A phase II pilot evaluation of lurbinectedin in patients with advanced gastrointestinal malignancies with DNA repair mutations.
- 1HonorHealth Research Institute, Scottsdale, AZ, USA.
- 2University of Arizona Cancer Center, Tucson, AZ, USA.
- 3Translational Genomics Research Institute, Phoenix, AZ, USA.
Abstract
Over 17% of gastrointestinal (GI) malignancies involve deficient DNA damage repair (DDR) mechanisms that have poor outcomes on standard chemotherapy but are sensitive to targeted therapies like immune checkpoint inhibitors and poly (ADP-ribose) polymerase inhibitors. Lurbinectedin is an alkylating agent that demonstrated a 35.2% overall response rate (ORR) as second-line therapy in small-cell lung cancer patients who progressed on platinum-based chemotherapies. The drug inhibits DDR, promoting apoptosis in tumor cells through double-stranded DNA breaks (DSBs). Since repair-deficient tumors cannot efficiently and adequately fix these DSBs, DNA damage accumulates and results in enhanced tumor killing. Therefore, lurbinectedin's mechanism makes it suitable for use in cancers with DDR mutations. Our study evaluated the efficacy of lurbinectedin monotherapy in patients with advanced GI malignancies who harbored DDR mutations. This was a prospective open-label, single-arm phase II study at a single institution. Participants were age ≥18 years, had Eastern Cooperative Oncology Group (ECOG) performance status score ≤1, and locally advanced unresectable or metastatic GI cancer with ≥1 deleterious DDR mutation. Intravenous lurbinectedin was administered at 3.2 mg/m2 on day 1 every 3 weeks. Hematology and chemistry labs were obtained on days 1, 8, and 15 of cycles 1 and 2, and day 1 of every subsequent cycle. Tumor markers (CA 19-9 or carcinoembryonic antigen) were collected on day 1 of each cycle. Tumor assessment via imaging occurred at least every three cycles. The primary outcome was ORR according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary outcomes included duration of response, tumor marker normalization, progression-free survival (PFS), overall survival (OS), and safety using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Eight participants (7 pancreatic cancer, 1 rectal cancer) with at least two prior therapy lines were enrolled and had DDR mutations in ATM (25.0%), ARID1A (62.5%), BRCA1 (25.0%), CHEK2 (12.5%), and FANC (12.5%). Median age was 63.5 years, 62.5% were female, and 87.5% were white. The ORR at 12 weeks was 0%. Median (95% confidence interval) PFS and OS were 1.2 (0.7-2.8) and 2.4 (1.2-4.1) months, respectively. The most common related adverse events (AEs) 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 (1 each). In this trial of individuals with advanced GI malignancies with known DDR mutations, there was no clinical benefit of lurbinectedin, as all experienced progressive disease while on the agent (NCT05229588). Interpretation of the study is limited by the small sample size, only two types of GI cancers represented, early termination, and that most participants (62.5%) only completed one dose of the drug.
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BibTeX
@article{viniotis2026phase,
title = {{A phase II pilot evaluation of lurbinectedin in patients with advanced gastrointestinal malignancies with DNA repair mutations.}},
author = {Alexa F Viniotis and Gayle S Jameson and Betsy C Wertheim and Denise J Roe and Daniel Mocan and Shelby Pearse and Sunil Sharma and Michael S Gordon and Daniel D Von Hoff and Erkut H Borazanci},
journal = {Journal of gastrointestinal oncology},
year = {2026},
month = aug,
doi = {10.21037/jgo-2026-0468},
url = {https://europepmc.org/article/MED/42996844},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A phase II pilot evaluation of lurbinectedin in patients with advanced gastrointestinal malignancies with DNA repair mutations.
AU - Alexa F Viniotis
AU - Gayle S Jameson
AU - Betsy C Wertheim
AU - Denise J Roe
AU - Daniel Mocan
AU - Shelby Pearse
AU - Sunil Sharma
AU - Michael S Gordon
AU - Daniel D Von Hoff
AU - Erkut H Borazanci
PY - 2026
DA - 2026/08/25
JO - Journal of gastrointestinal oncology
DO - 10.21037/jgo-2026-0468
UR - https://europepmc.org/article/MED/42996844
AB - Over 17% of gastrointestinal (GI) malignancies involve deficient DNA damage repair (DDR) mechanisms that have poor outcomes on standard chemotherapy but are sensitive to targeted therapies like immune checkpoint inhibitors and poly (ADP-ribose) polymerase inhibitors. Lurbinectedin is an alkylating agent that demonstrated a 35.2% overall response rate (ORR) as second-line therapy in small-cell lung cancer patients who progressed on platinum-based chemotherapies. The drug inhibits DDR, promoting apoptosis in tumor cells through double-stranded DNA breaks (DSBs). Since repair-deficient tumors cannot efficiently and adequately fix these DSBs, DNA damage accumulates and results in enhanced tumor killing. Therefore, lurbinectedin's mechanism makes it suitable for use in cancers with DDR mutations. Our study evaluated the efficacy of lurbinectedin monotherapy in patients with advanced GI malignancies who harbored DDR mutations. This was a prospective open-label, single-arm phase II study at a single institution. Participants were age ≥18 years, had Eastern Cooperative Oncology Group (ECOG) performance status score ≤1, and locally advanced unresectable or metastatic GI cancer with ≥1 deleterious DDR mutation. Intravenous lurbinectedin was administered at 3.2 mg/m2 on day 1 every 3 weeks. Hematology and chemistry labs were obtained on days 1, 8, and 15 of cycles 1 and 2, and day 1 of every subsequent cycle. Tumor markers (CA 19-9 or carcinoembryonic antigen) were collected on day 1 of each cycle. Tumor assessment via imaging occurred at least every three cycles. The primary outcome was ORR according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary outcomes included duration of response, tumor marker normalization, progression-free survival (PFS), overall survival (OS), and safety using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Eight participants (7 pancreatic cancer, 1 rectal cancer) with at least two prior therapy lines were enrolled and had DDR mutations in ATM (25.0%), ARID1A (62.5%), BRCA1 (25.0%), CHEK2 (12.5%), and FANC (12.5%). Median age was 63.5 years, 62.5% were female, and 87.5% were white. The ORR at 12 weeks was 0%. Median (95% confidence interval) PFS and OS were 1.2 (0.7-2.8) and 2.4 (1.2-4.1) months, respectively. The most common related adverse events (AEs) 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 (1 each). In this trial of individuals with advanced GI malignancies with known DDR mutations, there was no clinical benefit of lurbinectedin, as all experienced progressive disease while on the agent (NCT05229588). Interpretation of the study is limited by the small sample size, only two types of GI cancers represented, early termination, and that most participants (62.5%) only completed one dose of the drug.
SN - 2078-6891
SN - 2219-679X
ER -