[Translation] A Study of LOXO-783 as Monotherapy and in Combination with Other Anticancer Therapies in Patients with Advanced Breast Cancer and Other Solid Tumors with PIK3CA H1047R Mutations

主要目的：确定在PIK3CA H1047R突变的晚期乳腺癌和其他实体瘤患者中 LOXO-783单药治疗和与其他抗癌疗法联合治疗的LOXO-783的MTD/RP2D

[Translation]

Primary Objective: To determine the MTD/RP2D of LOXO-783 as monotherapy and in combination with other anticancer therapies in patients with advanced breast cancer and other solid tumors harboring the PIK3CA H1047R mutation

Start Date27 Nov 2023

Sponsor / Collaborator

Eli Lilly Suzhou Pharmaceutical Co. Ltd.

[+2]

CTR20230192

/ RecruitingPhase 3

EMBER-4：一项在既往接受过2-5年辅助内分泌治疗的ER+、HER2-早期乳腺癌且具有较高复发风险的患者中比较Imlunestrant辅助治疗和标准辅助内分泌治疗的随机、开放性、III期研究

[Translation] EMBER-4: A randomized, open-label, phase III study comparing adjuvant IMLUNESTRANT with standard adjuvant endocrine therapy in patients with ER+, HER2- early breast cancer at high risk of recurrence who have received 2-5 years of adjuvant endocrine therapy

本研究的主要目的是在雌激素受体阳性（ER+）和人表皮生长因子受体2阴性（HER2-）早期乳腺癌受试者中评价Imlunestrant相比标准内分泌治疗的疗效。入组研究的受试者必须符合以下条件：既往接受过2-5年的内分泌治疗、具有较高的复发风险。受试者参与研究的持续时间可能长达10年。

[Translation]

The primary objective of this study is to evaluate the efficacy of Imlunestrant compared with standard endocrine therapy in subjects with estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) early breast cancer. Subjects enrolled in the study must meet the following criteria: they have received 2-5 years of endocrine therapy in the past and have a high risk of recurrence. The duration of the subject's participation in the study may be up to 10 years.

Start Date12 May 2023

Sponsor / Collaborator

Eli Lilly Suzhou Pharmaceutical Co. Ltd.

[+2]

CTIS2022-501007-28-00

/ RecruitingPhase 3

J2J-MC-JZLH EMBER-4: A Randomized, Open-Label, Phase 3 Study of Adjuvant Imlunestrant vs Standard Adjuvant Endocrine Therapy in Patients who have Previously Received 2 to 5 years of Adjuvant Endocrine Therapy for ER+, HER2- Early Breast Cancer with an Increased Risk of Recurrence - 18459

Start Date27 Apr 2023

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with Imlunestrant

100 Translational Medicine associated with Imlunestrant

100 Patents (Medical) associated with Imlunestrant

Literatures (Medical) associated with Imlunestrant

27 Mar 2025·NEW ENGLAND JOURNAL OF MEDICINE

Imlunestrant with or without Abemaciclib in Advanced Breast Cancer

Article

Author: Jhaveri, Komal L. ; Pradhan, Kamnesh R. ; Lim, Elgene ; Sohn, Joohyuk ; Llombart-Cussac, Antonio ; Saura, Cristina ; Ruíz Borrego, Manuel ; Mattar, André ; Harbeck, Nadia ; Cramer von Laue, Christoph ; Wang, Xuejing Aimee ; Barrett, Emily ; Carey, Lisa A. ; O’Shaughnessy, Joyce ; Neven, Patrick ; Nakamura, Rikiya ; Martinez Rodriguez, Jorge Luis ; Kim, Sung-Bae ; Tokunaga, Eriko ; Cao, Shanshan ; Huang, Chiun-Sheng ; Zhang, Qingyuan ; Bidard, François-Clément ; Smyth, Lillian M. ; Casalnuovo, Monica Lis ; Hung, Chih-Chiang ; Curigliano, Giuseppe ; García Tinoco, María de la Luz ; Aftimos, Philippe

BACKGROUND:

Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα (ESR1).

METHODS:

In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib. Primary end points were investigator-assessed progression-free survival with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently.

RESULTS:

Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant-abemaciclib. Among 256 patients with ESR1 mutations, the median progression-free survival was 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001). In the overall population, the median progression-free survival was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P = 0.12). Among 426 patients in the comparison of imlunestrant-abemaciclib with imlunestrant, the median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001). The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant-abemaciclib.

CONCLUSIONS:

Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status. (Funded by Eli Lilly; EMBER-3 ClinicalTrials.gov number, NCT04975308.).

01 Mar 2025·Nature Reviews Clinical Oncology

Imlunestrant shows efficacy both with and without abemaciclib

Article

Author: Killock, David

17 Feb 2025·CANCER RESEARCH

Imlunestrant Is an Oral, Brain-Penetrant Selective Estrogen Receptor Degrader with Potent Antitumor Activity in ESR1 Wild-Type and Mutant Breast Cancer

Article

Author: Shen, Weihua ; de Dios, Alfonso ; Kindler, Lisa ; Dowless, Michele S. ; Garcia-Tapia, David ; Ortiz Ruiz, Maria Jesus ; Bastian, Jolie ; Rodrik-Outmezguine, Vanessa ; Rodriguez Cruz, Vivian ; Yu, Chunping ; Castanares, Mark A. ; Marugán, Carlos ; Bhagwat, Shripad V. ; Klippel, Anke ; Mattioni, Brian ; Fei, Dongling ; Vandekopple, Matthew ; Cohen, Jeff D. ; Ismail-Khan, Roohi ; Gong, Xueqian ; Stephens, Jennifer R. ; Peng, Sheng-Bin ; Capen, Andrew ; Bacchion, Francesca ; Zhao, Baohui ; Puca, Loredana ; Lallena, María Jose ; Yuen, Eunice ; Manro, Jason R. ; Baker, Thomas K. ; Pulliam, Nicholas ; Mur, Cecilia ; Huber, Lysiane

Abstract:

Targeting of the estrogen receptor (ER) by antiestrogens is the standard of care for patients with ER+ HER2− advanced/metastatic breast cancer. Although antiestrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations. These limitations indicate a need for more robust ER-targeted therapies. Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective ER degrader. Imlunestrant degraded ERα and decreased ERα-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared with vehicle or alternative selective ER degrader therapies. Together, these findings support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1-WT and mutant breast cancer, including brain metastatic tumors.Significance: Imlunestrant, a next-generation, brain-penetrant oral ERα degrader, displays potent activity in ESR1 wild-type and mutant breast cancer, enhances combination activity with standard-of-care agents, and inhibits growth of ER+ intracranial tumors.

News (Medical) associated with Imlunestrant

13 Mar 2025

·www.prnewswire.com

VERZENIO's Market Potential Soars as Demand for CDK4/6 Inhibitors Grows | DelveInsight

As VERZENIO gains traction in early-stage treatments and broadens its approved uses, its revenue is expected to keep growing. While the global CDK4/6 inhibitor market remains highly competitive, VERZENIO's distinct clinical advantages and ongoing studies could contribute to further market expansion. LAS VEGAS, March 13, 2025 /PRNewswire/ -- DelveInsight's " VERZENIO Market Size, Forecast, and Market Insight Report" highlights the details around VERZENIO, which is a targeted treatment known as a CDK4/6 inhibitor. The drug is a non-chemotherapy oral tablet. The report provides product descriptions, patent details, and competitor products (marketed and emerging therapies) of VERZENIO. The report also highlights the historical and forecasted sales from 2020 to 2034 segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. Eli Lilly and Company's VERZENIO (abemaciclib) Overview VERZENIO (abemaciclib) is a prescription medication used to treat adults with HR-positive, HER2-negative breast cancer that has metastasized (spread to other parts of the body). It is administered orally and is prescribed in combination with an aromatase inhibitor as an initial endocrine-based therapy. Additionally, the drug is being developed for the treatment of prostate cancer. VERZENIO is approved for the following indications: In combination with endocrine therapy for the adjuvant treatment of adults with HR+/HER2-, node-positive, early-stage breast cancer at high risk of recurrence. In combination with an aromatase inhibitor as the initial endocrine-based therapy for adults with HR+/HER2- advanced or metastatic breast cancer. In combination with fulvestrant for adults with HR+/HER2- advanced or metastatic breast cancer that has progressed after prior endocrine therapy. As monotherapy for adults with HR+/HER2- advanced or metastatic breast cancer that has progressed following endocrine therapy and prior chemotherapy in the metastatic setting. Learn more about VERZENIO projected market size for breast cancer @ VERZENIO Market Potential HR+/HER2- breast cancer is the most common subtype of breast cancer, defined by the presence of estrogen and progesterone hormone receptors but lacking HER2 overexpression. This form of breast cancer generally has a favorable prognosis and is primarily managed with hormone therapy to suppress hormone-driven tumor growth. According to DelveInsight's estimates, around 211,000 new cases of HR+/HER2− breast cancer were reported in the US in 2024. Over the past decade, endocrine therapy has remained the cornerstone of treatment, including for cases with visceral involvement. The current preferred approach involves combining endocrine therapy—using aromatase inhibitors or fulvestrant—with CDK4/6 inhibitors. The approval of CDK4/6 inhibitors has significantly transformed the treatment landscape for HR+/HER2− breast cancer. Currently, five selective CDK4/6 inhibitors— ENHERTU, DATROWAY, IBRANCE, KISQALI, and VERZENIO—are used in combination with endocrine therapy. In November 2023, the FDA approved TRUQAP (capivasertib) in combination with FASLODEX for patients with advanced HR+/HER2− breast cancer harboring specific biomarker alterations (PIK3CA, AKT1, or PTEN). The NCCN Guidelines have designated KISQALI as the only Category 1 Preferred CDK4/6 inhibitor for first-line treatment in combination with an aromatase inhibitor, strengthening its position in the U.S. market. This led to KISQALI recovering its lost market share, with its U.S. revenue contribution rebounding to 50%, following declines to 46% in 2020, 36% in 2021, and 38% in 2022. In January 2025, the FDA approved DATROWAY for patients with unresectable or metastatic HR+/HER2- breast cancer (IHC 0, IHC 1+, or IHC 2+/ISH-) who had previously received endocrine-based therapy and chemotherapy. Additionally, ENHERTU was approved for patients with unresectable or metastatic HR+, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer that had progressed after at least one prior endocrine therapy in the metastatic setting. Also, in January 2025, Roche reported positive topline results from its Phase III INAVO120 trial, assessing ITOVEBI in combination with IBRANCE and fulvestrant for patients with PIK3CA-mutated HR+/HER2−, endocrine-resistant, locally advanced, or metastatic breast cancer. Among the seven major markets, the US accounted for the largest market share in HR+/HER2− breast cancer, generating USD 7.5 billion in revenue in 2023. The market is expected to experience substantial growth from 2025 to 2034, driven by the introduction of novel therapeutic options. Discover more about the breast cancer market in detail @ Metastatic HR+/HER2- Breast Cancer Market Report Emerging Competitors of VERZENIO Some of the competing emerging key players in HR+/HER2- breast cancer market are, Merck (KEYTRUDA), Arvinas (ARV-471 (vepdegestrant)), Olema Pharmaceuticals (OP1250 (palazestrant)), Celcuity (Gedatolisib), Roche (Giredestrant (RG6171, GDC-9545); Inavolisib), AstraZeneca and Daiichi Sankyo (Datopotamab Deruxtecan (Dato-DXd)), AstraZeneca (Camizestrant (AZD9833); Capivasertib), Eli Lilly (LY3484356/Imlunestrant), Sermonix Pharmaceuticals (Lasofoxifene), Veru Pharma (Enobosarm), DualityBio/BioNtech (DB-1303), Evgen Pharma (SFX-01), Carrick Therapeutics (Samuraciclib (CT-7001)), EQRx/G1 Therapeutics (Lerociclib), Immutep (Eftilagimod Alpha (LAG-3lg/IMP321)), and others. To know more about the number of competing drugs in development, visit @ VERZENIO Market Positioning Compared to Other Drugs Key Milestones of VERZENIO In 2024, Phase III trials did not meet primary endpoints or were terminated for futility. Negative Phase III CYCLONE-2 results, in which VERZENIO added to abiraterone did not meet the primary endpoint of improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC). In December 2023, Eli Lilly and Company presented results from the MONARCH 3 clinical trial at the 2023 San Antonio Breast Cancer Symposium (SABCS). Results from MONARCH 3 show a numerical improvement in overall survival (OS) of 13.1 months for women with HR+, HER2- metastatic breast cancer treated with VERZENIO plus an aromatase inhibitor in the intent-to-treat population and 14.9 months for women with visceral disease. In March 2023, the US FDA approved an expanded indication for VERZENIO in combination with endocrine therapy for the adjuvant treatment of adult patients with HR+/HER2−, node-positive, early breast cancer (EBC) at a high risk of recurrence. This expanded adjuvant indication removes the Ki-67 score requirement for patient selection. In February 2022, the CHMP adopted a positive opinion recommending a change to the terms of the marketing authorization for the medicinal product VERZENIO. VERZENIO, in combination with endocrine therapy, is indicated for the adjuvant treatment of adult patients with HR+/HER2− negative, node-positive early breast cancer at high risk of recurrence. In October 2021, the US FDA approved VERZENIO, in combination with endocrine therapy (tamoxifen or an aromatase inhibitor), for the adjuvant treatment of adult patients with HR+/HER2−, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of ≥20% as determined by an FDA-approved test. Ki-67 is a marker of cellular proliferation. In September 2018, VERZENIO was approved in Europe for treating advanced HR+ breast cancer in women if the cancer has already spread to other parts of the body or is locally advanced. In September 2018, VERZENIO was approved for the treatment of patients with HR+/HER2− unresectable or recurrent breast cancer in combination with fulvestrant or an aromatase inhibitor (AI) in Japan. In February 2018, the US FDA approved VERZENIO in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for the treatment of postmenopausal women with HR+/HER2− advanced or metastatic breast cancer In September 2017, the US FDA approved VERZENIO in combination with an endocrine therapy to treat adult patients who have HR+/HER2− advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient's hormones (endocrine therapy). In October 2015, the US FDA granted Breakthrough Therapy Designation to abemaciclib for patients with refractory hormone-receptor-positive (HR+) advanced or metastatic breast cancer Discover how VERZENIO is shaping the breast cancer treatment landscape @ VERZENIO Breast Cancer VERZENIO Market Dynamics The oral administration of VERZENIO enhances patient convenience, while its expanded approval for the adjuvant treatment of adult patients with HR+/HER2- early breast cancer highlights its role as a differentiated CDK4/6 inhibitor in reducing the risk of recurrence. The rising prevalence of HR+/HER2- breast cancer is driving market demand for effective treatments like VERZENIO. Additionally, its demonstrated efficacy in combination with endocrine therapy and its ability to penetrate the central nervous system further strengthen its market position. Favorable reimbursement policies and increasing awareness among healthcare providers also contribute to its adoption. However, its adoption may be hindered by regulatory hurdles and potential side effects, including severe or life-threatening lung inflammation and serious liver problems. High treatment costs and access disparities in certain regions could also limit market penetration. Competition from other CDK4/6 inhibitors such as IBRANCE and KISQALI poses a challenge, along with concerns over long-term safety data. Additionally, the Phase III CYCLONE-2 trial failed to meet primary endpoints in mCRPC, which may impact its broader clinical prospects and investor confidence. Dive deeper to get more insight into VERZENIO's strengths & weaknesses relative to competitors @ VERZENIO Market Drug Report Table of Contents Related Reports CDK4/6 Inhibitor Market CDK4/6 Inhibitor Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key CDK4/6 inhibitor companies including Pfizer, Prelude Therapeutics, G1 Therapeutics, Pepper Bio, among others. Metastatic HR+/HER2− Breast Cancer Market Metastatic HR+/HER2− Breast Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key metastatic HR+/HER2− breast cancer companies including Pfizer, Novartis, Stemline Therapeutics, Olema Pharmaceuticals, Arvinas, Immutep, AstraZeneca, Roche, Genentech, Evexta Bio, EQRx, Sermonix Pharmaceuticals, Celcuity, Veru Pharma, Evgen Pharma, Eli Lilly, Biotheryx, among others. HR+/HER2− Breast Cancer Pipeline HR+/HER2− Breast Cancer Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key HR+/HER2− breast cancer companies, including Regor Therapeuics, Seagen Inc., CytomX Therapeutics, Taizhou EOC Pharma, Chia Tai Tianqing Pharmaceutical Group, AstraZeneca, Daiichi Sankyo, Inc., Tyme, Inc., Seagen Inc., Context Therapeutics, Eisai Inc., Shanghai Hengrui Pharmaceutical Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Kind Pharmaceuticals, Merus N.V., Atossa Therapeutics, Roche, among others. Breast Cancer Market Breast Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key breast cancer companies, including Veru, Sanofi, Roche, AstraZeneca, Eli Lilly, EQRx, Gilead, Sermonix Pharmaceuticals, Evgen Pharma, Tyme, Genentech, Daiichi Sankyo, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Phase 3Drug ApprovalClinical ResultBreakthrough TherapyASCO

11 Mar 2025

·endpts.com

Arvinas, Pfizer’s PROTAC data fall short of hype in breast cancer

Arvinas and Pfizer’s targeted protein degrader has not managed to distinguish itself from other, similar breast cancer drugs, according to pivotal data released Tuesday. Results of the Phase 3 VERITAC-2 trial show that vepdegestrant extended progression-free survival in patients with mutated estrogen receptor genes, but not in the overall population. Arvinas’ shares $ARVN fell as much as 40% pre-market. The readout of VERITAC-2 was widely regarded as the first big test of a proteolysis-targeting chimera (PROTAC) drug. The hope was that a PROTAC would work in all comers, an achievement that has so far eluded the similar drugs known as SERDs — or selective estrogen receptor degraders. The Phase 3 trial assessed vepdegestrant monotherapy as a second-line treatment, following CDK4/6 inhibitors and hormone therapy, for estrogen receptor-positive, HER2-negative metastatic breast cancer. Arvinas and Pfizer said that vepdegestrant demonstrated a “statistically significant and clinically meaningful” improvement in progression-free survival over the hormone therapy Faslodex in the mutant population. The results in this cohort exceeded the prespecified target of a 40% cut in the risk of progression or death, though the partners did not give the actual figure. Significance was not reached in the intent-to-treat population, strongly suggesting that vepdegestrant has little effect in patients without mutations in the ESR1 gene, which codes for one of the two main types of estrogen receptors. Overall survival data were not mature at the time of the analysis, the companies said, with less than a quarter of the required number of events having occurred. Overall survival will continue to be monitored as a key secondary endpoint. The companies intend to present more VERITAC-2 results at a medical meeting later this year. They will also seek approval for the product, but a broad label encompassing wild-type patients is unlikely to be granted. If vepdegestrant is approved solely in mutant patients it would be on level terms with the only approved SERD, Menarini’s Orserdu. Analysts from Leerink wrote in a Feb. 3 note that if VERITAC-2 had demonstrated that best-in-class activity for vepdegestrant in both the mutants and in all comers, Arvinas’s market value could have tripled. Pfizer licensed vepdegestrant from Arvinas in 2021 for $1 billion upfront . Estrogen receptor degraders are intended to be more potent than inhibitors. Inhibitors bind transiently, blocking the action of the receptor only for a limited time. In contrast, degraders essentially destroy their target protein by co-opting the cell’s natural disposal systems. PROTACs, like vepdegestrant, bind to both the estrogen receptor and to what’s called the E3 ubiquitin. That recruits ubiquitin molecules to the receptor-PROTAC complex, which tags it for destruction by the proteasome. The proteasome is a complex of enzymes involved in breaking down intracellular proteins. This approach is distinct from SERDs, such as Eli Lilly’s imlunestrant and AstraZeneca’s camizestrant , both of which have scored recent Phase 3 successes in ESR1-mutant patients but have not been shown to work in wild-type subjects. SERDs enable receptor degradation via a more passive mechanism. Editor’s note: This article was updated to add Arvinas’ latest stock move.

Phase 3Clinical Result

11 Mar 2025

·firstwordpharma.com

Mixed pivotal data for Pfizer, Arvinas' protein degrader in breast cancer

Hotly anticipated late-stage data for Pfizer and Arvinas' oral oestrogen receptor-degrader vepdegestrant (ARV-471) debuted on Tuesday, with positive results seen in breast cancer patients with an ESR1 mutation. However, the drug failed to demonstrate benefit in those without the mutation, sending Arvinas shares down as much as 50%.While a number of oral selective oestrogen receptor degraders (SERDs) have delivered similarly mixed data — such as Menarini's Orserdu (elacestrant) and Eli Lilly's imlunestrant — hopes were high for vepdegestrant in the broader population. UBS analysts recently said "we think the potential for success in ESR1 [wild type] patients is greater than appreciated" for vepdegestrant, partially due to the design of the VERITAC-2 study.The trial enrolled 624 patients with oestrogen receptor-positive, HER2-negative advanced or metastatic breast cancer whose disease progressed following prior treatment with CDK 4/6 inhibitors and endocrine therapy. Participants were randomised to receive once-daily vepdegestrant or fulvestrant.PFS exceeded targetTop-line results showed that in patients with an ESR1 mutation, vepdegestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to fulvestrant, meeting the trial's primary endpoint in this population. Pfizer and Arvinas noted that PFS exceeded the pre-specified target hazard ratio of 0.60 in this group.However, the companies said that in the wider trial population, which also included those with ESR1 wild type, the study failed to reach statistical significance on improvement in PFS.OS data immaturePfizer and Arvinas noted that less than a quarter of the required number of events have occurred for the overall survival (OS) analysis — a key secondary endpoint — with the study continuing in order to evaluate this goal."The first Phase III data readout for a PROTAC degrader represents a significant achievement and these data show that vepdegestrant has the potential to provide clinically meaningful outcomes for…patients with metastatic breast cancer whose tumours harbour [ESR1] mutations," remarked John Houston, CEO at Arvinas. The companies noted that the data will be shared with global regulatory authorities, and presented at a medical conference later this year. Meanwhile, the Phase III VERITAC-3 study investigating vepdegestrant in combination with Pfizer's CDK 4/6 inhibitor Ibrance (palbociclib) in the first-line setting is also ongoing.Back in 2021, Pfizer paid $650 million upfront for rights to co-develop vepdegestrant, which utilises Arvinas' PROTAC (PROteolysis TArgeting Chimera) protein degrader platform.The VERITAC-2 results Tuesday follow a positive Phase III readout for AstraZeneca's oral SERD candidate camizestrant last month, showing a significant PFS benefit when paired with a CDK4/6 inhibitor in first-line patients with HR+/HER2- advanced breast cancer whose tumours have an emergent ESR1 mutation. In a recent interview with FirstWord to discuss the SERENA-6 study, key opinion leader Azka Ali described the results as a win-win for both safety and efficacy, and would likely hasten the shift from aromatase inhibitors to oral SERDs in patients with ESR1 mutations. For the rest of that conversation, see – KOL Views Q&A: Battle for oral SERD supremacy in HR+ breast cancer boils down to efficacy.

Phase 3Clinical ResultClinical Trial Failure

100 Deals associated with Imlunestrant

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
ER-positive/HER2-negative Breast Cancer	NDA/BLA	Canada	Eli Lilly & Co.	01 Feb 2025
Liver Injury	Phase 1	United States	Eli Lilly & Co.	05 Jul 2022
Advanced breast cancer	Phase 1	United States	Eli Lilly & Co.	10 Dec 2019
Advanced breast cancer	Phase 1	Japan	Eli Lilly & Co.	10 Dec 2019
Advanced breast cancer	Phase 1	Australia	Eli Lilly & Co.	10 Dec 2019
Advanced breast cancer	Phase 1	Belgium	Eli Lilly & Co.	10 Dec 2019
Advanced breast cancer	Phase 1	France	Eli Lilly & Co.	10 Dec 2019
Advanced breast cancer	Phase 1	Spain	Eli Lilly & Co.	10 Dec 2019
Advanced breast cancer	Phase 1	Taiwan Province	Eli Lilly & Co.	10 Dec 2019
Endometrial Endometrioid Adenocarcinoma	Phase 1	United States	Eli Lilly & Co.	10 Dec 2019

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05509790 (Phase 1 study, AACR2025)	Phase 1	ER-positive/HER2-negative Breast Cancer ER positive	17	Imlunestrant 400 mg	coankumwqm(kyuroctlrs) = reported by ≥ 2 patients in the imlunestrant 200 mg cohort dbfoukchib (dpeyewtbbr ) View more	Positive	28 Apr 2025
				Imlunestrant 200 mg
NCT04975308 (EMBER-3, Pubmed \| N Engl J Med)	Phase 3	Advanced breast cancer	874	Imlunestrant	ilnovtnerc(xpgvicgojf) = kboosfrmps irosjsblmf (vcjtkidxie ) View more	Positive	27 Mar 2025
				Standard Therapy	ilnovtnerc(xpgvicgojf) = ckjjsmugtc irosjsblmf (vcjtkidxie ) View more
NCT04975308 (EMBER-3, Pubmed \| SABCS2024) Manual	Phase 3	Advanced breast cancer	874	Imlunestrant	zkejvndidy(fzhuvpbirx) = otkbsrfvcr esgcqpfcpo (gpjbgureya ) View more	Positive	11 Dec 2024
				Standard therapy	zkejvndidy(fzhuvpbirx) = gcftexcmod esgcqpfcpo (gpjbgureya ) View more
NCT04188548 (EMBER, Pubmed \| J Clin Oncol) Manual	Phase 1	ER-positive/HER2-negative Breast Cancer HER2 Negative \| Estrogen receptor	262	Imlunestrant monotherapy	wpdbbknkik(pbwitpcinb) = ghoamjmkie defssseavz (lohmmlktqm ) View more	Positive	06 Sep 2024
				Imlunestrant + abemaciclib	bqlrxitlfl(jukcfcigxa) = gqozttfdre ydrpvqakci (lrwzgieidc, 13.8 - NA)
NCT04188548 (EMBER, ASCO2024) Manual	Phase 1	ER-positive/HER2-positive Breast Cancer HER2 Positive	45	Imlunestrant + Trastuzumab	vgyxstjpof(qsetevxoub) = lixipgrpje mfezuivbdq (idocpsbsoi ) View more	Positive	24 May 2024
				Imlunestrant + Trastuzumab + Abemaciclib	vgyxstjpof(qsetevxoub) = gkcuqoggwt mfezuivbdq (idocpsbsoi ) View more
NCT04188548 (EMBER, ASCO2024) Manual	Phase 1	Endometrial Carcinoma ER+	72	Imlunestrant 400mg po daily	hagkhckmks(txefpqokxa) = pfivqxdbhi ifyippswfn (pedxxliivc ) View more	Positive	24 May 2024
				Imlunestrant 400mg po daily + Abemaciclib 150mg po twice daily	hagkhckmks(txefpqokxa) = wpshroebgq ifyippswfn (pedxxliivc ) View more
NCT04188548 (EMBER, ESMO_BC2024) Manual	Phase 1	ER-positive/HER2-negative Breast Cancer HER2 Negative \| ER Positive	109	Imlunestrant	klzxsnikwb(aobvtsuwdk) = bxbiaijzgp ptwqwfdrst (ivnznzbpna, 32 - 52)	Negative	14 May 2024
				Imlunestrant (without baseline detectable ctDNA)	klzxsnikwb(aobvtsuwdk) = smsapjtiny ptwqwfdrst (ivnznzbpna )
EMBER (Biospace) Manual	Phase 1	ER-positive/HER2-negative Breast Cancer Last line ER Positive \| HER2 Negative	-	Imlunestrant + Verzenio + AI	reftopvxuo(hksstytixh) = cungictbhn iaecxnskbd (vbbagqkxza ) View more	Positive	05 Dec 2023
				Imlunestrant + Verzenio	reftopvxuo(hksstytixh) = jnbplkhrny iaecxnskbd (vbbagqkxza ) View more
NCT04188548 (EMBER, ESMO 12023 \| ESMO 22023) Manual	Phase 1	ER-positive/HER2-negative Breast Cancer HER2 Negative \| ER Positive	177	Imlunestrant	luyclwgowf(xcuaggjjkh) = Imlunestrant monotherapy (Nausea 40%,Fatigue 32%,Diarrhea 31%);Imlunestrant + everolimus ( Diarrhea 55%,Fatigue 45%, AST increase 38%);Imlunestrant + alpelisib (Diarrhea 86%,Rash 67 %,Hyperglycaemia 62%) ewmvgkgxpr (lslaqonmse )	Positive	22 Oct 2023
				Imlunestrant + everolimus
NCT04188548 (EMBER, ASCO2022)	Phase 1	Endometrial Endometrioid Adenocarcinoma \| Estrogen receptor positive breast cancer	138	Imlunestrant	lnrfbrheoq(rfezvflkhs) = zhklbyufwp bligmlbrln (qhpbyuzwpq ) View more	-	02 Jun 2022

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