학술논문
Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses.
Document Type
Academic Journal
Author
Konstantinopoulos PA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Cheng SC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Lee EK; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; da Costa AABA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA.; Gulhan D; Department of Biomedical Informatics and Ludwig Center at Harvard, Harvard Medical School, Boston, MA.; Wahner Hendrickson AE; Department of Medical Oncology, Mayo Clinic, Rochester, MN.; Kochupurakkal B; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA.; Kolin DL; Department of Pathology, Brigham and Women's Hospital, Boston, MA.; Kohn EC; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.; Liu JF; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Penson RT; Department of Medical Oncology, Massachusetts General Hospital, Boston, MA.; Stover EH; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Curtis J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Sawyer H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Polak M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Chowdhury D; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.; D'Andrea AD; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA.; Färkkilä A; Research Program in Systems Oncology, FIMM and HiLife, University of Helsinki, Helsinki, Finland.; Shapiro GI; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Matulonis UA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Source
Publisher: American Society of Clinical Oncology Country of Publication: United States NLM ID: 101705370 Publication Model: Print Cited Medium: Internet ISSN: 2473-4284 (Electronic) Linking ISSN: 24734284 NLM ISO Abbreviation: JCO Precis Oncol Subsets: MEDLINE
Subject
Language
English
Abstract
Purpose: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation).
Methods: We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib.
Results: At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06).
Conclusion: The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.
Methods: We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib.
Results: At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06).
Conclusion: The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.