midazolam. The study results, combined with mathematical modeling, suggest low potential of meaningful drug interactions for vepdegestrant in combination with CDK4/6 inhibitors and everolimus. Clinical data are anticipated from ongoing studies of vepdegestrant in combination with other anticancer therapies in patients with ER+/HER2- advanced breast cancer."

Combination therapy • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • CYP3A4 • ER • HER-2

Evaluation of the Combination of Vepdegestrant, a PROTAC Estrogen Receptor (ER) Degrader, Plus Palbociclib in CDK4/6 Inhibitor-Resistant WT ER and ER Y537S Mutant Patient-Derived Xenograft (PDX) Models (SABCS 2024) - "Previously, our studies revealed evidence of synergistic interactions between vepdegestrant and CDK4/6 inhibitors (palbociclib, abemaciclib and ribociclib) in ER+ breast cancer cells. These data suggest that in vitro, the combination of vepdegestrant and palbociclib leads to enhanced apoptosis in ER+ breast cancer cells and in vivo, vepdegestrant alone or vepdegestrant plus palbociclib is superior to fulvestrant alone or fulvestrant plus palbociclib, respectively, in the CDK4/6 inhibitor-resistant setting."

Clinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • ER • HER-2

Pfizer Showcases Scientific Leadership in Breast Cancer…at…SABCS (Pfizer Press Release) - "Key SABCS Presentations: Data from 30 company-sponsored, investigator-sponsored, and collaborative research abstracts will be presented at SABCS, including nine real-world analyses affirming IBRANCE (palbociclib) as a first-line standard-of-care treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). The company will also present new data from its expanding pipeline of innovative, next-generation therapy candidates that have the potential to address critical unmet patient needs across all subtypes and stages of breast cancer, including new and updated Phase 1 data for atirmociclib, vepdegestrant, and the novel KAT6 inhibitor, PF-07248144."

Clinical data • Real-world • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Arvinas and Pfizer Announce Initial Phase 1b Data from the TACTIVE-U Sub-Study of Vepdegestrant in Combination with Abemaciclib at 2024 San Antonio Breast Cancer Symposium (GlobeNewswire) - P1b/2 | N=37 | TACTIVE-U Sub-Study A (NCT05548127) | Sponsor: Pfizer | "Key findings included in the poster (data cut-off: August 30, 2024): 100% of patients had prior treatment with a CDK4/6 inhibitor; Tolerability is generally consistent with the profile of abemaciclib and with results previously observed in other clinical trials of vepdegestrant...There was no significant drug-drug interaction, and data reflected vepdegestrant has no clinically meaningful effect on abemaciclib exposure; Encouraging preliminary antitumor activity is observed with a clinical benefit rate (CBR, defined as the rate of confirmed complete response, partial response, or stable disease ≥ 24 weeks) of 62.5% in all CBR-eligible patients (10/16), 62.5% in patients with mutant ESR1 (5/8), and 62.5% in patients with wild-type ESR1 (5/8); The objective response rate (ORR) in evaluable patients was 26.7% overall (4/15), 37.5% in patients with mutant ESR1 (3/8), and 14% in patients with wild-type ESR1 (1/7)."

P1 data • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

TACTIVE-U Sub-Study A: TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer (Sub-Study A) (clinicaltrials.gov) - P1/2 | N=36 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2025 ➔ Sep 2025 | Trial primary completion date: Dec 2025 ➔ Sep 2025

Combination therapy • Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • HER-2

Molecular properties, including chameleonicity, as essential tools for designing the next generation of oral beyond rule of five drugs. (PubMed, ADMET DMPK) - "Molecular descriptors of ARV-110, ARV-471, and DT-2216 are reported and the main limitations of the applied experimental approaches are discussed. Moreover, a simple computational method shows how predicting the presence of chameleonic effects. A full complete physicochemical characterization of three degraders in clinical trials is reported to highlight the differences in physicochemical descriptors between PROTACs dosed orally and intravenously."

Journal • Targeted Protein Degradation

VERITAC-2: A Study to Learn About a New Medicine Called Vepdegestrant (ARV-471, PF-07850327) in People Who Have Advanced Metastatic Breast Cancer (clinicaltrials.gov) - P3 | N=624 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα). (PubMed, J Med Chem) - "ERD-12310A achieved a DC50 value of 47 pM and is 10 times more potent than ARV-471...Importantly, ERD-12310A achieved strong tumor growth inhibition in MCF-7 xenograft tumors harboring the clinically relevant ESR1Y537S mutation, which confers resistance to traditional antiestrogens. Our data position ERD-12310A as a promising candidate for further development as a potential therapy for ER+ breast cancer."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER

Safety and pharmacokinetics of vepdegestrant in Japanese patients with ER+ advanced breast cancer: a phase 1 study. (PubMed, Int J Clin Oncol) - P1 | "Vepdegestrant 200 mg QD was well tolerated in Japanese patients with ER+/HER2- advanced breast cancer with no notable differences in pharmacokinetics from Western patients."

Journal • Metastases • P1 data • PK/PD data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER • HER-2

Arvinas Announces Upcoming Vepdegestrant Poster Presentations at the 2024 San Antonio Breast Cancer Symposium (GlobeNewswire) - "Arvinas, Inc...announced that three posters for vepdegestrant, including clinical data, will be presented at the 2024 San Antonio Breast Cancer Symposium (SABCS)...Vepdegestrant is a novel investigational PROTAC estrogen receptor (ER) degrader that is being jointly developed by Arvinas and Pfizer for the treatment of patients with early and locally advanced or metastatic estrogen receptor positive/human epidermal growth factor receptor 2 (HER2) negative (ER+/HER2-) breast cancer."

Clinical data • Preclinical • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer