Exploring Endpoint Correlation Between Progression Free Survival (PFS) and Overall Survival (OS) in Previously Untreated Metastatic Melanoma Using Pseudo Individual Patient Data (IPD)
Kanters S1, Kurt M2, Moshyk A2, Leung L1
1Evidinno Outcomes Research Inc., Vancouver, BC, Canada, 2Bristol Myers Squibb, Lawrenceville, NJ, USA
OBJECTIVES: Lack of IPD poses challenges in estimating the correlation between two endpoints. We proposed a novel approach to parameterize an illness-death model with pseudo-IPD and applied it to estimate the correlation between PFS and OS in previously untreated metastatic melanoma.
METHODS: For each trial identified by a systematic literature review, pseudo-IPD were reconstructed from digitized PFS and OS Kaplan-Meier curves by applying the Guyot algorithm. In the model, time-to-progression and OS were assumed to be independent Weibull random variables with shared shape and independent scale parameters to invoke a closed-form equation for estimating Pearson’s correlation between PFS and OS. Transitions between the model states were simultaneously estimated by iteratively applying fractional polynomial Bayesian models assuming a fixed but different proportion of patients progressing before death in each iteration. Candidate models were ranked according to their deviance information criteria. Predicted OS curves from best-fitting models were compared with reported OS curves visually and via restricted mean survival time (RMST). An overall correlation estimate was obtained through a random-effects meta-analysis of the arm-specific estimates using Fisher’s Z transformation.
RESULTS: Analyses included 24 trials (published between 2000-2020) with a total of 49 arms. The estimated proportion of patients experiencing progression (mean=0.816, standard error=0.011) had a tendency to be higher for modern treatments (0.70-0.94 across 36 arms) and lower in control arms in general. In 31/49 trial-arms, predicted OS captured the observed OS trend adequately with a statistically insignificant RMST at the 95% confidence level. The estimated endpoint correlations were 0.987 (95% CI: 0.979-0.992) on the full evidence base and 0.986 (95% CI: 0.975-0.992) among the aforementioned 31 trial-arms with better fit.
CONCLUSIONS: Modelling PFS and OS dependently using pseudo-IPD can strengthen surrogacy analyses by enabling endpoint correlation assessment. Our case-study found strong correlation between PFS and OS in previously untreated metastatic melanoma using published data.
Conference/Value in Health Info
Value in Health, Volume 25, Issue 12S (December 2022)
Relating Intermediate to Long-term Outcomes