The value of surrogate endpoints for predicting real-world survival across five cancer types

Abstract

Objective It is unclear how well different outcome measures in randomized controlled trials (RCTs) perform in predicting real-world cancer survival. We assess the ability of RCT overall survival (OS) and surrogate endpoints – progression-free survival (PFS) and time to progression (TTP) – to predict real-world OS across five cancers.

Methods We identified 20 treatments and 31 indications for breast, colorectal, lung, ovarian, and pancreatic cancer that had a phase III RCT reporting median OS and median PFS or TTP. Median real-world OS was determined using a Kaplan–Meier estimator applied to patients in the Surveillance and Epidemiology End Results (SEER)-Medicare database (1991–2010). Performance of RCT OS and PFS/TTP in predicting real-world OS was measured using t-tests, median absolute prediction error, and R² from linear regressions.

Results Among 72,600 SEER-Medicare patients similar to RCT participants, median survival was 5.9 months for trial surrogates, 14.1 months for trial OS, and 13.4 months for real-world OS. For this sample, regression models using clinical trial OS and trial surrogates as independent variables predicted real-world OS significantly better than models using surrogates alone (P = 0.026). Among all real-world patients using sample treatments (N = 309,182), however, adding trial OS did not improve predictive power over predictions based on surrogates alone (P = 0.194). Results were qualitatively similar using median absolute prediction error and R² metrics.

Conclusions Among the five tumor types investigated, trial OS and surrogates were each independently valuable in predicting real-world OS outcomes for patients similar to trial participants. In broader real-world populations, however, trial OS added little incremental value over surrogates alone.

Keywords:

• Comparative effectiveness research
• neoplasms
• observational study
• progression-free survival
• survival
• surrogate endpoints

Declaration of funding

This work was supported by Novartis Pharmaceuticals. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the manuscript.

Declaration of financial/other relationships

J.S. and D.P. have disclosed that they are employees of Precision Health Economics, which provides consulting and other research services to pharmaceutical, device, governmental, and non-governmental organizations. R.B. and R.A.F. have disclosed that they are consultants for Precision Health Economics. D.N.L. has disclosed that he is Chief Strategy Officer at Precision Health Economics. J.P. and J.Z. have disclosed that they are employees of Novartis.

 The CMRO peer reviewer on this manuscript has received an honorarium from CMRO for the review work, but has no relevant financial or other relationships to disclose.

Acknowledgments

We would like to thank Seanna Vine, a Research Scientist at Precision Health Economics, who provided research and programming support.

 Previous presentation: Preliminary results from this study were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting.