Progression-Free Survival as Surrogate for Overall Survival in First-Line Treatment of DLBCL

Key Points

  • Progression-free survival was strongly correlated with overall survival at both trial and individual patient level.
  • Progression-free survival at 24 months did not meet surrogacy criteria at the trial level but was significantly associated with overall survival at the patient level.

In an individual patient-level analysis reported in the Journal of Clinical Oncology, Shi et al found that progression-free survival could serve as a surrogate endpoint for overall survival in the first-line treatment of diffuse large B-cell lymphoma (DLBCL).

The study involved data from 7,507 patients from 13 multicenter randomized trials of active treatment in previously untreated patients with DLBCL published between 2002 and 2015. The objective was to evaluate progression-free survival (ie, time from initiation of induction treatment to the earliest occurrence of progressive disease, relapse, or death resulting from any cause) and progression-free survival at 24 months as surrogate endpoints.

Trial-level surrogacy examining the correlation of treatment effect estimates of these endpoints as well as overall survival was evaluated using linear regression (R2-WLS) and Copula bivariable models (R2-Copula). R2-Copula takes into account patient-level correlation between the two endpoints, whereas R2-WLS does not. Prespecified criteria for surrogacy were R2-WLS or R2-Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% confidence interval [CI] > 0.60.

Strength of Surrogacy

Trial-level surrogacy of progression-free survival for overall survival was strong, meeting the prespecified criteria with R2-WLS = 0.83 and R2-Copula = 0.85. At the patient level, progression-free survival was also strongly correlated with overall survival; the surrogate threshold effect had a hazard ratio of 0.89, meaning that an observed hazard ratio ≤ 0.89 for progression-free survival would predict a significant treatment effect on overall survival in a future trial. The strength of surrogacy of progression-free survival for overall survival was consistent across comparisons with or without rituximab and with rituximab maintenance trials.

Trial-level surrogacy for progression-free survival at 24 months was relatively strong but did not meet predefined criteria with R2-WLS = 0.77 and R2-Copula = 0.78. At the patient level, progression-free survival at 24 months was significantly correlated with overall survival; the surrogate threshold effect had an odds ratio of 1.51, meaning that an observed odds ratio ≥ 1.51 for progression-free survival at 24 months would predict a significant treatment effect on overall survival in a future trial.

The investigators concluded, “This large pooled analysis of individual patient data supports [progression-free survival] as a surrogate endpoint for [overall survival] in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this endpoint may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before [overall survival] results are mature.”

The study was supported by grants from Celgene.

Qian Shi, PhD, of the Department of Health Science Research, Mayo Clinic, Rochester, is the corresponding author for the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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