Time to Deterioration: Promising Surrogate Endpoint?

TOPLINE:

Time to deterioration of physical function showed "meaningful superiority" over progression-free survival (PFS) as an early surrogate for overall survival in trials of immune checkpoint inhibitors (ICIs), new research shows.

METHODOLOGY:

• The US Food and Drug Administration and other regulatory agencies have increasingly been approving cancer drugs on the basis of PFS, objective response rate, and other surrogate endpoints, but their validity as surrogates for overall survival remains controversial.
• In the current analysis, the researchers investigated the role of time to deterioration in quality of life (QOL) or physical function as surrogate endpoints for overall survival.
• Researchers performed a pooled analysis of 138 phase 3 randomized controlled trials in solid cancers, which reported overall survival, PFS, and time to deterioration in QOL or physical function.
• Overall, 47 trials evaluated ICI therapies and 91 investigated non-ICI agents.
• The research team used weighted regression models to assess the relationship between the surrogate endpoints and overall survival; the coefficient of determination (R²) was used to quantify surrogacy.

TAKEAWAY:

• Across all trials, PFS and time to deterioration in QOL or physical function were relatively poor surrogate endpoints for overall survival treatment efficacy.
• Time to deterioration in QOL and time to deterioration in physical function performed similarly to PFS as surrogates of overall survival (R², 0.18 vs 0.19 and 0.10 vs 0.09, respectively).
• For ICI studies, time to deterioration in physical function had a higher association with overall survival compared with PFS (R², 0.38 vs 0.19).
• PFS and time to deterioration in physical function were not correlated with each other (R², 0), but when used together, both endpoints predicted overall survival treatment effect (R², 0.57) better than either endpoint alone.

IN PRACTICE:

Time to deterioration of physical function appears to be an overall survival surrogate measure of "particular importance for ICI treatment efficacy," the authors concluded. The combination of time to deterioration of physical function and PFS "may enable better prediction" of overall survival treatment benefit in ICI trials than either alone, the authors added.

SOURCE:

The study, led by Adel Shahnam, MD, of the Peter MacCallum Cancer Centre Melbourne, Australia, was published online August 10 in the Journal of the National Cancer Institute.

LIMITATIONS:

Definitions of time to deterioration varied across trials, and it was not possible to perform meaningful subgroup analyses. The study addresses correlation with overall survival at the trial level but not the patient level.

DISCLOSURES:

The authors have no relevant conflicts interest. The study had no commercial funding.

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