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 ( 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.

Trial registration: ClinicalTrials.gov NCT01148446.

Figures

Fig 1.

Flowchart of study selection. Abbreviation: IPD, individual patient data.

Fig 2.

(A) Trial-level treatment effect correlation between progression-free survival (PFS) and overall survival (OS). Circle/triangle size is proportional to sample size. Solid line indicates fitted weighted least squares (WLS) regression line; gray dashed lines indicate 95% prediction limits. (B) PFS surrogacy sensitivity analysis: leave-one-out cross-validation. For each comparison, the open circle/triangle is the predicted log (hazard ratio [HR]) on OS based on the estimated WLS regression line at trial level, removing the comparison listed; the horizontal bars indicate 95% prediction interval. (C) PFS surrogacy sensitivity analysis: leave-one-out re-estimation. For each labeled comparison, R2WLS and R2Copula were estimated by excluding the labeled comparison; vertical bars indicate 95% CI. ANZINTER, Intergruppo Italiano Linfomi; MegaCHOEP, cyclophosphamide, doxorubicin, vincristine, and prednisone plus etoposide; MInT, MabThera International Trial Group; NHL, non-Hodgkin lymphoma; PIX, pixantrone; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Fig 3.

(A) Trial-level treatment effect correlation between progression-free survival at 24 months (PFS24) and overall survival (OS). Circle/triangle size is proportional to sample size. Solid line indicates fitted weighted least squares (WLS) regression line; gray dashed lines indicate 95% prediction limits. (B) PFS24 surrogacy sensitivity analysis: leave-one-out cross-validation. For each comparison, the open circle/triangle is the predicted log (hazard ratio [HR]) on OS based on the estimated WLS regression line at trial level, removing the comparison listed; horizontal bars indicate 95% prediction interval. (C) PFS24 surrogacy sensitivity analysis: leave-one-out re-estimation. For each labeled comparison, R2WLS and R2Copula were estimated by excluding the labeled comparison; vertical bars indicate 95% CI. ANZINTER, Intergruppo Italiano Linfomi; MegaCHOEP, cyclophosphamide, doxorubicin, vincristine, and prednisone plus etoposide; MInT, MabThera International Trial Group; NHL, non-Hodgkin lymphoma; PIX, pixantrone; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Fig A1.

Distribution of (A) progression-free survival in overall population pooling of all patients across studies and (B) overall survival in overall population pooling of all patients across studies at a median follow-up time of 52 months.