Progression-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)

Qian Shi, Norbert Schmitz, Fang-Shu Ou, Jesse G Dixon, David Cunningham, Michael Pfreundschuh, John F Seymour, Ulrich Jaeger, Thomas M Habermann, Corinne Haioun, Hervé Tilly, Hervé Ghesquieres, Francesco Merli, Marita Ziepert, Raoul Herbrecht, Jocelyne Flament, Tommy Fu, Bertrand Coiffier, Christopher R Flowers

Research output: Contribution to journalArticle

Abstract

Purpose 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.

Original languageEnglish
Pages (from-to)2593-2602
Number of pages10
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume36
Issue number25
DOIs
Publication statusPublished - Sep 1 2018

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Lymphoma, Large B-Cell, Diffuse
Disease-Free Survival
Biomarkers
Survival
Therapeutics
Randomized Controlled Trials
Cell- and Tissue-Based Therapy
Linear Models
B-Lymphocytes
Odds Ratio
Maintenance
Clinical Trials

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Progression-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). / Shi, Qian; Schmitz, Norbert; Ou, Fang-Shu; Dixon, Jesse G; Cunningham, David; Pfreundschuh, Michael; Seymour, John F; Jaeger, Ulrich; Habermann, Thomas M; Haioun, Corinne; Tilly, Hervé; Ghesquieres, Hervé; Merli, Francesco; Ziepert, Marita; Herbrecht, Raoul; Flament, Jocelyne; Fu, Tommy; Coiffier, Bertrand; Flowers, Christopher R.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 36, No. 25, 01.09.2018, p. 2593-2602.

Research output: Contribution to journalArticle

Shi, Q, Schmitz, N, Ou, F-S, Dixon, JG, Cunningham, D, Pfreundschuh, M, Seymour, JF, Jaeger, U, Habermann, TM, Haioun, C, Tilly, H, Ghesquieres, H, Merli, F, Ziepert, M, Herbrecht, R, Flament, J, Fu, T, Coiffier, B & Flowers, CR 2018, 'Progression-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)', Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 36, no. 25, pp. 2593-2602. https://doi.org/10.1200/JCO.2018.77.9124
Shi, Qian ; Schmitz, Norbert ; Ou, Fang-Shu ; Dixon, Jesse G ; Cunningham, David ; Pfreundschuh, Michael ; Seymour, John F ; Jaeger, Ulrich ; Habermann, Thomas M ; Haioun, Corinne ; Tilly, Hervé ; Ghesquieres, Hervé ; Merli, Francesco ; Ziepert, Marita ; Herbrecht, Raoul ; Flament, Jocelyne ; Fu, Tommy ; Coiffier, Bertrand ; Flowers, Christopher R. / Progression-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). In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018 ; Vol. 36, No. 25. pp. 2593-2602.
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abstract = "Purpose 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.",
author = "Qian Shi and Norbert Schmitz and Fang-Shu Ou and Dixon, {Jesse G} and David Cunningham and Michael Pfreundschuh and Seymour, {John F} and Ulrich Jaeger and Habermann, {Thomas M} and Corinne Haioun and Herv{\'e} Tilly and Herv{\'e} Ghesquieres and Francesco Merli and Marita Ziepert and Raoul Herbrecht and Jocelyne Flament and Tommy Fu and Bertrand Coiffier and Flowers, {Christopher R}",
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TY - JOUR

T1 - Progression-Free Survival as a Surrogate End Point for Overall Survival in First-Line Diffuse Large B-Cell Lymphoma

T2 - An Individual Patient-Level Analysis of Multiple Randomized Trials (SEAL)

AU - Shi, Qian

AU - Schmitz, Norbert

AU - Ou, Fang-Shu

AU - Dixon, Jesse G

AU - Cunningham, David

AU - Pfreundschuh, Michael

AU - Seymour, John F

AU - Jaeger, Ulrich

AU - Habermann, Thomas M

AU - Haioun, Corinne

AU - Tilly, Hervé

AU - Ghesquieres, Hervé

AU - Merli, Francesco

AU - Ziepert, Marita

AU - Herbrecht, Raoul

AU - Flament, Jocelyne

AU - Fu, Tommy

AU - Coiffier, Bertrand

AU - Flowers, Christopher R

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Purpose 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.

AB - Purpose 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.

U2 - 10.1200/JCO.2018.77.9124

DO - 10.1200/JCO.2018.77.9124

M3 - Article

C2 - 29975624

VL - 36

SP - 2593

EP - 2602

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 25

ER -