Vepdegestrant

CHICAGO Too often, cancer has a way of evading treatment. Tumors that were held in check begin to spread anew, forcing doctors to try different drugs in a desperate race to keep malignant cells from multiplying.For a common type of breast cancer, this usually happens because of changes in a gene called ESR1. Mutations there can drive cancer growth even as physicians first choice of therapy chokes off the resources that tumors had relied on to survive.Afterwards, the prognosis for patients gets worse. Multiple second-line medicines exist, but their benefit is limited, quality of life decreases and survival rates are low, according to Nicholas Turner, director of clinical research and development at the Royal Marsden Hospital in London.New study results from Turner and others show an experimental drug from AstraZeneca, camizestrant, can help sustain the benefit of first-line therapy. Unveiled Sunday, their research found that, once ESR1 mutations are detected, swapping out a standard component of that initial regimen for AstraZenecas drug reduced the risk of disease progression or death by more than half.Data from the study, which AstraZeneca funded and in February said succeeded, will be presented Sunday afternoon at the American Society of Clinical Oncologys annual meeting.Patients have an urgent need for new treatments that can prolong time on first-line therapy and delay disease progression, Turner said in a statement provided by ASCO.In their clinical trial, Turner and colleagues enrolled 3,256 people with advanced breast cancer positive for hormone receptors but negative for a protein called HER2. These individuals are typically treated with a kind of hormone therapy known as an aromatase inhibitor along with another type of targeted drug that interrupts cancer cell division.Participants in the study were monitored via blood tests for the emergence of ESR1 mutations, which were eventually detected in about 550 people. Three-hundred and fifteen were then randomly assigned to receive camizestrant instead of the aromatase inhibitor or to continue on with their initial regimen. These patients continued to receive those targeted drugs, CDK 4/6 inhibitors.Patients who were switched to camizestrant had a 56% lower risk of their cancer progressing or killing them than those who continued on, researchers calculated. Put another way, people in the camizestrant group lived a median of 16 months without disease progression or death, compared to 9.2 months for those in the control arm.Data also showed camizestrant helped maintain quality of life for longer than did aromatase inhibitors, too.Researchers continue to follow study participants to measure differences between the groups in overall survival, but dont yet have enough follow-up data to determine whether there is a benefit on that score.Less than 2% of patients in either group discontinued treatment due to side effects, which, for camizestrant, were consistent with what AstraZeneca has observed in prior testing.Hormone receptor-positive, HER2-negative tumors are the most common type of breast cancer, accounting for an estimated 70% of cases. Hormone receptors provide a dock for estrogen, which spurs the tumor to grow. In first-line therapy, hormone therapy shuts off estrogen signaling by either gumming up hormone receptors on the surface of breast cancer cells, or by blocking the body from making estrogen.But about 40% of patients whose breast cancer is responsive to hormone therapy develop ESR1 mutations during their initial therapy, according to an estimate cited by ASCO. Research done a decade ago at Memorial Sloan Kettering Cancer Center discovered that ESR1 mutations change the shape of the estrogen receptor, essentially flipping it on, whether or not cancer cells continue to receive an estrogen growth signal.Camizestrant offers a way to get ahead of that change by breaking down the estrogen receptor entirely. Its one of a new crop of so-called selective estrogen receptor degraders, or SERDs, that are taken orally rather than injected like the drug fulvestrant, which has been a staple of breast cancer treatment for decades.One member of this fresh class, Orserdu, won U.S. approval in 2023. Others from Eli Lilly and Roche, as well as a different kind of degrader from partners Pfizer and Arvinas, are in late-stage testing. Data from a Phase 3 trial involving Pfizer and Arvinas vepdegestrant in people whose hormone receptor-positive, HER2-negative breast cancer progressed following initial treatment were presented at ASCO Saturday.The setting envisioned by camizestrants trial is one step earlier, subbing in a SERD before initial disease progression to allow patients to remain on first-line therapy longer.When patients progress on scans, were already behind. Weve already lost control, in some sense, Eleonora Teplinsky, head of breast and gynecologic medical oncology at New Jerseys Valley-Mount Sinai Comprehensive Cancer Care, said in a press conference held by ASCO. An early switch approach, before we see disease progression on imaging, [allows] us to stay ahead of the curve.Switching early requires regular monitoring, which Turner and his colleagues accomplished by using liquid biopsies, tests that pick up fragments of tumor DNA circulating in the blood. While these are relatively expensive, Turner said he hopes insurance would cover them should camizestrant win approval in the tested setting.Clearance would also change doctors testing practice. Soon after Orserdu won U.S. approval, ASCO updated its treatment guidelines to recommend testing for ESR1 mutations following disease progression or recurrence. Camizestrants benefit lies in delaying that progression, making active surveillance beforehand essential.The difference here is this serial monitoring for evidence of the evolving mutation, said Julie Gralow, an oncologist and ASCOs chief medical officer, at the press conference.Establishing reimbursement and updating guidelines will be important to that goal, acknowledged Mohit Manrao, a senior vice president in AstraZenecas U.S. oncology division. The good part here is that the test exists, he added It is already being done at the point of progression, he said.AstraZeneca plans to use the data presented at ASCO to request regulatory approval. It is also studying replacing aromatase inhibitors with camizestrant upfront, rather than waiting for ESR1 mutations to emerge. Two other trials are examining camizestrants potential in early breast cancer. '

NEW HAVEN, CT and NEW YORK, NY, USA I May 31, 2025 I Arvinas, Inc. (Nasdaq: ARVN) and Pfizer Inc. (NYSE: PFE) today announced detailed results from the Phase 3 VERITAC-2 clinical trial (NCT05654623) evaluating vepdegestrant monotherapy versus fulvestrant in adults with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer (MBC) whose disease progressed following prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapy. These data, which were highlighted in the American Society of Clinical Oncology (ASCO ® ) press briefing and selected for Best of ASCO, will be presented today in a late-breaking oral presentation (Abstract LBA1000) and have been simultaneously published in the New England Journal of Medicine . In the trial, vepdegestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) among patients with an estrogen receptor 1 (ESR1) mutation, reducing the risk of disease progression or death by 43% compared to fulvestrant [Hazard Ratio (HR)=0.57 (95% CI 0.42–0.77); 2-sided P<0.001]. The median PFS, as assessed by blinded independent central review (BICR), was 5.0 months with vepdegestrant versus 2.1 months with fulvestrant. Investigator-assessed PFS was consistent with the BICR-assessed PFS. In patients with ESR1 mutations, vepdegestrant demonstrated a consistent PFS benefit over fulvestrant across all pre-specified subgroups. The trial did not reach statistical significance in improvement in PFS in the intent-to-treat (ITT) population, with a median PFS of 3.7 months for vepdegestrant versus 3.6 for fulvestrant [HR=0.83 (95% CI 0.68–1.02); 2-sided P=0.07]. “Many patients with ER+/HER2- metastatic breast cancer who progress on endocrine therapy have tumors with ESR1 mutations, which drive resistance to standard treatments,” said Erika P. Hamilton, M.D., Director, Breast Cancer Research, Sarah Cannon Research Institute, and a principal investigator of the VERITAC-2 trial. “The VERITAC-2 results are promising and suggest that vepdegestrant could offer a much-needed treatment option for these patients, with a low incidence of burdensome GI effects that can meaningfully affect daily life.” Vepdegestrant was generally well tolerated in the trial, with a safety profile consistent with what has been observed in previous studies, and mostly low-grade treatment-emergent adverse events (TEAEs). Rates and severity of gastrointestinal adverse events were low with vepdegestrant (nausea, 13.5%; vomiting, 6.4%; diarrhea, 6.4%). Grade 4 TEAEs were reported in 5 patients (1.6%) in the vepdegestrant arm versus 9 patients (2.9%) in the fulvestrant arm. The three most common TEAEs observed with vepdegestrant were fatigue (26.6%), increased alanine transaminase (ALT) (14.4%) and increased aspartate aminotransferase (AST) (14.4%). TEAEs leading to treatment discontinuation occurred in 2.9% of patients taking vepdegestrant versus 0.7% of patients taking fulvestrant. “Based on these strong data from VERITAC-2, we believe that vepdegestrant has the potential to be a best-in-class monotherapy treatment for patients in the second-line ESR1-mutant setting,” said John Houston, Ph.D., Chairperson, Chief Executive Officer and President at Arvinas. “We are excited to engage with regulatory authorities on next steps to potentially bring vepdegestrant to healthcare providers and their patients as swiftly as possible.” Overall survival (OS), the key secondary endpoint in VERITAC-2, was immature at the time of the analysis, with less than a quarter of the required number of events having occurred. Additional secondary endpoints include clinical benefit rate (CBR) and objective response rate (ORR) and duration of response by BICR. In patients with an ESR1 mutation, CBR was 42.1% with vepdegestrant versus 20.2% with fulvestrant [odds ratio 2.88 (95% CI: 1.57–5.39); nominal P<0.001] and ORR was 18.6% with vepdegestrant versus 4.0% with fulvestrant [odds ratio 5.45 (95% CI: 1.69–22.73); nominal P=0.001]. The median duration of response was not reached. “Patients whose tumors harbor ESR1 mutations can face a poor prognosis, often experiencing rapid disease progression on endocrine therapy,” said Johanna Bendell, M.D., Chief Oncology Development Officer, Pfizer. “These results highlight the important role vepdegestrant may play in combating ESR1 mutation treatment resistance for these patients.” Approximately 2.3 million new breast cancer diagnoses were reported globally in 2022, and it is estimated there will be nearly 320,000 new diagnoses in the United States in 2025. ER+/HER2- breast cancer accounts for approximately 70% of all cases. Nearly 30% of women initially diagnosed with early-stage breast cancer will ultimately develop metastatic disease, 1 with resistance to current standard-of-care treatments often emerging during first-line therapy, leading to disease progression. ESR1 mutations are a common cause of acquired resistance and are found in approximately 40% of patients in the second-line setting. 2,3,4 Vepdegestrant, an investigational oral PROTAC ER degrader for ER+/HER2- breast cancer being jointly developed by Arvinas and Pfizer, is designed to harness the body’s natural protein disposal system to specifically target and degrade the ER. These detailed results follow the March 2025 announcement of the topline results from VERITAC-2. The companies plan to submit a New Drug Application (NDA) for vepdegestrant to the U.S. Food & Drug Administration (FDA) in the second half of 2025. ASCO Presentation Details “Vepdegestrant, a PROTAC Estrogen Receptor Degrader, vs Fulvestrant in ER-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results of the Global, Randomized, Phase 3 VERITAC-2 Study” will be presented by Dr. Erika Hamilton, MD, Sarah Cannon Research Institute, in the Oral Abstract Session, Breast Cancer—Metastatic on Saturday, May 31, 1:15 – 4:15 p.m. CDT in Hall B1. Abstract LBA1000. Investor Call and Webcast Details Arvinas will host a conference call and webcast on June 2, 2025, at 8:00 a.m. ET to review these data. Participants are invited to listen by going to the Events and Presentation section under the Investors page on the Arvinas website at www.arvinas.com . A replay of the webcast will be available on the Arvinas website following the completion of the event and will be archived for up to 30 days. About the VERITAC-2 Clinical Trial The Phase 3 VERITAC-2 clinical trial ( NCT05654623 ) is a global randomized trial evaluating the efficacy and safety of vepdegestrant (ARV-471) as a monotherapy compared to fulvestrant in patients with ER+/HER2- advanced or metastatic breast cancer. The trial enrolled 624 patients at sites in 26 countries who had previously received treatment with a CDK4/6 inhibitor plus endocrine therapy. Patients were randomized 1:1 to receive either vepdegestrant once daily, orally on a 28-day continuous dosing schedule, or fulvestrant, administered intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each 28-day cycle starting from Day 1 of Cycle 2. In the trial, 43% of patients (n=270) had ESR1 mutations detected. The primary endpoint was progression-free survival (PFS) in the ESR1-mutation and intent-to-treat populations as determined by blinded independent central review. Overall survival is the key secondary endpoint. About Vepdegestrant Vepdegestrant is an investigational, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with ER-positive (ER+)/human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) breast cancer. Vepdegestrant is being developed as a potential monotherapy for ER+/HER2- advanced or metastatic breast cancer with estrogen receptor 1 (ESR1) mutations in the second line-plus setting. In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer will share worldwide development costs, commercialization expenses, and profits. The U.S. Food and Drug Administration (FDA) has granted vepdegestrant Fast Track designation as a monotherapy in the treatment of adults with ER+/HER2- advanced or metastatic breast cancer previously treated with endocrine-based therapy. About Arvinas Arvinas (Nasdaq: ARVN) is a clinical-stage biotechnology company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases. Through its PROTAC protein degrader platform, Arvinas is pioneering the development of protein degradation therapies designed to harness the body’s natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. Arvinas is currently progressing multiple investigational drugs through clinical development programs, including vepdegestrant, targeting the estrogen receptor for patients with locally advanced or metastatic ER+/HER2- breast cancer; ARV-393, targeting BCL6 for relapsed/refractory non-Hodgkin Lymphoma; and ARV-102, targeting LRRK2 for neurodegenerative disorders. Arvinas is headquartered in New Haven, Connecticut. For more information about Arvinas, visit www.arvinas.com and connect on LinkedIn and X . 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In addition, to learn more, please visit us on www.pfizer.com and follow us on X at @Pfizer and @Pfizer_News , LinkedIn , YouTube and like us on Facebook at Facebook.com/Pfizer . 1 Redig AJ, McAllister SS. Breast cancer as a systemic disease: a view of metastasis. J Intern Med . 2013;274(2):113-126. doi:10.1111/joim.12084. 2 Bidard F-C, et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. Journal of Clinical Oncology. 2022 May https://doi.org/10.1200/JCO.22.00338 . 3 Kalinsky, K. Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial. Journal of Clinical Oncology. 2024 Dec. https://pubmed.ncbi.nlm.nih.gov/39693591/ . 4 Tolaney, S. et al. AMEERA-3: Randomized Phase II Study of Amcenestrant (Oral Selective Estrogen Receptor Degrader) Versus Standard Endocrine Monotherapy in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer. Journal of Clinical Oncology. https://ascopubs.org/doi/full/10.1200/JCO.22.02746 . SOURCE: Arvinas