학술논문
Surrogate endpoints for overall survival in randomized clinical trials testing immune checkpoint inhibitors: a systematic review and meta-analysis.
Document Type
Report
Author
Sala I; Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy.; Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.; Pagan E; Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy.; Pala L; Department of Medical Oncology, Humanitas Gavazzeni, Bergamo, Italy.; Oriecuia C; Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.; Musca M; Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy.; Methodology for Clinical Research Laboratory, Istituto di Ricerche Farmacologiche Mario Negri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.; Specchia C; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.; De Pas T; Department of Medical Oncology, Humanitas Gavazzeni, Bergamo, Italy.; Cortes J; International Breast Cancer Center, Pangaea Oncology, Quiron Group, Madrid, Spain.; International Breast Cancer Center, Pangaea Oncology, Quiron Group, Barcelona, Spain.; Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid, Spain.; Giaccone G; Meyer Cancer Center, Weill Cornel Medicine, New York, NY, United States.; Postow M; Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, United States.; Gelber RD; Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Harvard Tseng-Hsi (T.H.) Chan School of Public Health, and Frontier Science and Technology Research Foundation, Boston, MA, United States.; Bagnardi V; Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy.; Conforti F; Department of Medical Oncology, Humanitas Gavazzeni, Bergamo, Italy.; University of Milan, Milan, Italy.
Source
Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
Subject
Language
English
Abstract
Introduction: There is debate on which are the best surrogate endpoint and metric to capture treatment effect on overall survival (OS) in RCTs testing immune-checkpoint inhibitors (ICIs).
Methods: We systematically searched for RCTs testing ICIs in patients with advanced solid tumors. Inclusion criteria were: RCTs i) assessing PD-(L)1 and CTLA-4 inhibitors either as monotherapy or in combination with another ICI, and/or targeted therapy, and/or chemotherapy, in patients with advanced solid tumors; ii) randomizing at least 100 patients. We performed a meta-analysis of RCTs to compare the surrogacy value of PFS and modified-PFS (mPFS) for OS in RCTs testing ICIs, when the treatment effect is measured by the hazard ratio (HR) for OS, and by the HR and the ratio of restricted mean survival time (rRMST) for PFS and mPFS.
Results: 61 RCTs (67 treatment comparisons and 36,034 patients) were included in the analysis. In comparisons testing ICI plus chemotherapy, HRPFS and HR mPFS both had a strong surrogacy value (R 2 = 0.74 and R 2 = 0.81, respectively). In comparisons testing ICI as monotherapy, HR PFS was the best surrogate, although having a moderate correlation (R 2 = 0.58). In comparisons testing ICI plus other treatment(s), the associations were very weak for all the surrogate endpoints and treatment effect measures, with R 2 ranging from 0.01 to 0.22.
Conclusion: In RCTs testing ICIs, the value of potential surrogates for HROS was strongly affected by the type of treatment(s) tested. The evidence available supports HR PFS as the best surrogate, and disproves the use of alternative endpoints, such as the mPFS, or treatment effect measures, such as the RMST.
Competing Interests: Author JC was employed by the company Pangaea Oncology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Sala, Pagan, Pala, Oriecuia, Musca, Specchia, De Pas, Cortes, Giaccone, Postow, Gelber, Bagnardi and Conforti.)
Methods: We systematically searched for RCTs testing ICIs in patients with advanced solid tumors. Inclusion criteria were: RCTs i) assessing PD-(L)1 and CTLA-4 inhibitors either as monotherapy or in combination with another ICI, and/or targeted therapy, and/or chemotherapy, in patients with advanced solid tumors; ii) randomizing at least 100 patients. We performed a meta-analysis of RCTs to compare the surrogacy value of PFS and modified-PFS (mPFS) for OS in RCTs testing ICIs, when the treatment effect is measured by the hazard ratio (HR) for OS, and by the HR and the ratio of restricted mean survival time (rRMST) for PFS and mPFS.
Results: 61 RCTs (67 treatment comparisons and 36,034 patients) were included in the analysis. In comparisons testing ICI plus chemotherapy, HR
Conclusion: In RCTs testing ICIs, the value of potential surrogates for HR
Competing Interests: Author JC was employed by the company Pangaea Oncology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Sala, Pagan, Pala, Oriecuia, Musca, Specchia, De Pas, Cortes, Giaccone, Postow, Gelber, Bagnardi and Conforti.)