海报库PosterKeep
PO.CTP01.03 · 进行中的临床试验

ADELA：一项双盲、安慰剂对照、随机3期试验，比较依拉司群（Ela）+依维莫司（EVE）对比依拉司群+安慰剂在ESR1突变肿瘤、内分泌治疗（ET）+CDK4/6i进展的ER+/HER2- 晚期乳腺癌（aBC）患者中的疗效

ADELA: A double-blind, placebo-controlled, randomized phase 3 trial of elacestrant (Ela) + everolimus (EVE) versus elacestrant + placebo in ER+/HER2- advanced breast cancer (aBC) patients with ESR1 -mutated tumors progressing on endocrine therapy (ET) + CDK4/6i

编号 CT226 展板 21 时间 4/21 09:00–12:00 区域 Section 51 主讲 Tomer Wasserman
分会场 Phase II and Phase III Clinical Trials in Progress
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作者与单位 Authors & Affiliations

Antonio Llombart-Cussac1, José Manuel Pérez-García1, Elena Lopez-Miranda1, Cristina Saavedra2, Vicente Carañana3, Isabel Blancas4, Carmen Hinojo-González5, Alfonso Cortes-Salgado6, Elena Galve7, Rui Rui Zhang1, Miguel Sampayo-Cordero1, Daniel Alcalá-López1, Juliana Carvalho-Santos1, Olga Boix1, Ana Garrido1, Carlos H. Barrios8, Giuseppe Curigliano9, Rupert Bartsch10, Anne Claire Hardy Bessard11, Tomer Wasserman12, Javier Cortés1

1Medica Scientia Innovation Research (MEDSIR), Barcelona (Spain), Ridgewood (New Jersey, USA), Barcelona, Spain,2IOB Madrid, Institute of Oncology, Hospital Beata Maria Ana, Madrid, Spain,3Hospital Arnau de Vilanova, FISABIO, Valencia, Spain,4San Cecilio Clinic University Hospital, Granada, Spain,5Hospital Universitario Marqués de Valdecilla – Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain,6Medical Oncology Department, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, Spain,7Hospital Universitario de Basurto, Bilbao, Spain,8Latin American Cooperative Oncology Group (LACOG) - Porto Alegre, Brazil Oncoclinicas Group, Porto Alegre, Brazil,9European Institute of Oncology, IRCCS, Milan, Italy,10Medical University of Vienna, Department of Medicine 1, Division of Oncology, Vienna, Austria,11Centre Armoricain d'Oncologie, CARIO-HPCA, and UNICANCER, Plérin, France,12Menarini Group, New York, NY

摘要 Abstract

中文摘要
背景：ET+CDK4/6i是一线ER+/HER2- aBC的标准治疗（SOC）；然而，肿瘤最终会产生耐药。PI3K/AKT/mTOR通路的组成性激活可导致乳腺癌的内分泌耐药。ESR1突变（ESR1m）是一种常见的获得性耐药类型，在长期暴露于芳香化酶抑制剂后，40-50%的转移性患者（pts）中出现。对于ET+CDK4/6i后进展的ER+/HER2- aBC伴ESR1m肿瘤患者，存在克服耐药机制并改善结局的新型治疗方法的未满足需求。Ela是一种新一代口服SERD，可结合并降解ERα。在3期EMERALD试验中，单药Ela在ESR1m肿瘤患者中相比SOC ET改善了mPFS（HR 0.55；95% CI 0.39-0.77；P=0.0005）[Bidard 2022]。在既往接受ET+CDK4/6i≥12个月的患者中，Ela的mPFS为8.6个月，而SOC ET为1.9个月（HR 0.41；95% CI 0.26-0.63）[Bardia 2024]。ER与PI3K/AKT/mTOR通路之间的相互作用为评估Ela+EVE（一种mTORC1抑制剂）提供了理论依据。在ELEVATE 2期试验（NCT05563220）中，Ela 345 mg + EVE 7.5 mg的联合方案在所有（N=50）ET+CDK4/6i后进展的ER+/HER2- aBC患者中显示出具有临床意义的mPFS为8.3个月（95% CI, 4.0-10.2），无论ESR1m状态如何（Rugo, SABCS 2025）。安全性与EVE+SOC ET的已知特征一致。 设计和方法：ADELA（NCT06382948）是一项国际性、多中心、双盲、安慰剂对照、随机3期试验，比较Ela+EVE对比Ela+安慰剂在ET+CDK4/6i进展的ER+/HER2- aBC伴ESR1m肿瘤患者中的疗效。合格患者为成人（≥18岁），患有ER+/HER2- aBC且中心确认ESR1m，既往因aBC接受1-2线ET，且在aBC接受ET+CDK4/6i≥6个月后进展。接受基于CDK4/6i辅助治疗的患者，若在治疗≥12个月后但在CDK4/6i完成后<12个月内发生进展，则符合条件。排除标准包括既往针对aBC的化疗以及活动性未控制/有症状的脑转移和/或软脑膜疾病。患者将按1:1随机分配至28天周期的Ela 345 mg + EVE 7.5 mg每日一次（QD）或Ela 345 mg + 安慰剂QD，直至疾病进展或不可接受的毒性。患者将在前8周期间接受地塞米松漱口液。分层因素为内脏转移（是对比否）和既往CDK4/6i治疗持续时间（≥12对比<12个月）。主要目的是由BICR评估的PFS。次要目的是研究者评估的OS、PFS、ORR、CBR、DoR、TTR、肿瘤负荷最佳百分比变化、安全性、HRQoL。 现状：计划入组240例患者。招募正在西班牙、法国、希腊、意大利、德国、奥地利、捷克共和国、英国和巴西进行中。
查看英文原文 English abstract
Background: ET+CDK4/6i is the standard-of-care (SOC) in 1L ER+/HER2- aBC; however, tumors eventually develop resistance. Constitutive activation of the PI3K/AKT/mTOR pathway can contribute to endocrine resistance in breast cancer. ESR1 mutations ( ESR1m ) are a common type of acquired resistance that emerges in 40-50% of patients (pts) in the metastatic setting after prolonged aromatase inhibitor exposure. There is an unmet need for novel therapeutic approaches to overcome resistance mechanisms and improve outcomes in pts with ER+/HER2- aBC with ESR1m tumors progressing after ET+CDK4/6i. Ela is a next-generation oral SERD that binds and degrades ERalpha. In the Ph3 EMERALD trial, single-agent Ela improved mPFS vs SOC ET in pts with ESR1m tumors (HR 0.55; 95% CI 0.39-0.77; P=0.0005) [Bidard 2022]. Among pts who received prior ET+CDK4/6i ≥12 months, mPFS with Ela was 8.6 vs 1.9 months with SOC ET (HR 0.41; 95% CI 0.26-0.63) [Bardia 2024]. The crosstalk between the ER and PI3K/AKT/mTOR pathways provides a rationale for evaluating Ela+EVE (a mTORC1 inhibitor). In the ELEVATE Ph2 trial (NCT05563220), the combination of Ela 345 mg + EVE 7.5 mg showed a clinically meaningful mPFS of 8.3 months (95% CI, 4.0-10.2) in all pts (N=50) with ER+/HER2- aBC who progressed after ET+CDK4/6i, regardless of ESR1 m status (Rugo, SABCS 2025). Safety was consistent with the known profile of EVE+SOC ET. Design and Methods: ADELA (NCT06382948) is an international, multicenter, double-blind, placebo-controlled, randomized Ph3 trial that compares Ela+EVE vs Ela+placebo in pts who have ER+/HER2- aBC with ESR1m tumors progressing on ET+CDK4/6i. Eligible pts are adults (≥18 years) with ER+/HER2- aBC and centrally confirmed ESR1m who received 1-2 prior lines of ET for aBC and progressed on ET+CDK4/6i for aBC after ≥6 months. Pts receiving CDK4/6i-based adjuvant therapy are eligible if progression occurred after ≥12 months of treatment but <12 months following CDK4/6i completion. Exclusion criteria include prior chemotherapy for aBC and active uncontrolled/symptomatic brain metastases and/or leptomeningeal disease. Pts will be randomized 1:1 to 28-day cycles of Ela 345 mg + EVE 7.5 mg QD or Ela 345 mg + placebo QD until disease progression or unacceptable toxicity. Pts will receive dexamethasone mouthwash during the first 8 weeks. Stratification factors are visceral metastases (yes vs no) and duration of prior CDK4/6i therapy (≥12 vs <12 months). Primary objective is PFS assessed by BICR. Secondary objectives are investigator-assessed OS, PFS, ORR, CBR, DoR, TTR, best percentage change in tumor burden, safety, HRQoL. Status: Planned enrollment is 240 pts. Recruitment is ongoing across Spain, France, Greece, Italy, Germany, Austria, Czech Republic, United Kingdom, and Brazil.
利益披露 Disclosure
A. Llombart-Cussac, oche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp&Dhome, Gilead, Daiichi Sankyo ). Lilly, Roche, Pfizer, Novartis); Other, Consulting/advisor. illy, Astrazeneca, Merck Sharp&Dhome, Pfizer, Novartis Other, Speaker's bureau. oche, Pfizer, Astrazeneca, Steamline therapeutics, Merck Sharp&Dhome Travel. J. M. Pérez-García, MEDSIR Employment. lly, Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics, MSD, Gilead Other, Advisory role. Roche Travel. E. Lopez-Miranda, straZeneca, Seagen, Lilly, Daichii-Sankyo Other, Honoraria. AstraZeneca, Daichii-Sankyo, Seagen Other, Consulting/advisory role. Lilly, AstraZeneca Other, Speaker's bureau. Gilead, Roche Travel. C. Saavedra, AstraZeneca; Daiichi Sankyo/Astra Zeneca; Novartis; Novartis Other, Speaker's bureau. AstraZeneca/Daiichi Sankyo; Lilly; Novartis; Pfizer; Pfizer Travel. V. Carañana, AstraZeneca Travel. I. Blancas, AstraZeneca Spain; Bristol Myers Squibb; Daiichi Sankyo/Astra Zeneca; Eisai; Gilead Sciences; GlaxoSmithKline; Grunenthal; Lilly; MSD; Novartis; Pfizer; Pierre Fabre; Roche; Seagen; Veracyte Other, Honoraria. AstraZeneca Spain; Bristol-Myers Squibb; Daiichi Sankyo/Astra Zeneca; Eisai; Lilly; Novartis; Pfizer; Pierre Fabre; Roche; Veracyte Other, Consulting/advisory role. Agendia (Inst); AstraZeneca Spain (Inst); Lilly; Pfizer (Inst); Roche (Inst) ). AstraZeneca; Daiichi Sankyo; Gilead Sciences; Lilly; Novartis; Pfizer; Pierre Fabre; Roche Travel. C. Hinojo-González, None. A. Cortes-Salgado, AstraZeneca; Daiichi Sankyo/Astra Zeneca; GlaxoSmithKline; Pfizer Other, Consulting/advisory. Accord Healthcare; AstraZeneca Spain; Eisai; GlaxoSmithKline; MSD; Pfizer Other, Speaker's bureau. Pfizer (Inst) ). GlaxoSmithKline; Pfizer Travel. E. Galve, None. R. Zhang, MEDSIR Employment. M. Sampayo-Cordero, MEDSIR Employment. D. Alcalá-López, MEDSIR Employment. J. Carvalho-Santos, MEDSIR Employment. O. Boix, MEDSIR Employment. A. Garrido, MEDSIR Employment. C. H. Barrios, MedSIR; Tummi Stock. AstraZeneca; Bayer; Boehringer Ingelheim; Eisai; GlaxoSmithKline; Lilly; MSD; Novartis; Pfizer; Roche/Genentech; Sanofi; Zodiac Pharma Other, Honoraria. AstraZeneca; Boehringer Ingelheim; Eisai; GlaxoSmithKline; Libbs; Lilly; MSD Oncology; Novartis; Pfizer; Roche/Genentech; United Medical Other, Consulting or advisory role. AB Science (Inst); Abbvie (Inst); Abraxis BioScience (Inst); Amgen (Inst); Asana Biosciences (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Biomarin (Inst); Boehringer Ingelheim (Inst) ). Bristol-Myers Squibb (Inst); Celgene (Inst); Clinica Atlantis (Inst); Covance (Inst); Daiichi Sankyo (Inst); Exelixis (Inst); GlaxoSmithKline (Inst); Halozyme (Inst) ). ImClone Systems (Inst); INC Research (Inst); inVentiv Health (Inst); Janssen (Inst); LEO Pharma (Inst); Lilly (Inst); Medivation (Inst); Merck (Inst); Merck KGaA (Inst); Merck KGaA (Inst); Merrimack ). Millennium (Inst); Mylan (Inst); Novartis (Inst); Pfizer (Inst); PharmaMar (Inst); Polyphor (Inst); Roche/Genentech (Inst); Sanofi (Inst); Shanghai Henlius Biotech (Inst); Taiho Pharmaceutical (Inst) ). AstraZeneca; BMS Brazil; Lilly; MSD Oncology; Novartis; Pfizer; Roche/Genentech Travel. G. Curigliano, ESMO; ESMO; ESMO Open; European Society of Breast Cancer Specialists (EUSOMA= Other, Leadership. Ellipses Pharma Other, Honoraria. AstraZeneca; Blueprint Medicines; Boehringer Ingelheim; Bristol-Myers Squibb; Celcuity; Daichi-Sankyo; Exact Sciences; Foundation Medicine; Gilead Sciences; GlaxoSmithKline; Guardant Health; Hengrui Other, Consulting or advisory role. Lilly; Menarini; Merck; Novartis; Pfizer; Roche/Genentech; Samsung; Seagen; Veracyte Other, Consulting or advisory role. AstraZeneca; Daiichi Sankyo; Exact Sciences; Foundation Medicine; Gilead Sciences; Lilly; Menarini; Novartis; Pfizer; Roche/Genentech; Samsung; Seagen Other, Speaker's bureau. Merck (Inst) ). AstraZeneca; Daichii Sankyo; Pfizer; Roche/Genentech Travel. R. Bartsch, AstraZeneca; Daiicho; Lilly; Novartis; Pfizer; Pfizer; Pierre Fabre; Roche; Seagen Honoraria. AstraZeneca; Daiichi; Eisai; Lilly; MSD Oncology; MSD Oncology; Novartis; Novartis; Pfizer; Pierre Fabre; Puma Biotechnology; Puma Biotechnology; Roche; Seagen Consulting or advisory role. Daiichi (Inst) ). Daiichi Sankyo Europe GmbH; Pfizer; Pfizer; Roche; Roche Travel. A. C. H. Bessard, Abbvie; AstraZeneca; Daiichi Sankyo/Astra Zeneca; Eisai; Gilead Sciences; GlaxoSmithKline; MSD; Novartis; Pfizer; Regeneron Other, Consulting or Advisory Role. T. Wasserman, Menarini Group Employment. J. Cortés, Leuko (I); MAJ3 Capital Stock. AstraZeneca; Celgene; Daiichi Sankyo; Eisai; Gilead Sciences; Lilly; Merck Sharp & Dohme; Novartis; Pfizer; Roche; Samsung; Steamline Therapeutics Other, Honoraria. Abbvie; AstraZeneca; Athenex; Bioasis; Biocon; Bioinvent; BioNTech SE; Boehringer Ingelheim; Bridgebio; Celgene; Cellestia Biotech; Circle Pharma; Clovis Oncology; Daiichi Sankyo; Delcath Systems Other, Consulting or Advisory Role. Ellipses Pharma; ERYTECH Pharma; Expres2ion Biotechnologies; GEMoaB; Gilead Sciences; GlaxoSmithKline; Hexagon Bio; HiberCell; Jazz Pharmaceuticals; Leuko; Lilly; Menarini; Merck Sharp & Dohme Other, Consulting or Advisory Role. Polyphor; Reveal Genomics; Roche; Seagen; SERVIER; Zymeworks Other, Consulting or Advisory Role. ARIAD (Inst); Astrazeneca (Inst); Baxalta (Inst); Bayer (Inst); Eisai (Inst); Guardant Health (Inst); Merck Sharp & Dohme (Inst); Pfizer (Inst); Piqur (Inst); Puma Biotechnology (Inst) ). Queen Mary university of London (Inst); Roche (Inst) ). AstraZeneca; Daiichi Sankyo; Eisai; Gilead Sciences; Merck Sharp&Dhome; Novartis; Pfizer; Roche; Steamline Therapeutics Travel.

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