ABSTRACT
Background:
Intermediate clinical endpoints (ICEs) are frequently used as primary endpoint in randomised trials (RCTs). We aim to assess whether changes in different ICEs can be used to predict changes in overall
survival (OS) in adjuvant
breast cancer trials.
Methods:
Individual
patient level data from adjuvant phase III RCTs conducted by the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo (MIG) study groups were used. ICEs were computed according to STEEP criteria. Using a two-stage meta-analytic model, we assessed the surrogacy of each
ICE at both the outcome (i.e., OS and
ICE are correlated irrespective of
treatment) and trial (i.e.,
treatment effects on
ICE and
treatment effect on OS are correlated) levels. The following ICEs were considered as potential
surrogate endpoints of OS
disease-free survival (DFS), distant
disease-free survival (DDFS), distant
relapse-free
survival (DRFS),
recurrence-free
survival (RFS),
recurrence-free interval (RFI), distant
recurrence-free interval (DRFI),
breast cancer-free interval (BCFI), and invasive
breast cancer-free
survival (IBCFS). The estimates of the degree of correlation were obtained by copula models and weighted
linear regression. Kendall's τ and R2 ≥ 0.70 were considered as
indicators of a clinically relevant surrogacy.
Findings:
Among the 12,397
patients enrolled from November 1992 to July 2012 in six RCTs, median age at enrolment was 57 years (interquartile range (IQR) 49-65). After a median follow-up of 10.3 years (IQR 6.4-14.5), 2131 (17.2%) OS events were observed, with 1390 (65.2%) attributed to
breast cancer. At the outcome-level, Kendall's τ ranged from 0.69 for BCFI to 0.84 for DRFS. For DFS, DDFS, DRFS, RFS, RFI, DRFI, BCFI, and IBCFS endpoints, over 95% of the 8-year OS variability was attributable to the variation of the 5-year
ICE. At the trial-level,
treatment effects for the different ICEs and OS were strongly correlated, with the highest correlation for RFS and DRFS and the lowest for BCFI.
Interpretation:
Our results provide evidence supporting the use of DFS, DDFS, DRFS, RFS, RFI, DRFI, and IBCFS as primary endpoint in
breast cancer adjuvant trials.
Funding:
This
analysis was supported by the Italian
Association for
Cancer Research ("Associazione Italiana per la Ricerca sul Cancro", AIRC; IG 2017/20760) and by Italian Ministry of
Health-5 × 1000
funds (years 2021-2022).
