PO.CTP01.03 · 进行中的临床试验
AACR自适应生物标志物驱动的胃食管腺癌器官保留试验（AACR-ADOPT-GEA）
AACR Adaptive Biomarker-Driven Organ Preservation Trial in GE Adenocarcinomas (AACR-ADOPT-GEA)
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：
局限性胃食管腺癌（GEA）在分子层面具有异质性，且往往对现有系统治疗敏感性有限。标准围手术期化疗的5年生存率约为40%，仅约15%的患者达到病理完全缓解（pCR）。AACR-ADOPT-GEA旨在克服这些障碍，并首次在GEA中评估通过向患者提供生物标志物匹配的靶向治疗是否可实现器官保留。值得注意的是，若干可靶向的生物标志物——HER2、MSI、EBV和CLDN18.2——已在转移性GEA中证明具有治疗相关性。在AACR-ADOPT-GEA中，我们假设在生物标志物选择的队列中，在局部晚期GEA的治疗中加入靶向药物可提高pCR率，并使约20%的患者实现5年器官保留。
方法：
AACR-ADOPT-GEA（NCT07290985）是一项前瞻性、多中心、两阶段自适应平台试验。合格参与者包括诊断为可切除（根据NCCN指南为II期或更高[≥T2 N0-3 M0或T0-4a N1-3 M0]）的胃、食管或胃食管交界处腺癌患者，ECOG体能状态评分为0-1，器官功能充足，为根治性手术的候选者，且检测出一种可靶向的肿瘤生物标志物阳性。参与者可在筛选期接受一个周期的FLOT/mFOLFOX。在筛选和生物标志物确认后，参与者将被纳入相应的子研究，并接受特定生物标志物的靶向药物，联合mFOLFOX加免疫检查点抑制剂（ICI）治疗4个月。术前治疗后进行手术，随后进行为期8个月的术后治疗，包括靶向药物和ICI。这项两阶段研究旨在评估每种靶向方案的pCR率，第一阶段初始队列每个子研究最多24例患者。在每个子研究入组12例可评估患者后进行中期分析，以剔除无效方案。达到pCR率≥25%（24例患者中6例）的方案将晋级并进入第二阶段，在该阶段将利用临床数据、肿瘤生物学和连续ctDNA动态开发一个机器学习预测模型，以建立预测pCR的特征。在第二阶段，将入组97例患者，以在双侧显著性水平0.05下，达到80%的检验效能来检验预测pCR的ROC曲线下面积0.80对比0.65。在此阶段，治疗4个月后达到完全临床/影像学缓解且预测为pCR的患者可省略手术，并继续进行8个月的维持治疗，同时按方案规定进行监测。有残留疾病者将接受手术切除，随后进行术后治疗。重要的是，在第二阶段获取治疗前后的组织样本将支持进行应答/耐药生物标志物的多组学分析，以推动该领域的未来工作。
查看英文原文 English abstract
Background:
Localized gastroesophageal adenocarcinomas (GEA) are molecularly heterogeneous and often exhibit limited sensitivity to current systemic therapies. The 5-year survival rate with standard perioperative chemotherapy is ~40%, and only ~15% of patients achieve a pathologic complete response (pCR). AACR-ADOPT-GEA was designed to overcome these barriers and assess, for the first time in GEA, if organ preservation is achievable by delivering biomarker-matched targeted therapies to patients. Notably, several targetable biomarkers - HER2, MSI, EBV, and CLDN18.2 - have demonstrated therapeutic relevance in metastatic GEA. In AACR-ADOPT-GEA, we hypothesize that in biomarker-selected cohorts, addition of a targeted agent for treatment of locally advanced GEA can increase pCR rates and enable 5-year organ preservation in approximately 20% of patients.
Methods:
AACR-ADOPT-GEA (NCT07290985) is a prospective, multi-center, two-stage adaptive platform trial. Eligible participants include patients diagnosed with resectable (stage II or higher [≥T2 N0-3 M0 or T0-4a N1-3 M0] as per NCCN guidelines) adenocarcinoma of the stomach, esophagus, or gastroesophageal junction, have an ECOG performance score of 0-1, adequate organ function, to be a candidate for curative surgery, and test positive for one of the targetable tumor biomarkers. Participants may receive one cycle of FLOT/mFOLFOX during the screening period. Following screening and biomarker confirmation, participants will be enrolled into a corresponding sub-study and treated with a biomarker-specific targeted agent in addition to mFOLFOX plus an immune checkpoint inhibitor (ICI) for 4 months. Pre-operative treatment will be followed by surgery and an 8-month post-operative treatment consisting of the targeted agent and an ICI. This two-stage study is designed to assess pCR rates for each targeted regimen with an initial cohort of up to 24 patients in Stage I. An interim analysis will be conducted after enrollment of 12 evaluable patients in each sub-study to drop futile regimens. Those regimens achieving a pCR rate ≥25% (6 out of 24 patients) will graduate and proceed to Stage II where a machine learning predictive model, utilizing clinical data, tumor biology, and serial ctDNA dynamics will be developed to establish a signature predictive of pCR. In stage II, 97 patients will be enrolled to achieve 80% power to test the area under the ROC curve of 0.80 against 0.65 to predict pCR at a two-sided significance level of 0.05. During this stage, patients with a complete clinical/radiological response and predicted pCR after 4 months of treatment may omit surgery and continue on 8 months of maintenance therapy with protocol-specified surveillance. Those with residual disease will undergo surgical resection followed by postoperative therapy. Importantly, access to pre- and post-treatment tissue samples in Stage II will enable multiomic analyses for response/resistance biomarkers to catalyze future work in this area.
利益披露 Disclosure
E. Elimova,
BMS ), Other, Consulting.
Zymeworks ), Other, Consulting.
Adaptimuune Consulting.
Astellas Other, Consulting.
Beigene Other, Consulting.
Viracta Tx Other, Consulting.
Novartis Other, Consulting.
Jazz ), Other, Consulting
Steering committee.
Natera Other, Consulting.
Abbvie Other, Consulting.
Daiichi-Sankyo Other, Consulting.
Roche Consulting.
Amgen ), Other, Consulting.
Astra Zeneca ), Other, Consulting
Steering Committee.
Bold therapeutics ).
Arcus Biosciences ).
Merck Other, Family memeber.
J. Ajani,
Jazz Pharmaceuticals, Zymeworks, and BeOne Medicines Other, Consultant.
S. J. Klempner,
Merck Other, consulting.
Astellas Other, Consulting.
Daiichi-Sankyo Other, Consulting.
Natera Other, Consulting.
Novartis Other, Consulting.
AstraZeneca Other, Consulting.
Mersana Other, consulting.
Beigene Other, Consulting.
Gilead Other, Consulting.
Elevation Oncology Other, Consulting.
EsoBiotec Other, Consulting.
Eisai Other, Consulting.
Boehringer-Ingelheim Other, Consulting.
I-Mab Other, Consulting.
Signet Therapeutics Other, Consulting.
Torrey Coast Foundation, the Degregorio Foundation, the Gastric Cancer Foundation, Debbie’s Dream Foundation, NIH/NCI, StandUp2Cancer, AACR. ).
K. Schalper, None.
Z. Wainberg,
Alligator, Amgen, Arcus, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Lilly, Merck, Merck KGaA, Novartis, and Pfizer Other, Consultant or advisor.
Merck, Novartis, and Plexxikon ).
Amgen, Lilly, and Merck Travel.
Y. Ying,
AbbVie, Affinixttx, Aktis Oncology, Amgen, Astellas, Avance, BioNTech, Blueprint, BrainChildBio, Bristol Myers Squibb, Cassava Sciences, Century Therapeutics, Cogent,CoRegen, GT Medical, Kyowa Kirin Other, Dr. Yuan served as a statistical consultant to these companies.
J. D. Baranski, None..
S. Boerner, None..
S. M. Durbin, None..
D. Gallagher, None..
H. Won Jae, None..
R. A. McLaughlin, None.
M. R. Strickland,
Astellas Pharma Other, Honoraria.
Bristol Myers Squibb, Sedgwick Claims Management, Astellas Pharma, Bayer, encapsulate Other, Consulting or Advisory Role.
UpToDate Other, Patents, Royalties, Other Intellectual Property: UpToDate Editor & Author.
E. H. Rubin,
Modex, PAQ, Eikon, Nurix, TCG Soleil, Generate, and Mestag. Other, Consultant (independent contractor) for these companies.
L. L. Siu,
Merck, Pfizer, AstraZeneca, Roche, GSK, Bayer, Voronoi, Arvinas, Marengo, Daiichi Sankyo, Amgen, LTZ Therapeutics, Tubulis, Incyte, EMD Serono, Accent Other, Consultant/Advisory role (self):.
Merck, Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GSK, Roche/Genentech, AstraZeneca, Bayer, Abbvie, Amgen, EMD Serono, Daiichi Sankyo, Gilead, Marengo, Incyte ).
Treadwell Therapeutics Other, Leadership role (spouse).
T. A. Yap,
Several Other, Dr. Yap reports other support from University of Texas MD Anderson Cancer Center; as Vice President, Head Clinical Development in the Therapeutics Discovery Division, which has a commercial interest in DNA damage response (DDR) and other inhibitors(IACS30380/ ART0380 was licensed to Artios), grants and personal fees from Acrivon, grants and personal fees from Artios, grants and personal fee.
P. LoRusso,
1. AbbVie: Advisory Board Member (2018-2019) 2. Roche-Genentech: imCORE Alliance (2016-2019) 3. Takeda: Advisory Board (2017-2020; 2023-2024) 4. SOTIO: Consultant (2018-2019); IDMC (2023) 5. Agenus: Other, Advisory boards for these companies.