PO.CT01.05 · 临床试验
lurbinectedin治疗携带DNA修复突变的晚期胃肠道恶性肿瘤患者的II期临床试验
A phase II clinical trial of lurbinectedin in patients with advanced gastrointestinal malignancies with DNA repair mutations
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：许多胃肠道（GI）恶性肿瘤涉及错配修复机制缺陷，这类肿瘤对靶向治疗敏感。此外，某些GI恶性肿瘤与脱氧核糖核酸（DNA）损伤修复相关的突变有关。lurbinectedin是一种烷化剂，可将致癌性转录因子从结合位点上移除并抑制DNA损伤修复，通过双链断裂促进肿瘤细胞凋亡1,2。该药作为小细胞肺癌的二线治疗也显示出令人鼓舞的结果，客观缓解率（ORR）为35.2%，且安全性可接受3。我们的这项开放标签、单臂II期研究评估了lurbinectedin治疗肿瘤携带DNA修复突变的晚期GI恶性肿瘤患者的疗效。
方法：受试者年龄≥18岁，东部肿瘤协作组（ECOG）体能状态（PS）评分≤1，经组织学或细胞学确诊为局部晚期不可切除或转移性GI癌，且携带已知的有害DNA修复突变。第1天静脉（IV）给予lurbinectedin 3.2 mg/m2，每3周一次。主要结局为根据实体瘤疗效评价标准1.1版（RECIST v.1.1）评估的ORR。次要结局包括缓解持续时间（DOR）、肿瘤标志物变化、无进展生存期（PFS）、总生存期（OS），以及根据美国国家癌症研究所常见不良事件术语标准5版（NCI-CTCAE v.5）评估的安全性。
结果：共入组8名受试者，中位年龄63.5岁。63%为女性，88%为白人。7名受试者患有胰腺癌，1名患有直肠癌。每名受试者携带以下一种或多种突变：ATM、ARID1、BRCA1、CHEK2和FANC。没有受试者达到完全缓解或部分缓解（CR或PR），因此12周时ORR为0%。在3名肿瘤标志物高于正常上限（ULN）两倍的受试者中，无一例恢复正常。中位（95%置信区间）PFS为1.2（0.7-2.8）个月，中位OS为2.4（1.2-4.1）个月。仅1名受试者在12个月时仍存活。可能或明确与lurbinectedin相关的最常见不良事件（AE）为1级和2级厌食（50.0%）和便秘（25.0%）；以及2级恶心（37.5%）、贫血（25.0%）和乏力（25.0%）。2名患者（25.0%）经历了可能与lurbinectedin相关的3级和4级中性粒细胞减少。
结论：在这项针对携带DNA修复突变的晚期GI恶性肿瘤患者的试验中，未观察到临床获益，因为所有受试者在接受lurbinectedin治疗期间均出现疾病进展。
查看英文原文 English abstract
Background: Many gastrointestinal (GI) malignancies involve deficient mismatch repair mechanisms that are sensitive to targeted therapy. Additionally, some GI malignancies are associated with mutations in deoxyribonucleic acid (DNA) damage repair. Lurbinectedin is an alkylating agent that removes oncogenic transcription factors from binding sites and inhibits DNA damage repair, promoting apoptosis in tumor cells through double-stranded breaks 1,2 . The drug has also shown promising results as second line therapy in small cell lung cancer with an overall response rate (ORR) of 35.2% and an acceptable safety profile 3 . Our open label, single arm phase II study evaluated the efficacy of lurbinectedin in patients with advanced GI malignancies whose tumors harbored DNA repair mutations.
Methods: Participants were ≥ 18 years old and had Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤ 1, histologically or cytologically confirmed locally advanced unresectable or metastatic GI cancer with a known deleterious DNA repair mutation. Intravenous (IV) lurbinectedin at 3.2 mg/m 2 was administered on Day 1 every 3 weeks. The primary outcome was ORR according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1). Secondary outcomes included duration of response (DOR), evolution of tumor markers, progression-free survival (PFS), overall survival (OS), and safety according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v.5).
Results: Eight participants were enrolled with a median age of 63.5 years. 63% were female and 88% were white. Seven participants had pancreatic cancer, and one had rectal cancer. Each participant had one or more of the following mutations: ATM, ARID1, BRCA1, CHEK2, and FANC. None of the participants achieved complete or partial response (CR or PR), so the ORR at 12 weeks was 0%. Of the three participants with tumor markers greater than two times the upper limit of normal (ULN), none normalized. Median (95% confidence interval) PFS was 1.2 (0.7-2.8) months, and median OS was 2.4 (1.2-4.1) months. Only one participant remained alive at 12 months. The most common adverse events (AEs) possibly or definitely related to lurbinectedin were grade 1 and 2 anorexia (50.0%) and constipation (25.0%); and grade 2 nausea (37.5%), anemia (25.0%), and fatigue (25.0%). Two patients (25.0%) experienced grade 3 and 4 neutropenia likely related to lurbinectedin.
Conclusion: In this trial of individuals with advanced GI malignancies with DNA repair mutations, there was no clinical benefit as all participants experienced progressive disease while on lurbinectedin.
利益披露 Disclosure
A. F. Viniotis, None.
G. S. Jameson,
Bristol Myers Squibb ).
B. C. Wertheim, None..
D. J. Roe, None..
D. Mocan, None..
S. Pearse, None.
S. Sharma,
Black Canyon Bio Employment, Stock, Stock Option, Other, Chief Medical Officer/Co-founder.
StingRay Therapeutics Employment, Stock, Other, Chief Medical Officer.
Cure CRC Independent Contractor, Travel, Other, Consulting.
M. S. Gordon,
Sphinx Health Solution g., Board of Directors, non-salaried role).
Deciphera; Springworks; Novartis Independent Contractor.
Remepy Stock Option.
Agenus; Corcept; Deciphera; Dynamicure; Fibrogen; Genentech; Marck; Novartis; Pyxis; Riboscience; Shenzhen Ionova; Tagworks; VIR Biotechnology; Celldex; Endocyte; Fore; Forma Thx; GSK; I-Mab; Tracon ).
IGM Biosciences; ImaginAb; Nikang; Nimbus Saturn; OncoResponse; Pfizer; Plexxicon; SQZ Biotech; Theseus ).
Agenus Travel.
UArizona/HonorHealth Patent.
SphinxMatch Trademark.
D. D. Von Hoff,
Medtronic; CerRx; SynDevRx; UnitedHealthcare; Anthem Inc; Stromatis Pharma Stock, Other Business Ownership.
Systems Oncology; StingRay; Orpheus Bioscience; AADi; Halia Therapeutics; Lycia Therapeutics; (3+2) Pharma; AcuViz; Blossom Hill Stock, Other Business Ownership.
Imaging Endpoints; CanBas; Lixte Biotechnology; TD2; Phosplatin Therapeutics; SOTIO; Immunophotonics; Oncology Venture; Novita Pharmaceuticals; Vicus Therapeutics; Sirnaomics; AiMed Bio Other, Consulting or Advisory Role.
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SMP Oncology fka SDP/Tolero; Red Arrow Therapeutics; Soley Therapeutics; Invios GmbH; Peptomyc; Remunity; SIWA Therapeutics; Xenthera; Panavance Therapeutics fka Geistlich; CyMon Bio; Bryologyx Other, Consulting or Advisory Role.
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Lilly; Genentech; Celgene; Incyte; Merrimack; Plexxikon; Minneamrita Therapeutics; Abbvie; Aduro Biotech; Cleave Biosciences; CytRx Corporation; Daiichi Sankyo; Deciphera; Endocyte; Exelixis ).
Five Prime Therapeutics; Gilead Sciences; Merck; Pfizer; Pharmacyclics; Phoenix Biotech; Samumed; Strategia; Halozyme ).
Intramedullary Catheter Patent, Other Intellectual Property.
Methods of Human Prostate Cancer Patent, Other Intellectual Property.
Use of 5,6-Dihydro-5-Azacytidine in the Treatment of Prostate Cancer Patent, Other Intellectual Property.
Targeting Ecto-5-Nucleotidase (Cd73) for the Treatment of Pancreatic Cancer Patent, Other Intellectual Property.
E. H. Borazanci,
Revolution Medicines Stock, Other, Consulting.
Corcept Other, Consulting.
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Immuneering Other, Consulting.
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