The Surrogate Threshold Effect for Event-Free Survival as a Potential Surrogate for Overall Survival in Patients Treated for Acute Myeloid Leukemia

• Activity Number: 95 - Statistical Validation of Surrogate Endpoints
• Type: Invited
• Date/Time: Monday, July 31, 2017 : 8:30 AM to 10:20 AM
• Sponsor: Pharmaceutical Research and Manufacturers of America
• Author(s): Marc Buyse* and Richard Schlenk and Hartmund Dohner and Tomasz Burzykowski
• Companies: IDDI Inc. and University Hospital of Ulm, Germany and University Hospital of Ulm, Germany and IDDI S.A.
• Keywords: Surrogate endpoint ; Acute Myeloid Leukemia ; Surrogate threshold effect ; Event-free survival ; Overall survival ; Correlation

Abstract

Event-free survival (EFS), defined as the time to no response to intensive induction therapy, relapse, or death of any cause, whichever comes first, has been proposed as a surrogate for overall survival (OS) in acute myeloid leukemia (AML). We analyzed the data of 1,811 patients from four randomized clinical trials split into seven independent sub studies carried out under the auspices of the German-Austrian Acute Myeloid Leukemia Study Group. Surrogacy was assessed through the correlation between these endpoints, and through the correlation between the treatment effects on these endpoints. The individual-level association between EFS and OS was moderate (Spearman's correlation coefficient = 0.76, 95% CI: [0.73, 0.79]), but there was a high trial-level association between the effects of all-trans-retinoic-acid based chemotherapy on EFS and on OS (R = 0.99, 95% CI: [0.85, 1.12]). The surrogate threshold effect (Burzykowski and Buyse, Pharm Statist 2006; 5:173-86) was equal to 0.90, meaning that, in a future trial, a hazard ratio on EFS smaller than 0.9 would predict a hazard ratio for OS smaller than 1.00, suggesting that EFS is a valid surrogate for OS in patients with AML.