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dc.contributor.authorShi, Q
dc.contributor.authorSchmitz, N
dc.contributor.authorOu, F-S
dc.contributor.authorDixon, JG
dc.contributor.authorCunningham, D
dc.contributor.authorPfreundschuh, M
dc.contributor.authorSeymour, JF
dc.contributor.authorJaeger, U
dc.contributor.authorHabermann, TM
dc.contributor.authorHaioun, C
dc.contributor.authorTilly, H
dc.contributor.authorGhesquieres, H
dc.contributor.authorMerli, F
dc.contributor.authorZiepert, M
dc.contributor.authorHerbrecht, R
dc.contributor.authorFlament, J
dc.contributor.authorFu, T
dc.contributor.authorCoiffier, B
dc.contributor.authorFlowers, CR
dc.date.accessioned2018-11-20T12:07:32Z
dc.date.issued2018-09
dc.identifier.citationJournal of clinical oncology : official journal of the American Society of Clinical Oncology, 2018, 36 (25), pp. 2593 - 2602
dc.identifier.issn0732-183X
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2949
dc.identifier.eissn1527-7755
dc.identifier.doi10.1200/JCO.2018.77.9124
dc.description.abstractPurpose Overall survival (OS) is the definitive and best-established primary efficacy end point to evaluate diffuse large B-cell lymphoma (DLBCL) therapies, but it requires prolonged follow-up. An earlier end point assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate progression-free survival (PFS) and PFS at 24 months (PFS24) as surrogate end points for OS in first-line DLBCL. Patients and Methods Individual patient data were analyzed from 7,507 patients from 13 multicenter randomized controlled trials of active treatment in previously untreated DLBCL, published after 2002, with sufficient PFS data to predict treatment effects on OS. Trial-level surrogacy examining the correlation of treatment effect estimates of PFS/PFS24 and OS was evaluated using both linear regression ( R2WLS) and Copula bivariable ( R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R2WLS = 0.83; R2Copula = 0.85) and met the predefined criteria for surrogacy. At the patient level, PFS strongly correlated with OS. The surrogate threshold effect had a hazard ratio of 0.89. Surrogacy was consistent across comparisons with or without rituximab and with rituximab maintenance trials. Trial-level surrogacy for PFS24 was relatively strong ( R2WLS = 0.77; R2Copula = 0.78) but did not meet prespecified criteria. At the patient level, PFS24 significantly correlated with OS. The surrogate threshold effect had an odds ratio of 1.51. Conclusion This large pooled analysis of individual patient data supports PFS as a surrogate end point for OS in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before OS results are mature.
dc.formatPrint-Electronic
dc.format.extent2593 - 2602
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectHumans
dc.subjectAntineoplastic Agents
dc.subjectTreatment Outcome
dc.subjectMulticenter Studies as Topic
dc.subjectRandomized Controlled Trials as Topic
dc.subjectLymphoma, Large B-Cell, Diffuse
dc.subjectBiomarkers
dc.subjectProgression-Free Survival
dc.titleProgression-Free Survival as a Surrogate End Point for Overall Survival in First-Line Diffuse Large B-Cell Lymphoma: An Individual Patient-Level Analysis of Multiple Randomized Trials (SEAL).
dc.typeJournal Article
rioxxterms.versionofrecord10.1200/JCO.2018.77.9124
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2018-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal of clinical oncology : official journal of the American Society of Clinical Oncology
pubs.issue25
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume36
pubs.embargo.termsNot known
icr.researchteamMedicine (RMH Smith Cunningham)en_US
dc.contributor.icrauthorCunningham, Daviden


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