PO.CTP01.03 · 进行中的临床试验
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
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作者与单位
摘要 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) ).
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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.