231P - Time to deterioration of quality of life as a surrogate of OS: A trial-level surrogacy analysis

Background

Overall survival (OS) is the optimal marker of efficacy for evaluation of treatments in randomized clinical trials (RCTs) but can take a considerable amount of time to mature. Evaluation of changes in tumor size through objective response rate (ORR) and progression free survival (PFS) has served as an early surrogate of OS however they are imperfect. Time to deterioration (TTD) in quality of life (QoL) measures could act as an early alternative patient centered surrogate of OS.

Methods

We utilised published phase 3 RCTs in solid malignancies that reported OS, PFS, ORR, and time to deterioration (TTD) evaluations of overall QoL or physical function (PF) published between 1^st of January 2010 and 30^th of June 2022. Weighted regression analysis was utilised to assess the relationship between PFS, ORR ratio, TTD QoL and TTD PF with OS. The coefficient of determination (R²) was used to quantify surrogacy.

Results

After identifying 9109 publications, 138 studies with 86199 patients were included for analysis. 47 RCT involved immunotherapy (IO) whilst 91 investigated non-IO agents. PFS (R²= 0.19) and ORR (R²= 0.05) were poor surrogates of OS. TTD QoL and TTD PF was available in 137 and 75 RCTs respectively. In the respected subset of studies, TTD QoL (TTD QoL R²= 0.18 vs. PFS R²= 0.19) and TTD PF (TTD PF R²= 0.10 vs PFS R²= 0.09) performed similarly to PFS as surrogates of OS. However, for IO agents, TTD PF (R²= 0.38) had a higher surrogacy to OS compared to PFS (R²= 0.19). Furthermore, combining PFS and TTD PF enabled improved prediction of OS (R²= 0.57). Importantly, TTD PF and PFS were not correlated with each other (R²= 0). TTD PF was not a surrogate endpoint of OS for non-IO trials.

Conclusions

Our trial level analysis identified TTD in PF as a potential marker of early OS in trials that utilized IO agents. It could potentially be used in conjunction with PFS to improve surrogacy in specific tumor types. Our results are based on published results and should be validated using patient-level data.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.