WHEN THE TAIL WAGS THE DOG II: HOW MUCH OF A MATURE OVERALL-SURVIVAL BENEFIT RESTS ON ASSUMPTION (TROPION-BREAST02)
Author(s)
Andrew Briggs, DPhil1, Alex Hill, PhD1, Anna Forsythe, MBA, MSc, PharmD2.
1London School of Hygiene & Tropical Medicine, London, United Kingdom, 2Founder, Oncoscope, Miami, FL, USA.
1London School of Hygiene & Tropical Medicine, London, United Kingdom, 2Founder, Oncoscope, Miami, FL, USA.
OBJECTIVES: In partitioned survival analysis, reaching the overall-survival median is often taken as a sign the curves are mature - but does this hold for incremental survival benefits? Using TROPION-Breast02 - a trial with mature, statistically significant overall survival (OS) - we quantified the extrapolated share with the Extrapolation Benefit Share (EBS: the share of incremental mean survival arising beyond the observed data) and the Survival Ratio Shift (SRS: whether the advantage is tail-concentrated), adding a relative-survival floor for OS.
METHODS: Pseudo-individual patient data were reconstructed (SurvdigitizeR) from the published progression-free survival (PFS) and OS Kaplan-Meier curves (datopotamab deruxtecan vs investigator-choice chemotherapy; advanced TNBC). Eight parametric distributions were fitted jointly (shared distribution, treatment covariate). Mean survival was decomposed into observed and extrapolated components over a 40-year horizon, with a boundary estimated from a reverse-Kaplan-Meier diagnostic. OS was additionally modelled as relative survival - excess hazard plus ONS UK female population mortality, indexed at age 56.
RESULTS: The two endpoints behaved differently. For PFS, EBS was 37-68% with incremental survival 7-13 months - much of the gain falls within the observed period. For OS - despite both medians being reached and roughly two-thirds of events observed - EBS was 65-82% with incremental survival 3-10 months under relative survival; distribution choice changed the OS gain about three-fold. The relative-survival floor barely altered OS, trimming only the most optimistic long-tailed fits, because disease-specific (excess) mortality dominates background mortality over this horizon.
CONCLUSIONS: Even with mature, significantly prolonged OS, most modelled benefit lay beyond the observed data and remained sensitive to distributional choice. A population-mortality floor did little to discipline the extrapolation where excess mortality dominates. Reaching median survival does not guarantee a robust lifetime extrapolation; reporting EBS alongside incremental survival makes explicit how much of the value claim rests on assumption rather than observation.
METHODS: Pseudo-individual patient data were reconstructed (SurvdigitizeR) from the published progression-free survival (PFS) and OS Kaplan-Meier curves (datopotamab deruxtecan vs investigator-choice chemotherapy; advanced TNBC). Eight parametric distributions were fitted jointly (shared distribution, treatment covariate). Mean survival was decomposed into observed and extrapolated components over a 40-year horizon, with a boundary estimated from a reverse-Kaplan-Meier diagnostic. OS was additionally modelled as relative survival - excess hazard plus ONS UK female population mortality, indexed at age 56.
RESULTS: The two endpoints behaved differently. For PFS, EBS was 37-68% with incremental survival 7-13 months - much of the gain falls within the observed period. For OS - despite both medians being reached and roughly two-thirds of events observed - EBS was 65-82% with incremental survival 3-10 months under relative survival; distribution choice changed the OS gain about three-fold. The relative-survival floor barely altered OS, trimming only the most optimistic long-tailed fits, because disease-specific (excess) mortality dominates background mortality over this horizon.
CONCLUSIONS: Even with mature, significantly prolonged OS, most modelled benefit lay beyond the observed data and remained sensitive to distributional choice. A population-mortality floor did little to discipline the extrapolation where excess mortality dominates. Reaching median survival does not guarantee a robust lifetime extrapolation; reporting EBS alongside incremental survival makes explicit how much of the value claim rests on assumption rather than observation.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
EE371
Topic
Clinical Outcomes, Economic Evaluation, Methodological & Statistical Research
Topic Subcategory
Trial-Based Economic Evaluation
Disease
Oncology