Evaluation of complete response rate at 30 months (CR30) as a surrogate for progression-free survival (PFS) in first-line follicular lymphoma (FL) studies: Results from the prospectively specified Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) analysis with individual patient data (IPD) of 3,837 patients (pts).

Lymphoma and Plasma Cell Disorders
Session Type and Session Title: 
Oral Abstract Session, Lymphoma
Abstract Number: 


J Clin Oncol 33, 2015 (suppl; abstr 8504)
Daniel J. Sargent, Qian Shi, Sabine De Bedout, Christopher Flowers, Nathan Hale Fowler, Tommy Fu, Anton Hagenbeek, Michael Herold, Eva Hoster, Jane Huang, Eva Kimby, Marco Ladetto, Franck Morschhauser, Tina Nielsen, Kenichi Takeshita, Nancy Valente, Umberto Vitolo, Emanuele Zucca, Gilles A. Salles, the FLASH (Follicular Lymphoma Analysis of Surrogacy Hypothesis) group; Mayo Clinic, Rochester, MN; Celgene, Boudry, Switzerland; Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA; The University of Texas MD Anderson Cancer Center, Houston, TX; Celgene Corporation, Summit, NJ; Academic Medical Center, Amsterdam, Netherlands; Helios Klinikum Erfurt, Erfurt, Germany; University Hospital of Munich, Munich, Germany; Genentech, Inc., South San Francisco, CA; Karolinska University Hospital, Stockholm, Sweden; Hematology Univ. Div., Torino, Italy; Centre Hospitalier Régional Universitaire de Lille, Hôpital Claude Huriez, Service Maladies du Sang, Lille, France; Pharma Development Oncology, F. Hoffmann-La Roche, Basel, Switzerland; Celgene Onc, Summit, NJ; Hematology, A.O. Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Onc Inst of Southern Switzerland, Bellinzona, Switzerland; Hospices Civils de Lyon, Université Claude Bernard, Pierre Bénite, France

Abstract Disclosures


Background: Although PFS is the standard endpoint for new drug approvals in first-line FL, advances in efficacy (median PFS >7 y) coupled with the indolent nature of FL necessitate extended patient follow-up in clinical trials. The FLASH group conducted a meta-analysis to evaluate whether treatment effects on CR30, an earlier endpoint, could accurately predict treatment effects on PFS. Methods: Correlation of CR30 odds ratio (OR) with PFS hazard ratio (HR) was evaluated using both linear regression (R2WLS) and copula bivariate (R2Copula) models. Prespecified criteria for CR30 surrogacy required either R2WLS or R2Copula ≥ 0.80 with a lower bound of the 95% confidence interval (CI) > 0.60, with neither estimate < 0.70. The minimum CR30 difference to predict significant PFS difference was calculated. Results: Data from 13 randomized first-line trials (8 induction, 5 maintenance trials) with IPD for 3837 pts were included. The prespecified threshold for surrogacy was met: R2WLS of 0.88 (95% CI, 0.77-0.96) and R2Copula of 0.86 (95% CI, 0.72-1.00, Table), supporting the hypothesis that treatment effects on CR30 predict effects on PFS in pts with previously untreated FL. Multiple sensitivity and IPD surrogacy analyses supported the robustness of the primary analysis. A minimum 10% absolute improvement in CR30 over a control CR30 of 50% predicted significant improvement in PFS. Conclusions: This large IPD meta-analysis of chemo/immunotherapy trials establishes CR30 as a surrogate endpoint for PFS in first-line FL trials and supports its use to expedite therapeutic development.

Trial typeTrials, N (pts)R2WLS (95% CI)aR2Copula (95% CI)a
Overall13 (3837)0.88 (0.77-0.96)0.86 (0.72-1.00)
Rituximab included9 (2851)0.85 (0.62-0.97)0.80 (0.56-1.00)
No rituximab4 (986)0.91 (0.05-1.00)0.96 (0.90-1.00)
Induction8 (2207)0.89 (0.75-0.98)0.89 (0.74-1.00)
Maintenance5 (1630)0.93 (0.84-1.00)0.89 (0.71-1.00)

a R2 values range from 0 (no association) to 1 (perfect prediction).