大约四分之三的乳腺癌为雌激素受体阳性，需要进行长期内分泌治疗，包括芳香化酶抑制剂、选择性雌激素受体调节剂、选择性雌激素受体降解剂。氟维司群是首个选择性雌激素受体降解剂，对雌激素受体阳性乳腺癌有效，尤其雌激素受体编码基因ESR1突变患者，但是口服无效，需要肌肉注射，给长期内分泌治疗带来不便。近年来，口服选择性雌激素受体降解剂不断问世，可惜三期临床研究大多折戟，目前仅艾拉司群脱颖而出，以EMERALD研究（ESR1突变患者占47.8%）获得美国批准用于治疗既往内分泌治疗后疾病进展的雌激素受体阳性HER2阴性ESR1突变晚期乳腺癌绝经女性或成年男性。那么，其他口服有效的选择性雌激素受体降解剂是否还有戏？
2024年3月27日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表西班牙马德里大学马拉尼翁医院米盖尔·马丁、澳大利亚新南威尔士大学圣文森特医院埃尔金·林、美国德克萨斯大学MD安德森癌症中心玛丽安娜·查韦斯·麦格雷戈、哈佛大学医学院麻省总医院阿迪亚·巴迪亚、复旦大学附属肿瘤医院吴炯、哈尔滨医科大学附属肿瘤医院张清媛等学者的acelERA研究报告，对口服选择性雌激素受体降解剂吉瑞司群与医师选择其他内分泌单药二或三线治疗雌激素受体阳性HER2阴性晚期乳腺癌的有效性和安全性进行了比较。
acelERA (NCT04576455): A Study Evaluating the Efficacy and Safety of Giredestrant Compared With Physician's Choice of Endocrine Monotherapy in Participants With Previously Treated Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer (A Phase II, Randomized, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of GDC-9545 Compared With Physician's Choice of Endocrine Monotherapy in Patients With Previously Treated Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer) 该国际多中心非盲随机对照二期临床研究于2020年11月27日至2021年10月27日从全球17个国家或地区85个研究中心入组年龄≥18岁、乳腺癌可测量或骨转移可评估、一或二线线全身治疗（≤1种靶向治疗、≤1种化疗方案、允许用过氟维司群）后疾病进展的绝经后获绝经前或围绝经女性或男性患者303例，按1∶1的比例随机分为两组，给予吉瑞德群（151例，每天1次口服30毫克）或根据当地指南由医师选择内分泌单药治疗（152例，氟维司群或芳香化酶抑制剂，男性和绝经前或围绝经女性加用黄体生成素释放激素激动剂）直至疾病进展或毒性反应无法耐受。根据内脏转移与非内脏转移、既往用过细胞周期蛋白依赖性激酶4/6抑制剂以及既往用过氟维司群对患者进行分层分析。主要终点为研究者评定的全部患者无进展生存，次要终点包括研究者评定的ESR1突变患者无进展生存、临床获益率、客观缓解率。 结果，截至2022年2月18日，中位随访7.9个月，对全部303例患者进行主要终点分析，吉瑞德群与医师选择内分泌单药治疗相比：- 风险比：0.81（95%置信区间：0.60～1.10，P=0.1757）
对循环肿瘤DNA可评估患者（232例）进行预设次要终点分析，吉瑞德群与医师选择内分泌单药治疗相比：- 风险比：0.60（95%置信区间：0.35～1.03）
- 风险比：0.88（95%置信区间：0.54～1.42）
亚组分析结果表明，吉瑞地群对大多数关键亚组的治疗效果一致。A、全部患者，B、ESR1突变患者，C、全部患者亚组分析 两组患者的药物相关3～4级不良事件、严重不良事件、不良事件所致停药发生率相似。 因此，该二期临床研究结果表明，虽然研究者评定的无进展生存主要终点并未达统计学显著优效性，但是吉瑞地群对大多数关键亚组的治疗效果一致，并且ESR1突变患者（占38.8%）有获益趋势。吉瑞司群的耐受性良好，安全性与医师选择内分泌单药治疗相似，并且与内分泌治疗已知风险一致。总体而言，这些数据支持对吉瑞德群开展进一步研究，尤其对于ESR1突变患者。J Clin Oncol. 2024 Mar 27. IF: 45.3Giredestrant for Estrogen Receptor-Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study. OPEN ACCESSMartín M, Lim E, Chavez-MacGregor M, Bardia A, Wu J, Zhang Q, Nowecki Z, Cruz FM, Safin R, Kim SB, Schem C, Montero AJ, Khan S, Bandyopadhyay R, Moore HM, Shivhare M, Patre M, Martinalbo J, Roncoroni L, Pérez-Moreno PD, Sohn J; acelERA Breast Cancer Study Investigators.Hospital Gregorio Maranón, Universidad Complutense, GEICAM, CIBERONC, Madrid, Spain; Garvan Institute of Medical Research, St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia; The University of Texas MD Anderson Cancer Center, Houston, TX; Massachusetts General Hospital, Harvard Medical School, Boston, MA; Fudan University Cancer Institute, Shanghai, China; Harbin Medical University Cancer Hospital, Harbin, China; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland; Núcleo de Pesquisa e Ensino da Rede Sao Camilo, Sao Paulo, Brazil; Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Tatarstan, Kazan, Russian Federation; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Krankenhaus Jerusalem, Mammazentrum Hamburg, Hamburg, Germany; University Hospitals/Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; Nottingham University Hospitals, City Hospital Campus, Nottingham, United Kingdom; Genentech, Inc, South San Francisco, CA; Roche Products Limited, Welwyn Garden City, United Kingdom; F. Hoffmann-La Roche Ltd, Basel, Switzerland; Inhibrx, La Jolla, CA; AstraZeneca, Barcelona, Spain; Yonsei University College of Medicine, Seoul, Korea.PURPOSE: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455).METHODS: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS).RESULTS: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = 0.1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms.CONCLUSION: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.KEY OBJECTIVE: Can the oral, selective estrogen receptor antagonist and degrader (SERD) giredestrant improve outcomes compared with physician's choice of endocrine therapy (PCET) in patients with pretreated, estrogen receptor-positive (ER+), HER2-negative, advanced breast cancer?KNOWLEDGE GENERATED: Giredestrant did not show statistically significant superiority to PCET with regards to investigator-assessed progression-free survival. In patients with ESR1-mutated tumors, there was a trend toward favorable benefit with giredestrant. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks.RELEVANCE: Hopeful results continue to emerge from studies of novel ER-targeting drugs, with a number appearing to show more activity than historically available agents in the presence of a tumor ESR1 mutation. However their significance in the treatment algorithm for women with ER+, HER2-negative breast cancer remains to be determined.DOI: 10.1200/JCO.23.01500
本站仅提供存储服务，所有内容均由用户发布，如发现有害或侵权内容，请
点击举报。
