PO.CT01.05 · 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
摘要 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.
Erimos Pharma; Pfizer; ImmuneOncia; Viracta Therapeutics; AlaMab; Xerient; Lycia Therapeutics; EXACT Therapeutics; ImagineAB; SignaBlok; Compass Therapeutics; Sellas Life Sciences Other, Consulting or Advisory Role.
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.
Moleculin Biotech; EnGeneIC; RaceOncology; Autonomix; Econic Biosciences; Crinetics Pharmaceuticals; Diakonos Research; Improve Bio; Duo Oncology; ImmuVia; WUGEN, Inc.; Origin Commercial Advisors Other, Consulting or Advisory Role.
Civala Other, Consulting or Advisory Role.
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.
Arcus Other, Consulting.
Immuneering Other, Consulting.
Merus Other, Consulting.
Taiho Other, Consulting.