Vepdegestrant, First Oral PROTAC Degrader, Demonstrates Significant PFS Benefit in ESR1-Mutated ER+/HER2- Advanced Breast Cancer: Phase 3 VERITAC-2 Trial Results

In hormone receptor (ER) Positive, Human Epidermal Growth Factor Receptor2（HER2) Negative advanced breast cancer in first-line treatment,CDK4/6 The combination of inhibitors and endocrine therapy significantly prolonged the progression-free survival of patients and has become an internationally recognized standard first-line treatment regimen.However, for patients who experience disease progression during endocrine therapy, a unified standard treatment consensus has not yet been established.In clinical practice, selectiveER Degradation agent Fulvestrant, new oral drugselacestrant AndPI3K/AKT Pathway inhibitor capivasertib (Capivasertib) and other targeted drugs are common choices for such patients. However, these options present clinical challenges: fulvestrant requires intramuscular injection, which limits its bioavailability and is less effective against mutant types.ER Issues such as insufficient binding affinity; while small-molecule targeted drugs often affect the continuity of medication due to adverse reactions like gastrointestinal effects and blood sugar metabolism disorders. In addition,ESR1  Mutation is still one of the core driver gene mutations leading to treatment resistance.ESR1 Mutation in treatment-naive primaryER+ The incidence rate in breast cancer is relatively low (approximately1 %）^[3]，But upon receivingCDK4/6 The incidence significantly increased to in patients who developed metastases after combination treatment with inhibitors and endocrine therapy.40%-50%^[4]. Therefore, the development of targetedESR1 The development of novel targeted innovative drugs that are both highly efficient and well-tolerant has become an urgent clinical challenge.

Vepdegestrant Is a based onPROTAC A new generation of orally administered selective estrogen receptor degraders (SERD), which can activate intracellular ubiquitin-Proteasome System Directly MediatesER Protein degradation. Traditional selective options such as fulvestrantER Degradation agents only indirectly promote by blocking receptor signalsER The mechanisms of degradation are different,vepdegestrant Can bind simultaneouslyER AndE3 Ubiquitin ligase, forming a ternary complex, inducesER Polyubiquitination tagging occurs and degradation takes place via the proteasome pathway. This dual mechanism of action makes it effective against both wild-type and mutant types.ER Both exhibited stronger degradation efficiency.^[5-6]. In the previous first-in-human I/Ⅱ Phase Clinical Study (NCT04072952) In,vepdegestrant Demonstrated good safety characteristics and showed efficacy in patients who failed multiple lines of therapy.ER+/HER2- Significant antitumor activity was observed in patients with advanced breast cancer.^[7]. This sessionASCO Annual Meeting JointNew England Journal of Medicine Heavyweight ReleaseⅢ PeriodVERITAC-2 The results of the study, which directly comparedvepdegestrant Compared with Fulvestrant inER+、HER2- Efficacy Differences in Patients with Advanced or Metastatic Breast Cancer.

Figure1：Vepdegestrant Mechanism of Action; Figure Source:ASCO

VERITAC-2 The study adopted an open-label, randomized design aimed at evaluatingER+/HER2- In patients with advanced or metastatic breast cancervepdegestrant Differences in efficacy and safety compared to fulvestrant. Patient inclusion criteria for the study include:

• At the age of18 Years old, confirmed as disease progression by imaging evaluationER+/HER2- Advanced Breast Cancer;

• Previously received first-lineCDK4/6 Inhibitor Combined with Endocrine Therapy (ET) treatment, and useET Medication does not exceed1 Type;

• Final CompletionET Treatment ≥6 Months;

• Have not received Fulvestrant,elacestrant WaitSERD Treatment;

• Advanced/No chemotherapy was performed during the metastatic stage.

Eligible patients are enrolled according to1:1 Randomized in proportion, respectively receivingvepdegestrant（200 mg Once daily orally, every28 days as a cycle) and fulvestrant (Day1 Cycle Day1 Tianhe No.15 Tiangge500 mg Intramuscular injection, subsequent cycle Day1 Daily medication) treatment, and the patient population was divided according toESR1 Stratification based on mutation status and the presence of visceral metastases.The primary endpoint of the study was assessed by blinded independent central review.ESR1 Progression-Free Survival in Mutation Subgroups and Overall Patients（PFS）, usingKaplan-Meier Method for Estimating MedianPFS, and through stratificationCox Proportional hazards model calculates hazard ratio (HR). Secondary endpoints include overall survival (OS), Objective Response Rate (ORR) and treatment-related adverse events (AEs) Incidence rate.

Figure2：VERITAC-2 Study Design

ESR1 Mutation Subgroup Patients: Primary EndpointPFS Significantly Improve

VERITAC-2 Test (NCT05654623) in2023 Year3 Month to2024 Year10 Month in25 Country213 A total of test centers were launched, with a total of624 For example, the baseline characteristics of the two groups were basically balanced, and the median age of the enrolled patients was60 Years old, of which approximately80% Previously received first-line treatment, approximately20% Previously received second-line treatment.43.3%（270 Person,vepdegestrant Group136 Human, Fulvestrant Group134 Patients carryESR1 Mutation. As of2025 Year1 Month31 Day,vepdegestrant The median follow-up time for the group and the fulvestrant group were respectively7.4 Months and6.0 Months.

In the primary endpoint analysis, for carriersESR1 MutationER+/HER2- Subgroup of advanced breast cancer,Vepdegestrant Compared with fulvestrant, it showed statistically significant and clinically valuablePFSImprove,vepdegestrant The median progression-free survival period for the group of patients was5.0 Months (95% CI，3.7~7.4), Fulvestrant group is2.1 Months (95% CI，1.9~3.5）（HR，0.58 ；95% CI，0.43~0.78；P < 0.001). In the primary endpoint analysis of the total population,Vepdegestrant Comparison of FulvestrantPFS No significant difference in benefit,vepdegestrant The median progression-free survival of the group was3.8 Months (95% CI，3.7~5.3), Fulvestrant group is3.6 Months (95% CI，2.6~4.0）（HR，0.83 ；95% CI，0.69~1.01；P = 0.07). Subgroup analysis showed that,ESR1 Mutated Patients and Overall PatientsPFS The results of the pre-specified subgroup analysis were similar to those of the primary analysis. The investigator-assessed progression-free survival was consistent with the blinded independent review-assessed progression-free survival.

Figure3：VERITAC-2 Subgroup and Overall Population Primary EndpointPFS Analysis results; Figure source: Literature2

ESR1 Mutation Subgroup: Secondary EndpointORR Significant Improvement

Analysis of secondary endpoints further validatedVepdegestrant InESR1 Efficacy advantage in the mutation subgroup,Vepdegestrant Clinical Benefit Rate of the Group (CBR) Da42.1%, significantly higher than the fulvestrant group20.2%（OR 2.88，P<0.001); Objective Response Rate (ORR) Also showed significant advantages, the two groupsORR Respectively18.6% vs. 4.0%（OR 5.45，P = 0.001). In the entire population,Vepdegestrant Group and Fulvestrant GroupCBR AndORR Respectively34.3% vs. 28.7%（p = 0.16) and10.9% vs. 3.6% （p = 0.003). Overall survival (OS) The exploratory analysis shows that the current data has not yet reached the preset maturity: inESR1 In the mutation subgroup, a total of43 Example of death events (accounting for22%); In the entire enrolled population, the cumulative number of death events80 Example (Accounting for the total number of target events)20%）。

Figure 4: The secondary endpoint objective response rate (ORR) and clinical benefit rate (CBR) Results

Vepdegestrant Good safety

In terms of safety,Vepdegestrant Demonstrated good safety and controllable tolerability.Vepdegestrant The overall incidence rates of adverse events in the group and the fulvestrant group were respectively86.9% And81.4%, the majority of which are1-2 Grade mild event. In terms of serious adverse events,Vepdegestrant Group3 The incidence rate of Grade and above adverse events is23.4%, slightly higher than the fulvestrant group17.6%; The proportion of permanent discontinuation due to treatment-related adverse events was respectively2.9% And0.7%. Meanwhile,Vepdegestrant Common adverse events include fatigue (26.6%), Elevated aspartate aminotransferase (14.4%) and nausea (13.5%). The fulvestrant group, on the other hand, experienced fatigue (15.6%), Arthralgia (10.7%), Elevated aspartate aminotransferase (10.4%) and elevated alanine aminotransferase (9.8%) as the main adverse event.

Figure 5：VERITAC-2 Study on the Safety and Tolerance of All Patients

Vepdegestrant YesThe FirstEnterIII Oral assessment in clinical researchPROTAC Estrogen receptor degraders. InESR1 Mutation (ESR1m) In the population, compared with fulvestrant,Vepdegestrant In progression-free survival (PFS) showed statistically significant and clinically meaningful improvement; but in the overall population,PFS Improvement did not reach a statistically significant difference. The current overall survival (OS) The analysis is not yet mature, and follow-up work is still in progress.Vepdegestrant Generally well tolerated, with treatment-related adverse events (TEAEs) leading to a lower discontinuation rate. These findings supportVepdegestrant As previously treatedESR1 Mutant TypeER+/ HER2- Breast Cancer (aBC) A potential oral treatment option for patients.

Other OptionsER The degrader also includeselacestrant Andimlunestrant。Elacestrant Is currently the world's only approved for use inESR1 Treatment Drugs for Mutated Patients (U.S. Food and Drug AdministrationFDA Approved for marketing, currently under development in ChinaⅢ Phase clinical trial). InEMERALD In the study, assessed by blinded independent central review, carryingESR1 Patients with mutations useelacestrant MedianPFS Extended by approximately compared to the standard treatment group2 Months (3.8 Monthsvs. 1.9 months); the objective response rate of the patients in this group was7.1%, superior to the standard treatment group4.7%^[8]. And inEMBER-3 In the study, the researchers evaluatedimlunestrant MedianPFS Extended nearly compared to the standard treatment group2 Months (5.5 Monthsvs. 3.8 months), the objective response rates of the two groups were respectively14.3% And7.7%^[9]. The results of this study show,vepdegestrant Used forESR1 Median of Mutated PatientsPFS Extended nearly compared to Fulvestrant3 Months (5.0 Monthsvs. 2.1 months), with objective response rates of18.6% And4.0%, The improvement in both indicators is better thanelacestrant Andimlunestrant。However, due to inherent differences in trial design and patient populations, cross-trial comparisons should be interpreted with caution.

In vivo study data show that, inESR1 In wild-type breast cancer, compared with fulvestrant,vepdegestrant Can induce strongerER Degradation, and exhibit superior anti-tumor activity^[10]. However, in the current full-population cohort analysis of clinical trials,vepdegestrant Median of the group and fulvestrant groupPFS No significant difference (3.8 Monthsvs. 3.6 months). In view ofER The complexity of signal transduction pathways makes this result unsurprising. Although the exact mechanism of this phenomenon has not been clarified, the research findings suggest:ESR1 Mutant breast cancer still retains sensitivity to endocrine therapy; whereas withoutESR1Mutated tumors may be driven by various alternative pathways, which could limit the overall efficacy of second-line endocrine monotherapy.。In addition, fulvestrant inESR1 Activity is limited in mutant patients, possibly due to its lower bioavailability; this speculation is consistent with the in vitro fulvestrant activity on mutant types.ER The binding affinity is lower than that of the wild type.ER The experimental data are consistent.^[11]。