The Crux: Correlating Surrogate Endpoints With Real-World Evidence in Oncology

A new study has analyzed data from randomized controlled trials (RCTs) in oncology that used surrogate endpoints and measured their relation with treatment effectiveness and patient survival in the real world.

A significant concern with using surrogate endpoints in clinical trials, especially in oncology, has been figuring out how they translate once the drugs are used in clinics post approval. Defined by the National Institutes of Health as a “biomarker intended to substitute for a clinical endpoint,” these intermediate markers substitute for a clinically meaningful endpoint and can be measured much earlier (such as time to progression [TTP], progression-free survival [PFS], etc) and need a much smaller sample size and a shorter follow-up time.

For the study, the authors used data from 21 phase 3 RCTs that reported overall survival (OS) in addition to surrogates such as PFS or TTP endpoints in breast, colorectal, lung, ovarian, and pancreatic cancers. Using Surveillance and Epidemiology End Results-Medicare data, the researchers estimated real-world OS as the mortality hazard ratio (MHR) among patients meeting RCT inclusion criteria. The primary outcome was real-world OS.

Results of the analysis found that treatment arm therapies in the trials reduced mortality compared with the respective control arm (average RCT MHR, 0.85; range 0.56-1.10) and lowered disease progression (average RCT surrogate hazard ratio [SHR], 0.73; range 0.43-1.03) in the real world. However, this did not necessarily translate in the real world: real-world MHRs were 0.6& (95% CI, -3.5%—4.8%) higher than RCT MHRs and real-world MHRs were 15.7% (95% CI, 11.0%-20.5%) higher than RCT SHRs.

The data point to the effective translation of OS when a treatment moves into the real world, as opposed to surrogate endpoints like PFS or TTP.

“Real-world OS treatment benefits were similar to those observed in RCTs based on OS endpoints, but were 16% less than RCT efficacy estimates based on surrogate endpoints,” the authors concluded, with variance based on tumor type.

Surrogate endpoints have been ingrained in cancer clinical trials, however. David Fabrizio, of Foundation Medicine, Inc, a participant at The American Journal of Managed Care^®’s 2016 Patient-Centered Oncology Care^™ meeting has expressed his confidence in the role of surrogate endpoints to accelerate drug discovery. Acknowledging that there are challenges associated with using these endpoints, he affirmed the need to continue exploring surrogates for OS.

The results of the current study have been published in the journal Value in Health.