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)

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 ( R) and Copula bivariable ( R) models. Prespecified criteria for surrogacy required either R or R ≥ 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R = 0.83; R = 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 ( R = 0.77; R = 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.

Pre-Therapeutic Total Lesion Glycolysis on [18F]FDG-PET Enables Prognostication of 2-Year Progression-Free Survival in MALT Lymphoma Patients Treated with CD20-Antibody-Based Immunotherapy

“…Furthermore, PFS is recognized by the FDA as a valid surrogate endpoint for non-Hodgkin lymphomas (https:// www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/ DevelopmentResources/UCM614369.xlsx). For DLBCL, a recent analysis of multiple randomized trials with a total sample size of 7507 patients also clearly supported the use of PFS, and showed that 2-year PFS significantly correlates with OS [20].…”

A population‐based multistate model for diffuse large B‐cell lymphoma–specific mortality in older patients

“…This issue is an important one to consider in other very large clinical data sets with direct ascertainment of the treatment regimen, dosing, timing of dose delivery, and outcomes. Large clinical data sets, such as the Surrogate Endpoints for Aggressive Lymphoma (SEAL) collaboration, now are becoming available to address such questions …”

“…Large clinical data sets, such as the Surrogate Endpoints for Aggressive Lymphoma (SEAL) collaboration, now are becoming available to address such questions. 55 In terms of methodology, even though the Aalen-Johansen estimator is the canonical nonparametric maximum likelihood estimator for multistate models with guaranteed asymptotical convergence, [17][18][19]21,29,56 caution must be exercised because the size of the available data gets smaller. This is unlikely to pose an issue for subpopulation analyses (eg, patients using R-CHOP) but might be a concern for individualized predictions because each covariate defining an individual patient also shrinks the size of the available data that the estimator uses.…”

Microsatellite instability and its associations with the clinicopathologic characteristics of diffuse large B‐cell lymphoma

“…For the survival analyses, the endpoints were progression-free survival (PFS) and overall survival (OS). 13 OS was counted from the date of diagnosis to the date of death from any cause. PFS was counted from the date of diagnosis to the date of lymphoma recurrence or death from any cause or the date of last follow-up.…”

“…The associations between the MSI status and clinicopathologic features were analyzed by Pearson's chi‐square test, Mann‐Whitney test or the Fisher's exact test. For the survival analyses, the endpoints were progression‐free survival (PFS) and overall survival (OS) . OS was counted from the date of diagnosis to the date of death from any cause.…”