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 breaks1, 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 profile3. 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/m2 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. Citation Format: Alexa F. Viniotis, Gayle S. Jameson, Betsy C. Wertheim, Denise J. Roe, Daniel Mocan, Shelby Pearse, Sunil Sharma, Michael S. Gordon, Daniel D. Von Hoff, Erkut H. Borazanci. A phase II clinical trial of lurbinectedin in patients with advanced gastrointestinal malignancies with DNA repair mutations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT161.
Viniotis et al. (Fri,) studied this question.