A Multiregional, Randomized, Double-Blinded, Placebo-Controlled Phase 3 Study of Lerociclib With Letrozole, Versus Placebo in Combination With Letrozole, in Participants With Advanced/Metastatic or Recurrent, Grade 1 or Grade 2 Endometrioid Endometrial Carcinoma

This is a randomized, double-blinded, placebo-controlled Phase 3 clinical trial to compare the combination of lerociclib (administered at 150 mg twice a day (BID) with letrozole (administered at 2.5 mg once a day (QD) to that of placebo with letrozole (2.5 mg QD) in female participants with Grade 1 or Grade 2 (ie, low-grade histology) endometrioid endometrial cancer (EC) and advanced/metastatic or recurrent disease.
The study population will consist of female participants with endometrioid EC who are treatment-naïve in the advanced/metastatic setting (ie, the first-line [1L] population). Participants may have received prior adjuvant chemotherapy/chemoradiation for localized disease if the adjuvant therapy was administered ≥ 6 months prior. All participants must also be naïve to prior endocrine therapy for EC, and confirmed as medically postmenopausal to be eligible.
The study will comprise a Screening Period of up to 28 days in duration; a Study Treatment Phase; a Safety Follow-up Period spanning the time of study treatment discontinuation-including discontinuation due to confirmed disease progression, as applicable-through 28 days after the participant's last dose of any study intervention or the start of subsequent anticancer therapy (whichever occurs first); and a Survival Follow-up Period that will continue until the participant's death or until at least 50% of all study participants have died (whichever occurs first).
While receiving their randomized assigned study treatment, participants will undergo imaging assessments via computed tomography (CT) of the chest/abdomen/pelvis with contrast- or, if CT is medically contraindicated (eg, due to iodine allergy), via magnetic resonance imaging (MRI) with gadolinium-every 8 weeks for the first 12 months and then every 12 weeks thereafter.

开始日期2023-04-18

申办/合作机构

EQRx International, Inc.

[+2]

NCT05860582

/ Completed临床1期

A Study of [14C]GB491 on Mass Balance and Biotransformation in Chinese Male Healthy Subjects

This is an open-label, single-center study to evaluate the mass-balance and pharmacokinetics of GB491 in 4-8 healthy male subjects receiving a single oral 150mg dose of GB491 containing approximately 50 uCi of [14C]GB491. This study will help understand how the drug appears in the blood, urine, and feces after it is administered.
In addition, this study will also evaluate the safety of a single dose of [14C]GB491 when given to healthy subjects.

开始日期2022-09-14

申办/合作机构

嘉和生物药业有限公司

NCT05851014

/ Recruiting临床3期

A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of GB491 in Combination With Letrozole in Subjects With HR Positive and HER2 Negative Locally Advanced or Metastatic Breast Cancer Who Have Not Previously Received Systemic Therapy in This Disease Setting

The main purpose of this study is to evaluate the efficacy and safety of GB491 combined with Letrozole versus placebo combined with Letrozole in the treatment of HR+/HER2- locally advanced or metastatic breast cancer without prior systemic antitumor therapy

开始日期2022-01-14

申办/合作机构

嘉和生物药业有限公司

100 项与盐酸来罗西利相关的临床结果

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100 项与盐酸来罗西利相关的转化医学

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100 项与盐酸来罗西利相关的专利（医药）

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项与盐酸来罗西利相关的文献（医药）

2025-01-23·JOURNAL OF MEDICINAL CHEMISTRY

Elucidating Binding Selectivity in Cyclin-Dependent Kinases 4, 6, and 9: Development of Highly Potent and Selective CDK4/9 Inhibitors

Article

作者: Xing, Yajie ; Cao, Qixiong ; Chen, Jiean ; Wang, Rui ; Pan, Shuqiong ; Yang, Qianqian ; Feng, Meixi ; He, Zhipeng ; Huang, Yong ; Jiang, Chenran ; Lian, Chenshan ; Kang, Wei ; Yang, Jinglei ; Liu, Zhihong ; Wu, Yun-Dong ; Yin, Feng ; Ye, Yuxin ; Zhao, Juan ; Song, Chunli

CDK4/6 inhibitors are effective in treating HR⁺/HER2^- breast cancer but face limitations due to therapeutic resistance and hematological toxicity, particularly from strong CDK6 inhibition. To address these challenges, designing selective inhibitors targeting specific cyclin-dependent kinases (CDK) members could offer clinical advantages and broaden CDK inhibitor indications. However, the highly conserved binding pockets of CDKs complicate selective targeting. This study leverages in silico modeling and structural analysis of cocrystal data to identify subtle differences in key CDK binding pockets. Notably, a sequence difference in the αD-helix motif between CDK4 and CDK6 provides a targetable "sweet spot" for selectivity. By incorporating a 1,4-trans-cyclohexanediamine side chain, we designed molecules that favor interactions with CDK4 over CDK6 and explored potential dual CDK4/9 inhibition. This approach yielded a lead compound with distinct in vitro selectivity and promising in vivo pharmacokinetics, offering valuable insights for the development of selective next-generation CDK inhibitors.

2024-03-01·Journal of pediatric surgery

CDK4/6 Inhibition With Lerociclib is a Potential Therapeutic Strategy for the Treatment of Pediatric Sarcomas

Article

作者: Stewart, Jerry E ; Horton, Sara C ; Aye, Jamie ; Bownes, Laura V ; Yoon, Karina J ; Beierle, Andee M ; Beierle, Elizabeth A ; Quinn, Colin H ; Julson, Janet R

BACKGROUND:

Sarcomas are a heterogenous collection of bone and soft tissue tumors. The heterogeneity of these tumors makes it difficult to standardize treatment. CDK 4/6 inhibitors are a family of targeted agents which limit cell cycle progression and have been shown to be upregulated in sarcomas. In the current preclinical study, we evaluated the effects of lerociclib, a CDK4/6 inhibitor, on pediatric sarcomas in vitro and in 3D bioprinted tumors.

METHODS:

The effects of lerociclib on viability, proliferation, cell cycle, motility, and stemness were assessed in established sarcoma cell lines, U-2 OS and MG-63, as well as sarcoma patient-derived xenografts (PDXs). 3D printed biotumors of each of the U-2 OS, MG-63, and COA79 cells were utilized to study the effects of lerociclib on tumor growth ex vivo.

RESULTS:

CDK 4/6, as well as the intermediaries retinoblastoma protein (Rb) and phosphorylated Rb were identified as targets in the four sarcoma cell lines. Lerociclib treatment induced cell cycle arrest, decreased proliferation, motility, and stemness of sarcoma cells. Treatment with lerociclib decreased sarcoma cell viability in both traditional 2D culture as well as 3D bioprinted microtumors.

CONCLUSIONS:

Inhibition of CDK 4/6 activity with lerociclib was efficacious in traditional 2D sarcoma cell culture as well as in 3D bioprints. Lerociclib holds promise and warrants further investigation as a novel therapeutic strategy for management of these heterogenous groups of tumors.

2020-04-01·Breast cancer research and treatment2区 · 医学

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer

2区 · 医学

Article

作者: Bae, Yeeun ; Desautels, Taylor K ; Baker, Jennifer G ; Wardell, Suzanne E ; Gutgesell, Lauren M ; Baldi, Robert ; Norris, John D ; Strum, Jay C ; Thompson, Delita A ; Andreano, Kaitlyn J ; Tonetti, Debra A ; Xiong, Rui ; Bisi, John E ; Zhao, Jiong ; Chao, Christina A ; Heetderks, Kendall A ; Thatcher, Gregory R J ; Sorrentino, Jessica A

Abstract:

Purpose:

The combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here, we report the identification of G1T48, a novel orally bioavailable, non-steroidal small molecule antagonist of ER.

Methods:

The pharmacological effects and the antineoplastic mechanism of action of G1T48 on tumors was evaluated using human breast cancer cells (in vitro) and xenograft efficacy models (in vivo).

Results:

G1T48 is a potent and efficacious inhibitor of estrogen-mediated transcription and proliferation in ER-positive breast cancer cells, similar to the pure antiestrogen fulvestrant. In addition, G1T48 can effectively suppress ER activity in multiple models of endocrine therapy resistance including those harboring ER mutations and growth factor activation. In vivo, G1T48 has robust antitumor activity in a model of estrogen-dependent breast cancer (MCF7) and significantly inhibited the growth of tamoxifen-resistant (TamR), long-term estrogen-deprived (LTED) and patient-derived xenograft tumors with an increased response being observed with the combination of G1T48 and the CDK4/6 inhibitor lerociclib.

Conclusions:

These data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.

项与盐酸来罗西利相关的新闻（医药）

2025-03-13

·PRNewswire

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

临床3期上市批准临床结果突破性疗法ASCO会议

2025-02-17

·ioncology

徐兵河院士：来罗西利顺势而上，开创HR+/HER2-晚期乳腺癌治疗新篇章

点击蓝字，关注我们编者按：在乳腺癌治疗领域，CDK4/6抑制剂（CDK4/6i）的问世为HR+/HER2-晚期乳腺癌患者带来了突破性的进展。然而，现有CDK4/6抑制剂在疗效和安全性等方面仍有一定可提升空间，尤其是在血液毒性、胃肠道毒性和肝毒性等方面。近年来，国内外专家学者在乳腺癌治疗领域进行了积极探索并取得了显著突破，由中国医学科学院肿瘤医院徐兵河院士牵头的Ⅲ期LEONARDA-1研究成果的公布，不仅展示了CDK4/6抑制剂来罗西利（Lerociclib）的卓越疗效和安全性，更标志着中国在乳腺癌治疗领域的创新能力和国际影响力的提升。本文将从HR+/HER2-乳腺癌患者CDK4/6抑制剂的应用现状、来罗西利的作用机制、LEONARDA-1研究的突破性进展等方面，邀请徐兵河院士深入介绍来罗西利在乳腺癌治疗中的独特价值及治疗意义。 01 HR+/HER2-乳腺癌治疗现状与挑战：CDK4/6抑制剂临床应用与安全性考量《肿瘤瞭望》：在乳腺癌患者治疗中，CDK4/6抑制剂的作用日益显著。请您为我们介绍下当前HR+晚期乳腺癌中CDK4/6抑制剂的地位及应用现状，并分享下开发新型原研CDK4/6抑制剂的必要性？徐兵河院士：乳腺癌是女性最常见的恶性肿瘤之一，GLOBALCAN数据显示，2022年中国乳腺癌新发病例数为35.72万例，中位发病年龄为51岁[1]。在新发病例中，约3%～10%的患者在确诊时即有远处转移[2]，而在早期患者中，约30%最终会发展为晚期乳腺癌[3]。晚期乳腺癌患者的预后相对较差，既往的一些报道表明，5年生存率仅为20%，中位总生存时间为2～3年[4]。在乳腺癌患者中，50%～70%的患者为HR+/HER2-亚型[5]。近年来，CDK4/6抑制剂的获批及应用改变了HR+/HER2-晚期乳腺癌的临床治疗模式，患者生存也获得突破性改善。作为一类重要的内分泌靶向治疗药物，CDK4/6抑制剂通过抑制细胞周期蛋白依赖性激酶4和6，阻断肿瘤细胞从G1期进入S期，从而抑制肿瘤细胞的增殖。目前，CDK4/6抑制剂+内分泌治疗（ET）已成为HR+/HER2-晚期乳腺癌患者的一线标准治疗，显著延长了患者的无进展生存期（PFS）和总生存期（OS）。然而，尽管CDK4/6抑制剂通常情况下的耐受性良好，但其血液毒性、胃肠道毒性、肝功能异常等不良反应也时有发生。这些不良反应不仅影响患者的生活质量，还可能导致治疗中断或剂量调整，最终影响疗效。因此，开发更加高效、低毒的新型CDK4/6抑制剂成为当前乳腺癌治疗领域的重要研究方向。 02 来罗西利展现持续抗肿瘤作用，是强效且更安全的CDK4/6抑制剂《肿瘤瞭望》：能否为我们介绍下来罗西利在作用机制上有哪些特征和优势？徐兵河院士：来罗西利是一种强效、选择性的口服CDK4/6抑制剂，对CDK4/cyclin D1和CDK6/cyclin D3具有高度效力（IC50分别为1 nM和2 nM），较其他CDK4/6i具有更强抑制作用[6-7]，但对CDK9/cyclin T的效力适中（IC50为28 nM）。体外研究表明，来罗西利可精确产生G1期阻滞效应，并抑制Rb和癌细胞增殖的磷酸化[6]。在乳腺癌、非小细胞肺癌和前列腺癌的异种移植模型中，每日口服来罗西利可显著抑制肿瘤生长[6,8]。此外，来罗西利的人体表观分布容积显著高于其他药物，具有最大程度的组织分布，并在肿瘤组织高度富集，肿瘤组织暴露是血浆暴露的18倍。给药24小时后，肿瘤组织药物浓度是血浆药物浓度的100倍以上，给药48小时后，肿瘤组织药物浓度可以高达约65 ng/mL，而血药浓度已无法检出[9]，这种高效的肿瘤组织分布使其在抑瘤作用上更具优势。来罗西利在药物分子结构上的改进，使其临床血液学和胃肠道毒性均更低。一项针对HR+/HER2−晚期乳腺癌患者的Ⅰ/Ⅱ期研究结果显示，持续使用来罗西利联合氟维司群显示出良好的安全性特征，4级中性粒细胞减少症、胃肠道毒性、疲劳、口腔炎和脱发的发生率较低[6]。药代动力学特征及安全性允许其连续给药（无治疗假期），实现了持续的靶点抑制和抗肿瘤作用，这使得患者能够更好地耐受长期治疗，提高了治疗的依从性和生活质量。 03 LEONARDA-1是更符合我国临床现状的研究，挑战更高的治疗难度《肿瘤瞭望》：日前，您牵头的针对中国患者群体的Ⅲ期LEONARDA-1研究，其结果已在《自然-通讯》上发表，您如何评价该研究结果，特别是来罗西利联合氟维司群治疗所展现出的疗效和安全性特征？徐兵河院士：LEONARDA-1是一项我们牵头的随机、双盲、Ⅲ期研究。纳入了既往接受过内分泌治疗复发或进展的HR+/HER2-局部晚期或转移性乳腺癌患者，评估了来罗西利联合氟维司群在治疗内分泌耐药的HR+/HER2-晚期乳腺癌患者中的疗效和安全性。该研究共纳入了275例具有各种高危因素的患者，包括：肝转移（40.9%）、原发耐药（24.8%）、转移器官数目≥4（26.3%）以及既往复发转移接受一线化疗（29.2%）等人群，比例接近临床治疗现状。近期，该研究结果在《自然-通讯》（Nature Communications）上进行了发表[10]。研究结果显示，来罗西利联合氟维司群显著延长了患者的无进展生存期（PFS）。研究者评估的中位PFS（主要终点）为11.07个月，较安慰剂组的5.49个月延长了一倍多，疾病进展或死亡风险降低了55%（HR 0.451，P＜0.0001）。独立评审委员会（BICR）评估的PFS（次要终点）也显示了类似的改善，疾病进展或死亡风险降低了65%（HR 0.353，P＜0.0001）。此外，来罗西利组的客观缓解率（ORR）和临床获益率（CBR）也显著高于安慰剂组，（研究者评估的ORR和CBR）分别为23.4% vs 8.7%和48.2% vs 24.6%。预先设定的PFS亚组分析显示，不同患者亚组中的结果与整体研究结果一致，包括年龄（＜65岁或≥65岁）、是否绝经、激素受体状态、既往内分泌治疗耐药情况、既往内分泌治疗目的、既往复发/转移期是否接受过化疗、是否内脏转移、是否肝转移、是否存在可测量病灶以及基线美国东部肿瘤协作组（ECOG）体能状态等。PFS亚组分析结果还显示，对于肝转移、原发耐药、转移器官数目≥4、既往复发/转移期接受过化疗等难治人群而言，来罗西利+氟维司群大幅度提高了PFS，显著降低了疾病进展及死亡风险。 CDK4/6抑制剂的安全性在血液学毒性、胃肠道症状和Q-T间期延长等方面有所不同。如阿贝西利与较少的血液学毒性和较多的胃肠道症状相关；哌柏西利和达尔西利可能有较高比例的3级或4级中性粒细胞减少；瑞波西利有可能延长Q-T间期。在安全性方面，来罗西利的表现同样令人瞩目。LEONARDA-1研究中，来罗西利治疗相关的最常见3级或4级不良事件是血液学毒性（主要是中性粒细胞减少和白细胞减少）。来罗西利组3或4级中性粒细胞减少的发生率为46.7%，其中4级发生率较低（5.1%），无发热中性粒细胞减少的报告。通过中断/减量和/或使用粒细胞集落刺激因子（G-CSF），中性粒细胞减少症得到有效管理，没有患者因中性粒细胞减少症而停止治疗。此外，在接受来罗西利治疗的患者中，包括腹泻、恶心和呕吐在内的胃肠道毒性（阿贝西利和瑞波西利的常见不良反应）发生率不到20%，并且未报告3级或4级腹泻。这些研究结果提示，尽管跨试验比较具有挑战性并可能存在偏倚，但来罗西利可能在胃肠道和血液学毒性方面有总体优势[10]。LEONARDA-1研究中，来罗西利组因不良事件终止治疗的比例仅为0.7%，低于其他CDK4/6i相关研究既往报道的数据（2.5%-15.9%）[10-14]。 04 LEONARDA-1研究结果公布展示中国科研创新与国际影响力《肿瘤瞭望》：LEONARDA-1研究结果的公布，让我们看到了新的CDK4/6抑制剂来罗西利针对中国患者的疗效，您认为它如何展示了中国科研人员在乳腺癌治疗领域的创新能力和国际影响力？徐兵河院士：作为首个针对中国患者群体的新的CDK4/6抑制剂研究，LEONARDA-1研究不仅证实了来罗西利在中国患者中的疗效和安全性，还展示了我国学者在临床试验设计、数据分析和结果解读方面的卓越能力。2023年ASCO大会上，我们报道了LEONARDA-1研究的初步结果[15]。今年1月，随着该研究结果成功发表在国际著名期刊《自然-通讯》上，进一步展现了中国学者在乳腺癌治疗领域的科研创新能力和国际影响力，有望提升我国在乳腺癌治疗领域的国际话语权。来罗西利的优异表现不仅为HR+/HER2-晚期乳腺癌患者提供了新的治疗选择，也为全球乳腺癌治疗领域的发展贡献了中国智慧和中国方案。来罗西利的研发和LEONARDA-1研究的成功，标志着中国在乳腺癌治疗领域的创新突破。随着更多临床数据的积累和应用的推广，来罗西利有望成为HR+/HER2-晚期乳腺癌患者的重要治疗选择，进一步延长患者的生存时间并提高患者的生活质量。参考文献：（滑动查看） 1、Bray, Freddie et al. “Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.” CA: a cancer journal for clinicians vol. 74,3 (2024): 229-263. doi:10.3322/caac.21834 2、Chang, Jenny et al. “Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor.” Cancer vol. 97,3 (2003): 545-53. doi:10.1002/cncr.11083 3、Gonzalez-Angulo, Ana Maria et al. “Overview of resistance to systemic therapy in patients with breast cancer.” Advances in experimental medicine and biology vol. 608 (2007): 1-22. doi:10.1007/978-0-387-74039-3_1 4、国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. CDK4/6抑制剂治疗激素受体阳性人表皮生长因子受体2阴性乳腺癌临床应用专家共识(2023版)[J]. 中华肿瘤杂志, 2023, 45(12):1003-1017.DOI: 10.3760/cma.j.cn112152-20230428-00188. 5、国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会乳腺癌专业委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. 中国晚期乳腺癌规范诊疗指南(2022版)[J]. 中华肿瘤杂志, 2022, 44(12):1262-1287.DOI: 10.3760/cma.j.cn112152-20221007-00680. 6、Bisi, John E et al. “Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors.” Oncotarget vol. 8,26 (2017): 42343-42358. doi:10.18632/oncotarget.16216 7、Sammons, Sarah L et al. “HR+, HER2- Advanced Breast Cancer and CDK4/6 Inhibitors: Mode of Action, Clinical Activity, and Safety Profiles.” Current cancer drug targets vol. 17,7 (2017): 637-649. doi:10.2174/1568009617666170330120452 8、Stice, J. P. et al. CDK4/6 therapeutic intervention and viable alternative to taxanes in CRPC. Mol. Cancer Res. 15, 660–669 (2017). 9、Bulat, I. et al. Lerociclib (G1T38), a continuously dosed oral CDK4/6 inhibitor, with fulvestrant in HR+/HER2-advanced breast cancer patients: Updated phase II results and dose selection. Ann. Oncol. 31, S380–S380 (2020). 10、Xu, Binghe et al. “Lerociclib plus fulvestrant in patients with HR+/HER2- locally advanced or metastatic breast cancer who have progressed on prior endocrine therapy: LEONARDA-1 a phase III randomized trial.” Nature communications vol. 16,1 716. 16 Jan. 2025, doi:10.1038/s41467-025-56096-2 11、Sledge, George W Jr et al. “MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy.” Journal of clinical oncology : official journal of the American Society of Clinical Oncology vol. 35,25 (2017): 2875-2884. doi:10.1200/JCO.2017.73.7585 12、Cristofanilli, Massimo et al. “Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.” The Lancet. Oncology vol. 17,4 (2016): 425-439. doi:10.1016/S1470-2045(15)00613-0 13、Slamon, Dennis J et al. “Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3.” Journal of clinical oncology : official journal of the American Society of Clinical Oncology vol. 36,24 (2018): 2465-2472. doi:10.1200/JCO.2018.78.9909 14、Xu, Binghe et al. “Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial.” Nature medicine vol. 27,11 (2021): 1904-1909. doi:10.1038/s41591-021-01562-9 15、https://dailynews.ascopubs.org/do/lerociclib-fulvestrant-may-reduce-risk-disease-progression-advanced-hr-positive-her2 徐兵河院士中国工程院院士中国医学科学院学部委员北京协和医学院长聘教授国家抗肿瘤新药临床研究中心主任中国抗癌协会乳腺癌专业委员会和肿瘤药物临床研究专业委员会名誉主任委员北京肿瘤学会和北京乳腺病防治学会理事长相关推荐 1 开年喜报！Nature子刊发表徐兵河院士牵头的Ⅲ期LEONARDA-1研究（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

临床3期CSCO会议临床结果

2025-01-26

·肿瘤界

Nat Commun丨徐兵河院士团队：LEONARDA-1研究完整数据发表

点击蓝字关注我们 Lerociclib（GB491）是一种高选择性口服CDK4/6抑制剂，在之前的ph1/2临床试验中显示出抗肿瘤活性以及差异化的安全性和耐受性。 2025年1月16日，中国医学科学院肿瘤医院徐兵河院士团队在Nature communications上在线发表题为“Lerociclib plus fulvestrant in patients with HR+/HER2− locally advanced or metastatic breast cancer who have progressed on prior endocrine therapy: LEONARDA-1 a phase III randomized trial”的研究论文。LEONARDA-1是一项随机、双盲、III期研究，旨在评估lerociclib在既往内分泌治疗复发或进展的HR+/HER2−局部晚期或转移性乳腺癌患者中的疗效和安全性。乳腺癌是最常被诊断出的癌症，也是全球女性癌症相关死亡的最主要因素。在被诊断为晚期乳腺癌患者中，超过70%表现为激素受体阳性（HR+）疾病，使他们符合接受内分泌治疗（ET）的条件。然而，由于耐药性的发生，这种疗法的疗效随着时间的推移而降低。ET抵抗和促进致癌生长的机制在细胞周期内相互交叉。细胞周期蛋白依赖性激酶4和6 （CDK4/6）是在细胞周期进程中起关键作用的酶，并参与调节细胞周期从G1期向S期的过渡，DNA合成在S期发生。CDK4/6抑制剂通过阻断CDK4和CDK6的活性发挥作用，从而阻止视网膜母细胞瘤蛋白（Rb）的磷酸化。这反过来又导致细胞周期从G1期进展到S期的抑制。多项3期临床试验评估了CDK4/6抑制剂联合氟维司群治疗HR+、HER2阴性（HER2-）内分泌耐药的疗效。虽然 CDK4/6 抑制剂通常可以耐受，但它们通常与血液学毒性、胃肠道毒性、肝功能异常、静脉血栓栓塞和皮肤不良反应等不良反应有关。在维持治疗效果的同时管理这些副作用是一项持续的挑战，这些副作用限制了 CDK4/6 抑制剂在一些乳腺癌患者中的临床应用。 Lerociclib（GB491）是一种强效且选择性的口服CDK4/6抑制剂，对CDK4/细胞周期蛋白D1和CDK6/细胞周期蛋白D3具有强效作用（IC50分别为1 nM和2 nM），但对CDK9/细胞周期蛋白T具有中等效力（IC50为28 nM）。体外研究表明，lerociclib产生精确的G1期阻滞，并抑制Rb的磷酸化和癌细胞增殖。在乳腺癌、非小细胞肺癌和前列腺癌的异种移植模型中，每日口服lerociclib对肿瘤生长产生了显著、持久和剂量依赖性抑制。在一项对HR+/HER2 - 晚期乳腺患者进行的1/2期研究中，连续给予lerociclib联合氟维司群显示出不同的安全性特征，4级中性粒细胞减少、胃肠道毒性、疲劳、口腔炎和脱发的发生率低。此外，疗效数据与氟维司群联合已批准的CDK4/6抑制剂的疗效数据一致。本文展示了LEONARDA-1研究（ClinicalTrials.gov：NCT05054751）的结果，这是一项 III 期试验，评估了lerociclib+氟维司群与安慰剂+氟维司群在HR+/HER2−内分泌耐药晚期乳腺癌中的疗效和安全性。研究设计共计275例患者以1∶1的比例被随机分组，分别接受lerociclib（137例患者，每日2次，每次150 mg）或安慰剂（138例患者）联合氟维司群治疗。研究者判定的无进展生存期（PFS）在lerociclib组显著优于安慰剂组（11.07个月vs 5.49个月；风险比为0.451，95%CI: 0.311~0.656，P=0.000016），均达到预设的主要终点。次要研究终点包括PFS （BICR）、客观缓解率（ORR）、缓解持续时间（DOR）、疾病控制率（DCR）、临床获益率（CBR）、总生存期（OS）、安全性和耐受性以及药代动力学特征。DOR未报告，OS数据在数据截止时不成熟，但报告了非计划的特别分析。这些研究结果支持将lerociclib+氟维司群作为HR+/HER2 -内分泌耐药晚期乳腺癌患者的治疗方案。推荐阅读 ● STTT(IF=40.8)丨徐兵河院士/马飞教授团队最新研究发表 ● BMC Cancer | 徐兵河院士/李俏教授团队研究揭示小分子TKI联合节拍化疗又添新数据 ● Nature Medicine | 徐兵河院士/马飞教授团队牵头的PD-1单抗用于晚期乳腺癌的最佳联合策略研究发表声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。来源：iNature 排版：lagertha 校对：松月

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100 项与盐酸来罗西利相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11455	-	-	DB16218

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
HR阳性/HER2阴性乳腺癌	申请上市	中国	嘉和生物药业有限公司	2023-03-28
HR阳性/HER2阴性乳腺癌	申请上市	中国	G1 Therapeutics, Inc.	2023-03-28
子宫内膜样腺癌	临床3期	-	EQRx International, Inc.	2023-04-18
复发性子宫内膜癌	临床3期	-	EQRx International, Inc.	2023-04-18
HR阳性HER2阴性淋巴结阳性乳腺癌	临床3期	中国	嘉和生物药业有限公司	2022-01-14
局部晚期乳腺癌	临床3期	中国	嘉和生物药业有限公司	2021-09-10
晚期乳腺癌	临床2期	美国	EQRx, Inc.	2021-12-21
晚期乳腺癌	临床2期	比利时	EQRx, Inc.	2021-12-21
晚期乳腺癌	临床2期	格鲁吉亚	EQRx, Inc.	2021-12-21
晚期乳腺癌	临床2期	意大利	EQRx, Inc.	2021-12-21

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05054751 (LEONARDA-1, Pubmed \| Nat Commun) 人工标引	临床3期	HR阳性/HER2阴性乳腺癌 Hormone Receptor Positive \| HER2 Negative	275	Lerociclib 150 mg twice daily + Fulvestrant	艱積餘鏇廠壓襯積顧遞(製觸糧鏇簾範醖獵夢築) = 鬱簾積構膚膚構淵醖蓋鑰鹹廠膚遞廠網襯襯網 (積網構繭夢願鬱觸構選, 9.23 ~ NR) 更多	积极	2025-01-16
				Placebo + Fulvestrant	艱積餘鏇廠壓襯積顧遞(製觸糧鏇簾範醖獵夢築) = 醖廠範衊選選選壓齋廠鑰鹹廠膚遞廠網襯襯網 (積網構繭夢願鬱觸構選, 3.81 ~ 7.36) 更多
CTR20212139 \| NCT05851014 (LEONARDA-2, ASCO2024) 人工标引	临床3期	HR阳性/HER2阴性乳腺癌一线 HER2 Negative \| Hormone Receptor Positive	279	Lerociclib + Letrozole	鏇衊壓襯艱繭廠艱廠積(膚夢齋範鑰製餘蓋願鏇) = 鏇蓋夢獵獵築壓夢鹽網憲壓蓋鑰壓構鑰餘艱衊 (壓遞廠憲願餘窪範網淵 ) 更多	积极	2024-05-24
				Placebo + Letrozole	鏇衊壓襯艱繭廠艱廠積(膚夢齋範鑰製餘蓋願鏇) = 齋廠鑰範繭蓋獵獵鏇壓憲壓蓋鑰壓構鑰餘艱衊 (壓遞廠憲願餘窪範網淵 ) 更多
NCT03455829 (CTgov)	临床1/2期	转移性非小细胞肺癌 \| EGFR突变的非小细胞肺癌	30	Lerociclib (Part 1: Cohort 1 Lerociclib at 200 mg QD)	廠餘鏇糧選積顧膚鏇鏇 = 觸顧膚製製夢觸蓋夢範膚醖廠廠鹹觸餘選醖顧 (膚遞鏇構艱鏇蓋鬱壓繭, 鏇襯顧獵鬱糧積鏇夢衊 ~ 鑰築獵顧膚構獵願鏇窪) 更多	-	2023-05-01
				Lerociclib (Part 1: Cohort 2 Lerociclib at 300 mg QD)	廠餘鏇糧選積顧膚鏇鏇 = 鏇鑰顧艱觸淵鹽鏇顧壓膚醖廠廠鹹觸餘選醖顧 (膚遞鏇構艱鏇蓋鬱壓繭, 膚鏇顧鹽襯蓋廠艱淵築 ~ 廠餘齋淵膚簾憲積範醖) 更多
NCT02983071 (ESMO2020) 人工标引	临床2期	乳腺癌	110	fulvestrant+Lerociclib (200–650 mg once daily and 100–250 mg twice daily (BID))	構壓艱繭鬱壓簾壓窪壓(窪構膚鬱構艱鹽艱艱淵) = neutropenia(30%) 簾醖鹽顧簾鹹積膚範淵 (齋糧積廠鹹膚膚築糧壓 ) 更多	积极	2020-09-17
				fulvestrant+Lerociclib (150 mg BID)
NCT02983071 (ASCO 12018 \| ASCO 22018) 人工标引	临床1期	乳腺癌	24	fulvestrant+G1T38	遞齋夢廠夢衊憲餘繭選(遞製築觸繭構憲觸衊築) = cytopenias and GI AEs 鬱選鹹網鹹鏇顧餘製積 (鹽鏇簾襯鏇顧餘齋憲築 ) 更多	积极	2018-06-02