RT Journal Article
SR Electronic
T1 Cancer patient survival can be accurately parameterized, revealing time-dependent therapeutic effects and doubling the precision of small trials
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.14.442837
DO 10.1101/2021.05.14.442837
A1 Deborah Plana
A1 Geoffrey Fell
A1 Brian M. Alexander
A1 Adam C. Palmer
A1 Peter K. Sorger
YR 2021
UL http://biorxiv.org/content/early/2021/05/17/2021.05.14.442837.abstract
AB Individual participant data (IPD) from completed oncology clinical trials are a valuable but rarely available source of information. A lack of minable survival distributions has made it difficult to identify factors determining the success and failure of clinical trials and improve trial design. We imputed survival IPD from ∼500 arms of phase III oncology trials (representing ∼220,000 events) and found that they are well fit by a two-parameter Weibull distribution. This makes it possible to use parametric statistics to substantially increase trial precision with small patient cohorts typical of phase I or II trials. For example, a 50-person trial parameterized using Weibull distributions is as precise as a 90-person trial evaluated using traditional statistics. Mining IPD also showed that frequent violations of the proportional hazards assumption, particularly in trials of immune checkpoint inhibitors (ICIs), arise from time-dependent therapeutic effects and hazard ratios. Thus, the duration of ICI trials has an underappreciated impact on the likelihood of their success.Competing Interest StatementP.K. Sorger is a member of the SAB or Board of Directors of Applied Biomath, Glencoe Software, RareCyte Inc and NanoString and has equity in the first three of these companies. In the last five years the Sorger lab has received research funding from Novartis and Merck. Sorger declares that none of these relationships are directly or indirectly related to the content of this manuscript. B.M. Alexander is an employee of Foundation Medicine. No potential conflicts of interest were disclosed by the other authors.