A phase III, randomized, open-label study evaluating efficacy and safety of Giredestrant compared with Fulvestrant, both combined with a CDK4/6 inhibitor, in patients with estrogen receptor-positive, HER2-negative advanced breast cancer with resistance to prior adjuvant endocrine therapy - PionERA

开始日期2024-05-15

申办/合作机构

F. Hoffmann-La Roche Ltd.

[+1]

NCT05708235

/ Active, not recruiting临床2期

A Proof of Concept Study to Evaluate Treatments' Efficacy by Monitoring Minimal Residual Disease Using ctDNA in HR-positive/HER2-negative Early Breast Cancer Population

This trial is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment study involving the periodic collection and analysis of blood samples from patients with HR-positive/HER2-negative early-stage BC at higher risk of relapse, who have undergone surgery within the previous five years, with no evidence of locoregional, contralateral, or distant disease.
The study design is composed by an initial pre-screening phase, a molecular follow-up phase (ctDNA surveillance phase), and an interventional therapeutic phase (treatment phase).
After informed consent is obtained, a total of1,260 eligible patients will enter a ctDNA surveillance in which primary tumor tissue and matched normal blood will be collected from each patient to obtain a patient-specific somatic mutations panel (tumor signature).
At the event of ctDNA positivity, patients will be screened to enter the treatment phase of the study. Upon confirmed eligibility, a total of 40 patients will be allocated in one of the following trial's arms adopting a sequential recruitment strategy:
Arm A: Control Arm (N=10) Arm B: Experimental Arm with giredestrant (N=10) Arm C: Experimental Arm with giredestrant + abemaciclib (N=10) Arm D: Experimental Arm with giredestrant + inavolisib (N=10)
If the strategy of ctDNA monitoring enables physicians to identify patients at high risk of relapse and assess whether treatment at molecular relapse can improve outcome, new cohorts may be added to the study.

开始日期2024-04-01

申办/合作机构

Medica Scientia Innovation Research SL

NCT06259929

/ Not yet recruiting临床2期IIT

NEOadjuvant Abemaciclib and GIredestrant triaL in Patients With ER-positive, HER2-negative Early Breast Cancer

The objective of the study is to evaluate the efficacy and the safety of abemaciclib and giredestrant before surgery in participants with early stage, oestrogen receptor-positive (ER+), human epidermal receptor 2 negative (HER2-) breast cancer (BC).
Primary objective:
● To evaluate the efficacy of abemaciclib and giredestrant in complete cell cycle arrest (CCCA) rate at Week 2.
Secondary objectives:
To evaluate the efficacy of abemaciclib and giredestrant in reducing the relative Ki67 expression from baseline to Week 2
To evaluate the efficacy of abemaciclib and giredestrant in risk of recurrence (ROR) score reduction, clinical and radiological tumor response;
To evaluate the safety of abemaciclib and giredestrant.
Exploratory objectives:
To evaluate the mechanisms of response and resistance to therapy;
To evaluate the correlation between Ki-67% reduction and 18- Fluorothymidine (FLT) uptake reduction;
To evaluate the pathological complete response (pCR) rate (ypT0/is, ypN0) of giredestrant plus abemaciclib

开始日期2024-04-01

申办/合作机构-

100 项与 Giredestrant 相关的临床结果

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100 项与 Giredestrant 相关的转化医学

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100 项与 Giredestrant 相关的专利（医药）

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项与 Giredestrant 相关的文献（医药）

2024-11-01·CANCER TREATMENT REVIEWS

Oral SERDs changing the scenery in hormone receptor positive breast cancer, a comprehensive review

Review

作者: Gheysen, Mathilde ; Neven, Patrick ; Wildiers, Hans ; Punie, Kevin

BACKGROUND:

Primary and acquired endocrine resistance remains a major issue in the treatment of hormone receptor positive breast cancer. Acquired resistance often results from estrogen receptor 1 (ESR1) mutations leading to estrogen independent estrogen receptor activation. Selective estrogen receptor degraders (SERDs) induce degradation of this receptor, thereby overcoming this resistance. The intramuscular administration and modest efficacy of fulvestrant, the first SERD, triggered development of oral, more potent SERDs. This narrative review gives an overview of the current evidence regarding this new drug class.

METHODS:

Medline/PubMed and Embase database were screened using a systematic search strategy. We assessed the San Antonio Breast Cancer Symposium abstract reports, the European Society of Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) meeting resources by applying the following terms: 'SERD', 'giredestrant', 'elacestrant', 'imlunestrant', 'amcenestrant', 'camizestrant' and 'rintodestrant'.

CLINICALTRIALS:

gov was consulted to include ongoing trials.

RESULTS:

The search retrieved 1191 articles. After screening, 108 articles were retained. In the phase 3 EMERALD trial, elacestrant demonstrated benefit in progression free survival (PFS) in second line metastatic disease in postmenopausal women or men, leading to Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for the ESR1 mutated population. This PFS advantage was more pronounced among patients who had priorly received at least 12 months of a cyclin-dependent kinases 4/6 inhibitor (CDK4/6i). In the phase 2 SERENA-2 trial, camizestrant improved PFS as second line treatment. However, trials of giredestrant and amcenestrant failed to show PFS benefit in second line metastatic setting. In the preoperative setting, several oral SERDs resulted in a significant reduction of tumoral proliferation. Furthermore, many trials are still in progress.

CONCLUSION:

Oral SERDs constitute an exciting new drug class. Ongoing and future research will further refine the role of these drugs next to standard endocrine treatments and targeted therapies.

2024-08-01·DRUG METABOLISM AND DISPOSITION

Mass Balance, Metabolic Pathways, Absolute Bioavailability, and Pharmacokinetics of Giredestrant in Healthy Subjects

Article

作者: Osaghae, Uyi ; Yu, Jiajie ; Tang, Yang Thomas ; Chen, Ya-Chi ; Zhao, Weiping ; Gates, Mary R ; Kawakatsu, Sonoko ; Khojasteh, S Cyrus ; Musib, Luna ; Zhang, Donglu ; De Bruyn, Tom ; Wang, Jing ; Kshirsagar, Smita ; Ma, Shuguang ; Malhi, Vikram ; Cho, Sungjoon

Giredestrant is a potent and selective small-molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination, and metabolite profile of [¹⁴C]giredestrant. In part 1 (mass balance), a single 30.8-mg oral dose of [¹⁴C]giredestrant (105 µCi) was administered to women of nonchildbearing potential (WNCBP; n = 6). The mean recovery of total radioactivity in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized, with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In part 2 (aBA), WNCBP (n = 10) received an oral (30-mg capsule) or intravenous (30-mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. SIGNIFICANCE STATEMENT: This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, a high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant.

2024-07-01·Cancer chemotherapy and pharmacology

UGT1A4 Polymorphism is not Associated with a Clinically Relevant Change in Giredestrant Exposure

Article

作者: Chen, Ya-Chi ; Nowicka, Malgorzata ; Yu, Jiajie ; Waldvogel, Marie ; Malhi, Vikram ; Hafner, Marc ; Lien, Yi Ting Kayla ; Moore, Heather M ; Agarwal, Priya ; Perez-Moreno, Pablo

Abstract:

Purpose:

Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure.

Methods:

Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively.

Results:

The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure.

Conclusion:

Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients’ UGT1A4 polymorphism status.

项与 Giredestrant 相关的新闻（医药）

2024-12-11

·药明康德

显著减缓脑部肿瘤进展！礼来降解剂3期结果登《新英格兰医学杂志》

▎药明康德内容团队编辑礼来（Eli Lilly and Company）今日宣布其3期临床试验EMBER-3的积极结果。分析显示，与标准内分泌治疗（SOC ET）相较，其口服选择性雌激素受体降解剂（SERD）imlunestrant显著改善了雌激素受体阳性（ER+）、人表皮生长因子受体2阴性（HER2-）晚期乳腺癌（ABC）患者的无进展生存期（PFS），将疾病进展或死亡的风险降低了38%，这些患者携带ESR1突变并在之前使用芳香化酶抑制剂（AI）治疗后出现进展。详细研究结果已发表在《新英格兰医学杂志》，并在圣安东尼奥乳腺癌研讨会（SABCS）中公布。目前，这些数据已提交给全球监管机构。根据全球癌症观察站（GLOBOCAN），乳腺癌是全球确诊人数第二高的癌症，仅次于肺癌。估计2022年新发病例达230万例，意味着约每4例新确诊的癌症中就有1例是乳腺癌。2022年乳腺癌导致约66.6万人死亡，成为全球癌症死亡的第四大原因。转移性/晚期乳腺癌是指癌症从乳腺组织扩散到身体其他部位。局部晚期乳腺癌则意味着癌症已扩散至原发部位之外，但尚未转移至其他身体部位。在美国，所有高风险早期乳腺癌病例中，约30%会进展为转移性乳腺癌；同时，6-10%的新发乳腺癌病例在确诊时已是转移性。对于确诊时处于晚期的患者，生存率更低：局部病变的五年相对生存率为99%，区域性/局部晚期为86%，而转移性/晚期疾病则仅为30%。肿瘤大小等其他因素也会对五年生存率产生影响。 EMBER-3是一项3期随机、开放标签试验，旨在评估imlunestrant、研究者选择的SOC ET以及imlunestrant联合CDK4/6抑制剂Verzenio（abemaciclib）在ER+/HER2-局部晚期或转移性乳腺癌患者中的疗效与安全性。这些患者的疾病在使用AI治疗后（有或无CDK4/6抑制剂）出现复发或疾病出现进展。试验共入组了874名成年患者。患者被随机分配接受imlunestrant单药、SOC ET（氟维司群或依西美坦）或imlunestrant联合abemaciclib治疗。这次公布的主要结果如下： Imlunestrant对比SOC ET 在携带ESR1突变的患者中，imlunestrant显著改善了患者的PFS。接受imlunestrant治疗患者的中位PFS为5.5个月，而接受SOC ET治疗患者的PFS为3.8个月（HR=0.62，95% CI：0.46-0.82，p<0.001）。而imlunestrant组患者的总缓解率（ORR）为14%，SOC ET组则为8%。在所有患者中，imlunestrant组与SOC ET组患者的中位PFS分别为5.6个月和5.5个月（HR=0.87，95% CI：0.72-1.04，p=0.12）。 ▲接受imlunestrant单药与SOC ET治疗的ESR1突变患者（上）与所有患者（下）的PFS结果（图片来源：参考资料[2]）与临床前数据显示imlunestrant具备中枢神经系统（CNS）穿透性与活性的结果一致，事后分析显示，在所有患者中，使用imlunestrant治疗患者的CNS进展率显著降低（HR=0.47，95% CI：0.16-1.38），而在携带ESR1突变患者中这一趋势更为明显（HR=0.18，95% CI：0.04-0.90）。然而，这些分析因事件数量较少以及未对所有患者进行连续无症状CNS成像而受到一定限制。 Imlunestrant与abemaciclib联合疗法对比imlunestrant单药联合疗法显著改善所有患者的PFS，联合疗法组患者的中位PFS为9.4个月，而接受单药治疗患者的中位PFS为5.5个月（HR=0.57，95% CI：0.44-0.73，p<0.001）。联合疗法对患者的PFS益处在所有患者亚群中表现一致，无论患者是否携带ESR1或PI3K信号途径的突变，以及无论患者之前是否曾接受CDK4/6抑制剂治疗。联合疗法与单药组患者的ORR分别为27%与12%。 ▲接受联合疗法与imlunestrant单药治疗的所有患者（上）与CDK4/6抑制剂经治患者（下）的PFS结果（图片来源：参考资料[2]）安全性方面，联合疗法组的不良事件与已知的氟维司群联合abemaciclib的安全性一致，大多为低级别不良反应，如腹泻（86%）、恶心（49%）、中性粒细胞减少症（48%）和贫血（44%）。停药率仅为6.3%。除了EMBER-3，imlunestrant还正在针对早期乳腺癌患者的3期辅助治疗试验EMBER-4中接受评估，预计将在全球范围内招募6000名患者。 Imlunestrant是一种具有脑渗透性的口服选择性雌激素受体降解剂，可持续抑制雌激素受体，包括抑制那些带有ESR1突变的癌细胞。雌激素受体是治疗ER+/HER2-乳腺癌患者的核心靶点。新型雌激素受体降解剂通过提供稳定的口服药效和便利的用药方式，有望克服内分泌治疗的耐药性。目前，imlunestrant正在被研究用于治疗晚期乳腺癌，以及作为早期乳腺癌的辅助疗法。参考阅读：造福数百万患者！这类疗法正在改变癌症治疗图片来源：123RF SERD类药物能与ER结合并引发ER的结构变化，使得细胞里的E3泛素连接酶能更好地识别ER，并在其表面打上“垃圾”标签，最终使ER被送到细胞的蛋白酶体中降解。早在2002年，首款SERD药物就获得美国FDA的批准上市，治疗对tamoxifen产生耐药性的ER受体阳性乳腺癌患者。然而它只能通过肌肉注射给药，限制了它与靶点的结合和效力。开发能够口服、疗效更好的SERD药物，便成了业内关注的重要方向。除了礼来的imlunestrant，目前产业界还有多款在研SERD类药物处于3期临床阶段。例如罗氏（Roche）的giredestrant，之前公布的2期试验coopERA结果显示，giredestrant与CDK4/6抑制剂palbociclib联用作为新辅助疗法，在治疗早期ER阳性、HER2阴性乳腺癌患者时，与活性对照组相比，可更有效地降低生物标志物Ki67的水平（Ki67的水平昭示了癌细胞的分裂速度）。而阿斯利康（AstraZeneca）的camizestrant（AZD9833）的2期临床试验的结果显示，与活性对照组相比，在晚期ER阳性，HER2阴性乳腺癌患者中，camizestrant可显著减少患者疾病进展或死亡风险。由Olema Oncology所开发的palazestrant是一款ER的完全拮抗剂和SERD。此前公布的1b/2期临床试验结果显示，无论是在ESR1突变型肿瘤还是ESR1野生型肿瘤患者中，都观察到了肿瘤的缓解和持久的疾病稳定（SD）。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] Lilly's Imlunestrant, an Oral SERD, Significantly Improved Progression-Free Survival as Monotherapy and in Combination with Verzenio® (abemaciclib) in Patients with ER+, HER2- Advanced Breast Cancer. Retrieved December 11, 2024 from https://investor.lilly.com/news-releases/news-release-details/lillys-imlunestrant-oral-serd-significantly-improved-progression [2] Jhaveri KL, Neven P, Casalnuovo ML, Kim SB, Tokunaga E, Aftimos P, Saura C, O'Shaughnessy J, Harbeck N, Carey LA, Curigliano G, Llombart-Cussac A, Lim E, García Tinoco ML, Sohn J, Mattar A, Zhang Q, Huang CS, Hung CC, Martinez Rodriguez JL, Ruíz Borrego M, Nakamura R, Pradhan KR, Cramer von Laue C, Barrett E, Cao S, Wang XA, Smyth LM, Bidard FC; EMBER-3 Study Group. Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. N Engl J Med. 2024 Dec 11. doi: 10.1056/NEJMoa2410858. Epub ahead of print. PMID: 39660834. 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床3期临床结果临床成功临床失败

2024-12-10

·EndPoints

Olema Oncology makes case for its oral SERD with fresh data cut from early breast cancer trial

Olema Oncology unveiled new data from a Phase 1b/2 breast cancer trial on Tuesday, as it strives to catch up with other companies with oral selective estrogen receptor degraders (SERDs). Olema’s vision is to co-administer palazestrant with front-line standard-of-care CDK4/6 inhibitors, such as Novartis’ Kisqali, in patients with advanced or metastatic ER-positive, HER2-negative breast cancer. The company says giving patients this combination could limit resistance to CDK4/6 inhibitors. Several companies, including Eli Lilly and Pfizer in partnership with Arvinas, are also at this year’s San Antonio Breast Cancer Symposium to report data from their respective oral SERDs. The new cut from Olema’s open-label trial focuses on 62 patients. After a year, the median progression-free survival had not been reached at the data cutoff of November 11, the company said. Among all patients, the six-month PFS rate was 73%, and 68% among those who received prior CDK4/6 plus endocrine therapy. The company said that palazestrant is a complete estrogen receptor antagonist as well as a SERD, and can thus treat both ESR1 mutated patients, in whom SERDs work best, and wild-type patients. Among ESR1-mutant patients, the six-month PFS rate was 81%. Importantly, it was 70% in wild-type patients, which is a “huge differentiator,” Olema CEO Sean Bohen told Endpoints News. “[We have shown] post CDK4/6, with the predominant population being wild type, what appears to be a very favorable PFS,” Bohen said. The palazestrant/Kisqali regimen could capture benefits across the whole patient population, which would be “a unique opportunity,” he said. Olema also disclosed two confirmed complete responses, eight confirmed partial responses and one unconfirmed partial response, giving an overall response rate of 27% among 37 response-evaluable patients with measurable disease. Patients in the trial had received palazestrant at increasing doses of up to 120 mg once daily, plus Kisqali. Bohen said 48 patients (77%) were second-, third- or later-line, and the rest were “previously untreated in the advanced or metastatic setting.” Perhaps the best comparators for Olema’s Tuesday data are those from the academic MAINTAIN trial. That study recruited patients with prior CDK4/6 treatment, 82% of whom were given AstraZeneca’s Faslodex, an endocrine therapy, plus Kisqali. In the overall MAINTAIN population, the six-month PFS rate was 41% and the mPFS was 5.3 months. Olema’s data clearly beat these. “The median follow-up [for Olema’s SERD] was 12 months and we’re still not at the median PFS,” Bohen said. “When do we hit that? We don’t know.” An earlier cut from this Phase 1b/2 trial, up to September 25, will be presented at the San Antonio Breast Cancer Symposium on Wednesday. Next year, Olema will kick off the pivotal OPERA-2 trial of the palazestrant/Kisqali combo in the first-line setting, and last week secured a supply of Novartis’s drug. However, other SERDs are already well into Phase 3 development in frontline disease. Expectations are particularly high for Roche’s giredestrant, whose PersevERA trial in combination with Pfizer’s CDK4/6 inhibitor Ibrance could report next year. Elsewhere, Olema is currently conducting a Phase 3 study, OPERA-1, of palazestrant monotherapy in second-line ER-positive, HER2-negative breast cancer, which Bohen said could lead to the monotherapy’s approval as second- and third-line therapy.

临床3期临床结果ASCO会议

2024-12-08

·医脉通

HR+/HER2-转移性乳腺癌：现有和新兴治疗策略

编者按乳腺癌是全球女性中最常见的恶性肿瘤之一，激素受体阳性（HR+）/人表皮生长因子受体2阴性（HER2-）乳腺癌是其主要分子亚型，约占70%。近年来，随着对疾病机制的深入理解和新药的开发，其治疗策略日新月异，为HR+/HER2- mBC患者带来了新的希望。《Cancer Treatment Reviews》杂志上发表的一篇综述详细阐述了HR+/HER2- mBC的当前和新兴的治疗手段，包括CDK4/6抑制剂（CDK4/6i）、口服选择性雌激素受体降解剂（SERD）、靶向PI3K/AKT/mTOR抑制剂、抗体偶联药物（ADC）等，旨在帮助临床医生了解当前的治疗策略，并为患者提供更精准的治疗方案[1]。「 CDK4/6抑制剂联合内分泌治疗」过去HR+/HER2- mBC多以内分泌治疗（ET）为首选方案，主要包括选择性雌激素受体调节剂（SERMs）、选择性雌激素受体降解剂（SERDs）和芳香酶抑制剂（AI）。随着疾病的进展，临床医生与患者不得不面对因内分泌耐药导致治疗难度加大等问题。如今，CDK4/6i联合内分泌治疗（ET）已成为HR+/HER2-晚期乳腺癌的一线标准治疗方案。CDK4/6i在多项关键研究中显示出良好疗效，可较ET单独使用显著延长无进展生存期（PFS），部分研究还显示出了总生存期（OS）的获益。如MONALEESA-3研究中瑞波西利联合内分泌治疗对比安慰剂联合内分泌治疗，mPFS为20.5个月vs12.8个月，HR=0.59（95% CI：0.48-0.73），P<0.001[2]。另有诸如MONARCH、PALOMA等系列研究展开了相关探索并取得了疗效获益。在安全性方面，与ET单独使用相比，CDK4/6i增加了3/4级中性粒细胞减少和腹泻的风险[3]，[4]。在治疗顺序方面，CDK4/6i经治进展后的最佳治疗顺序尚不明确，已有CDK4/6i跨线、靶向PI3K/AKT/mTOR抑制剂、ADC等药物展开探索。「 SERD等新型内分泌治疗策略」口服选择性雌激素受体降解剂（SERDs）等新型内分泌治疗药物，为HR+/HER2-mBC患者提供了新的治疗选择。氟维司群是首个获批的SERD，长久以来一直是HR+乳腺癌治疗的主要手段，存在生物利用度低、剂量依赖性疗效特点，长期应用进展后可能伴随ESR1突变。艾拉司群（Elacestrant）则是首个获批用于ESR1突变mBC的口服SERD。EMERALD研究表明，在接受过1-2线ET、CDK4/6i和≤1线化疗的ER+/HER2- mBC 患者中，艾拉司群较标准内分泌治疗延长了mPFS（2.8个月vs 1.9个月），在ESR1突变患者中的mPFS获益更显著（3.8个月vs1.9个月）[5]。其他口服SERD（如camizestrant、giredestrant）的相关临床研究也在探索中，值得期待。目前对于ESR1突变的检测仍存在一定的挑战。PADA-1研究尝试通过ctDNA监测ESR1突变，在发现突变时早期转换治疗策略可改善PFS，但该治疗策略广泛应用于临床实践则受到成本、可行性和药物可及性等因素限制[6]。此外，对于ESR1野生型ER+/HER2- mBC口服SERD的获益证据仍不充足，需进一步延展。其他新型内分泌药物，如第三代SERM Lasofoxifene、蛋白水解靶向嵌合抗体ARV-471、完全雌激素受体拮抗剂 OP-1250等的研究也在进行中，将为HR+/HER2-乳腺癌患者的治疗带来更多可能。「新型靶向PI3K/AKT/mTOR通路抑制剂」 PI3K/AKT/mTOR通路在HR+/HER2-乳腺癌的发生发展中扮演着重要角色，针对该通路关键信号节点开发靶向治疗药物是当今的主要研发趋势之一。在SOLAR-1研究中，对PIK3CA突变的HR+/HER2- mBC患者使用PI3K抑制剂阿培利司联合内分泌治疗，较安慰剂联合内分泌治疗可延长患者mPFS，为11.0个月vs 5.7个月（HR=0.65，95% CI：0.50-0.85，P<0.001）[7]。卡匹色替是一种AKT抑制剂，基于其靶向作用于PI3K/AKT/mTOR通路核心位点AKT的关键机制，可有效阻断信号传导，在对伴有PIK3CA/AKT1/PTEN变异的HR+/HER2- mBC患者治疗中发挥着重要作用[8]。此外，还有更多针对PI3K/AKT/mTOR通路的新型靶向治疗药物、新的联合治疗方案开发中。「 ADC：内分泌抵抗患者化疗的替代选择」内分泌抵抗是HR+/HER2- mBC治疗的难点，其机制复杂，可能与ER介导信号失调或其他致癌通路改变有关。目前，内分泌抵抗HR+/HER2- mBC患者的主要治疗策略包括化疗和ADC，在化疗方面，卡培他滨是其首选的一线化疗药物之一[9]，也有其他多种化疗药物可供选择，需根据患者情况权衡利弊。ADC由抗体、细胞毒性药物经过连接子结合组成，具有肿瘤特异性和细胞毒性，能将细胞毒性药物靶向递送至肿瘤细胞，从而成为此类患者的新选择，是化疗的有效替代方案。靶向HER2的ADC德曲妥珠单抗（T-DXd）已获批用于治疗既往在转移性疾病阶段接受过至少一种化疗的，或辅助化疗期间或完成辅助化疗之后6个月内复发的，不可切除或转移性HER2低表达（IHC1+或IHC2+/ISH-）成人乳腺癌患者[10]。DESTINY-Breast04研究显示，对于HER2低表达HR+晚期乳腺癌患者，T-DXd对比医生选择的化疗方案（TPC）的mPFS为10.1个月vs5.4个月，HR=0.51，95% CI：0.40-0.64，P <0.001，mOS为23.9个月vs17.5个月，HR=0.64，95% CI：0.48-0.86，P=0.003。安全性方面，T-DXd组与TPC组的≥3级不良事件发生率分别为52.6% vs 67.4%，常见不良事件为中性粒细胞减少、贫血、恶心等，安全性可管理[11]。靶向Trop-2的 ADC戈沙妥珠单抗（SG）已获批用于内分泌经治且在转移性乳腺癌阶段接受过≥2线系统治疗的HR+/HER2-晚期乳腺癌患者。在TROPiCS-02研究中，对于内分泌耐药的HR+/HER2- mBC患者，SG与TPC相比显著延长mPFS，为5.5个月vs 4.0个月， HR=0.66，95% CI：0.53-0.83，P=0.0003）[12]，mOS为14.4个月vs11.2个月，HR=0.79，95% CI：0.65-0.96，P=0.02 [13]。SG常见不良反应是腹泻和中性粒细胞减少，值得关注。研究者指出，T-DXd和SG在患者人群、研究设计和治疗方法不同，无法直接对比。现有证据中，DESTINY-Breast04研究纳入的患者在转移阶段接受了≥1线治疗，TROPiCS-02研究纳入的患者治疗线序更为靠后。研究者认为，在临床中综合考虑HER2状态、既往治疗和病史等因素合理安排治疗线序，其中HER2表达是决策T-DXd临床应用的关键因素。此外，尚有其他ADC如Dato-DXd、HER3-DXd、SKB264等新药也在评估中，正在不断挖掘可能的治疗方案。「总结」 HR+/HER2- mBC的治疗策略不断发展，CDK4/6i联合ET显著改善了患者的生存结果，新型内分泌疗法和靶向PI3K/AKT/mTOR通路的抑制剂为患者提供了更多选择，ADC则为内分泌抵抗患者带来了可豁免化疗且更有效的治疗手段。虽然可选择的治疗策略日益丰富，但如何优化这些药物的组合和治疗线序，如何克服此类新兴治疗策略耐药性，仍然是未来研究的重点方向。研究者们持续地开展临床研究和真实世界评估将有助于治疗策略的进一步优化，从而改善患者的治疗效果和生活质量。参考资料： [1] Jhaveri K, Marmé F. Current and emerging treatment approaches for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Cancer Treat Rev. 2024;123:102670. doi:10.1016/j.ctrv.2023.102670 [2] Slamon D, Neven P, Chia S, Fasching P, De Laurentiis M, Im S-A, 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. J Clin Oncol 2018;36:2465–72. https://doi-org.libproxy1.nus.edu.sg/10.1200/JCO.2018.78.9909. [3] Sledge Jr GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial. JAMA Oncol 2020;6:116–24. https://doi-org.libproxy1.nus.edu.sg/10.1001/jamaoncol.2019.4782. [4] Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016;375:1925–36. https:// doi.org/10.1056/NEJMoa1607303. [5] Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, 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. J Clin Oncol 2022;40:3246–56. https://doi-org.libproxy1.nus.edu.sg/10.1200/JCO.22.00338. [6] Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte RT, et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2022;23:1367–77. https://doi-org.libproxy1.nus.edu.sg/10.1016/S1470-2045(22)00555-1 [7] Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 2019;380:1929–40. https://doi-org.libproxy1.nus.edu.sg/10.1056/NEJMoa1813904. [8] Turner N., Oliveira M., Howell S.J., Dalenc F., Cort´ es J., Gomez H., et al. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the phase III CAPItello-291 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; Dec 6-10, 2022; San Antonio, TX. Philadelphia (PA ): AACR. Cancer Res 2023;83:Abstract GS3-04. https://doi-org.libproxy1.nus.edu.sg/10.1158/1538-7445.SABCS22-GS3-04. [9] O'Shaughnessy JA, Kaufmann M, Siedentopf F, et al. Capecitabine monotherapy: review of studies in first-line HER-2-negative metastatic breast cancer. Oncologist. 2012;17(4):476-484. doi:10.1634/theoncologist.2011-0281 [10] ENHERTU® (fam-trastuzumab deruxtecan-nxki) [prescribing information] Basking Ridge, NJ: Daiichi Sankyo Co., Ltd; 2022. Available at: https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true. [accessed March 31, 2023]. [11] Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 2022;387:9–20. https://doi-org.libproxy1.nus.edu.sg/10.1056/NEJMoa2203690. [12] Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2022;40:3365–76. https://doi-org.libproxy1.nus.edu.sg/10.1200/JCO.22.01002. [13] Rugo H.S., Bardia A., Marme F., Cortes J., Schmid P., Loirat D., et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet 2023:Online ahead of print. doi:10.1016/S0140-6736(23)01245-X. 声明：本材料由阿斯利康支持，仅供医药卫生专业人士参考。内容涉及阿斯利康未获批产品/适应症，阿斯利康不推荐任何未批准药品/适应症的使用审批编号：CN-147977 过期时间：2025-11-26 -THE END- 医脉通是专业的在线医生平台，“感知世界医学脉搏，助力中国临床决策”是平台的使命。医脉通旗下拥有「临床指南」「用药参考」「医学文献王」「医知源」「e研通」「e脉播」等系列产品，全面满足医学工作者临床决策、获取新知及提升科研效率等方面的需求。

抗体药物偶联物临床结果

100 项与 Giredestrant 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11961	-	-	-

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
ER阳性乳腺癌	临床3期	美国	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	日本	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	阿根廷	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	德国	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	希腊	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	意大利	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	新加坡	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	南非	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	韩国	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	西班牙	Genentech, Inc.	2022-08-03

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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


NCT04802759 (MORPHEUS- BREAST CANCER, ESMO2024) 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌 HER2 Negative \| ER Positive	33	Giredestrant 30 mg PO daily	齋觸淵鹹獵製繭鏇餘積(選餘繭網鏇糧襯觸餘醖) = 遞獵醖簾鏇淵觸遞壓範願獵壓選齋築觸構選選 (齋窪衊觸製蓋鑰壓艱積 ) 更多	积极	2024-09-16
				Giredestrant 30 mg PO daily + Samuraciclib 360 mg PO daily	齋觸淵鹹獵製繭鏇餘積(選餘繭網鏇糧襯觸餘醖) = 廠鏇獵糧鑰齋淵糧壓淵願獵壓選齋築觸構選選 (齋窪衊觸製蓋鑰壓艱積 ) 更多
NCT04576455 (acelERA BC, Pubmed) 人工标引	临床2期	HR阳性/HER2阴性乳腺癌 Estrogen Receptor-Positive \| HER2-Negative	303	Giredestrant	簾範窪遞艱廠簾艱膚鹽(襯衊遞願簾廠鹹糧願網): HR = 0.81 (95% CI, 0.6 ~ 1.1), P-Value = 0.1757 更多	积极	2024-06-20
				fulvestrant choice of endocrine monotherapy
NCT04802759 (ASCO2024) 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌 HER2 Negative	15	Giredestrant (G) + Everolimus (EVERO)	衊獵鬱積觸鹽窪鹽遞繭(艱繭鑰蓋鬱醖製壓淵獵) = 膚窪餘網鬱壓餘蓋餘簾製憲醖繭積選廠壓簾齋 (觸窪簾衊衊積膚網網膚 ) 更多	积极	2024-05-24
NCT03332797 (GO39932, Pubmed)	临床1期	ER+ \| HER2-negative \| ESR1-mutated tumors	175	Giredestrant 10 mg	鬱範鑰淵鬱鹽衊醖艱鏇(選獵選鹽醖鏇膚鹹衊鬱) = 糧鏇膚製遞窪廠獵壓簾齋蓋遞觸廠範鹹鑰襯淵 (願夢廠獵夢積選構遞範 )	积极	2024-01-23
				Giredestrant 30 mg	鬱範鑰淵鬱鹽衊醖艱鏇(選獵選鹽醖鏇膚鹹衊鬱) = 衊蓋簾顧淵襯選鏇遞壓齋蓋遞觸廠範鹹鑰襯淵 (願夢廠獵夢積選構遞範 )
NCT03332797 (phase Ia/Ib dose-escalation/-expansion study, Pubmed)	临床1期	晚期乳腺癌	-	Giredestrant 10 mg	鹹獵願顧襯壓顧鬱範艱(夢簾艱壓製鑰遞獵齋鑰) = 襯構憲蓋糧窪淵獵觸廠鬱鏇壓築鹹觸蓋糧觸網 (獵壓選膚壓夢積選廠構 )	积极	2023-12-15
				Giredestrant 30 mg	鹹獵願顧襯壓顧鬱範艱(夢簾艱壓製鑰遞獵齋鑰) = 構範餘鬱淵鬱糧憲廠廠鬱鏇壓築鹹觸蓋糧觸網 (獵壓選膚壓夢積選廠構 )
NCT04436744 (coopERA Breast Cancer, Pubmed \| Lancet Oncol)	临床2期	ER阳性/HER2阴性乳腺癌新辅助 oestrogen receptor-positive \| HER2-negative \| Ki67 score	221	Giredestrant 30 mg	鹽糧選醖觸醖顧壓鏇願(憲築願築網鹹襯築鹽鏇) = 衊膚憲襯膚廠艱觸鹽築選獵衊遞窪膚鬱糧壓夢 (鹹觸獵範窪醖窪淵鑰醖, -80 ~ -70)	积极	2023-09-01
				Anastrozole 1 mg	鹽糧選醖觸醖顧壓鏇願(憲築願築網鹹襯築鹽鏇) = 衊鑰選壓製獵糧積築蓋選獵衊遞窪膚鬱糧壓夢 (鹹觸獵範窪醖窪淵鑰醖, -73 ~ -59)
NCT04802759 (MORPHEUS BC, ASCO 12023 \| ASCO 22023) 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌 ER Positive \| HER2 Negative	40	Abemaciclib+Giredestrant	遞餘窪繭餘選構範餘醖(鹽選鬱繭齋憲選鑰窪範) = 壓觸艱觸糧淵襯願醖衊製網鏇廠繭膚膚蓋築醖 (鏇網廠鑰糧憲鑰築齋憲 ) 更多	积极	2023-05-26
				ribociclib +Giredestrant	遞餘窪繭餘選構範餘醖(鹽選鬱繭齋憲選鑰窪範) = 築範襯窪繭顧網襯築鏇製網鏇廠繭膚膚蓋築醖 (鏇網廠鑰糧憲鑰築齋憲 ) 更多
NCT04436744 (coopERA BC, ASCO 12023 \| ASCO 22023) 人工标引	临床2期	ER阳性/HER2阴性乳腺癌新辅助 ER Positive \| HER2 Negative	-	Palbociclib+Giredestrant	衊膚獵壓願衊構糧淵鹽(獵壓艱艱鏇鑰淵製餘醖) = 廠糧範齋艱鹽醖構襯衊壓衊齋襯獵鬱醖窪製壓 (獵淵築願鬱憲遞窪壓積 ) 更多	积极	2023-05-26
				Palbociclib+anastrozole	衊膚獵壓願衊構糧淵鹽(獵壓艱艱鏇鑰淵製餘醖) = 鏇鏇夢餘淵淵鹽築膚衊壓衊齋襯獵鬱醖窪製壓 (獵淵築願鬱憲遞窪壓積 ) 更多
NCT03916744 (CTgov)	临床1期	ER阳性乳腺癌	75	Surgery+Giredestrant (Giredestrant 10 mg)	壓鹹膚觸膚醖簾齋顧網(衊衊簾簾鹽積構廠構膚) = 醖製範鏇遞鬱壓簾願範淵願襯獵壓鹽顧鑰積膚 (艱簾膚鹽鹽醖鏇繭選壓, 糧鹽襯顧窪選築積遞蓋 ~ 願壓鑰築鬱衊壓積鏇築) 更多	-	2023-03-10
				Surgery+Giredestrant (Giredestrant 30 mg)	壓鹹膚觸膚醖簾齋顧網(衊衊簾簾鹽積構廠構膚) = 選築製鏇鑰積積窪願鏇淵願襯獵壓鹽顧鑰積膚 (艱簾膚鹽鹽醖鏇繭選壓, 壓窪製積積製餘網廠壓 ~ 鑰壓膚鬱壓鹽範鏇餘壓) 更多
NCT04436744 (coopERA \| coopERA BC \| coopERA Breast Cancer, CTgov)	临床2期	ER阳性/HER2阴性乳腺癌 \| 早期乳腺癌	221	Surgery+Giredestrant+palbociclib (Giredestrant + Palbociclib)	選構艱壓製襯簾衊壓壓(壓鑰鹹艱壓鏇觸膚網遞) = 鬱餘廠鹽餘鑰範築窪遞製夢鬱網壓鹹襯鑰鏇蓋 (齋衊齋壓製鏇築膚鑰構, 膚構蓋觸齋鑰鹽遞繭鬱 ~ 衊齋製壓鬱夢網醖構蓋) 更多	-	2023-02-02
				Surgery+palbociclib+anastrozole (Anastrozole + Palbociclib)	選構艱壓製襯簾衊壓壓(壓鑰鹹艱壓鏇觸膚網遞) = 衊醖憲醖鏇憲壓鏇鑰衊製夢鬱網壓鹹襯鑰鏇蓋 (齋衊齋壓製鏇築膚鑰構, 願鏇衊鏇選襯顧襯選築 ~ 膚鏇顧築糧顧蓋繭繭積) 更多